Rilimogene galvacirepvec(National Cancer Institute)

New-generation ICIs set to break biological ceiling With PD-1/CTLA-4 franchises such as Merck’s Keytruda (>$30bn in sales in 2025) reaching maturity, incremental value is shifting to next-generation checkpoints that can address adaptive resistance, extend duration of response, expand responder populations and support lifecycle management. Bristol Myers Squibb’s (BMS’s) Opdualag (LAG-3/PD-1 combination) provides the first commercial proof that dual-checkpoint strategies can extend durability and defend PD-1 backbones. We expect assets showing additive efficacy with PD-1/CTLA-4s and favourable safety are most likely to secure partnering and premium valuations. Cancer vaccines as immune-priming platforms Next-generation cancer vaccines are transitioning from monotherapy setbacks to high-value immune-priming partners capable of generating high-avidity, tumour-specific responses and converting immunologically cold tumours into ‘hot’ tumours. Moderna/Merck’s mRNA vaccine V940/mRNA-4157 provides the clearest validation in melanoma studies. We see cancer vaccines’ strongest commercial positioning in combination treatments, earlier-stage and minimal residual disease settings, where durable immune memory supports long treatment windows. Platform scalability, precision biomarker strategies and consistent combination benefit across tumour types will be critical to partnering activity and peak-sales realisation. CAR-T therapies at an inflection point CAR-T therapies (such as Gilead’s Yescarta and Novartis’s Kymriah) deliver potentially curative outcomes in select haematological cancers, but uptake remains constrained by limited solid-tumour efficacy, manufacturing complexity, high cost and toxicities. Next-wave strategies, including allogeneic platforms, bi-specific/multi-targeting constructs programmes and CRS-mitigation approaches, promise to reduce infrastructure intensity and enable earlier-line use, and will determine CAR-T’s evolution from niche therapy to a broader commercial modality. Immuno-oncology: The next phase of value creation Our immune system is naturally built to detect and eliminate abnormal cells while sparing healthy tissue. However, cancer has evolved several ways to evade immune recognition, allowing unchecked tumour growth. While traditional treatments like chemotherapy and radiation can be effective, they are associated with significant side effects. In contrast, IO is a class of cancer therapies that harness, activate or engineer the body’s natural defence mechanisms to recognise and destroy tumour cells, effectively removing the ‘brakes’ that cancer places on the immune system. Since approval, IO has reshaped cancer care, led by ICIs that have become the backbone treatment across multiple solid tumour types. Yet the first ICI wave has also exposed clear constraints: response rates remain limited in many indications, resistance emerges frequently and some tumour types remain stubbornly ‘cold’. In parallel, haematological malignancies remain an untapped frontier where ICIs have delivered more modest outcomes. The growing challenge is no longer whether immunotherapy works, but how to make it work for the majority of patients, across a broader range of tumours, with acceptable safety, cost and scalability. The next phase of value creation is therefore less about a single breakthrough drug and more about expanding the responder pool and durability of benefit through new checkpoint targets beyond the current PD-(L)1 and CTLA-4 combination strategies that address tumour-resistance mechanisms and new immunotherapy modalities such as therapeutic cancer vaccines and next-generation cell/CAR-T therapies. Commercially, this evolution should continue to drive partnering: big pharma’s PD-(L)1/CTLA-4 franchises, broad oncology footprints and overhang from the upcoming patent cliff (>$200bn in revenues at risk by 2030) create a natural pull for differentiated add-ons (novel checkpoints, vaccines, intratumoural immunotherapies) and for technologies that reduce toxicity and the healthcare burden in cell therapies. This report explores the scientific rationale for next-generation IO approaches, showcases leading biotech innovators advancing the field, examines the commercial dynamics driving deal-making and presents the investment case for biotechs at the forefront of this evolution. Market context: Oncology dominates therapeutic development Oncology remains the largest and most innovation-intensive therapeutic area in pharma, reflecting a combination of large addressable patient populations, persistent unmet need and the high economic value of clinically meaningful survival improvements. According to Evaluate Pharma, oncology accounted for 39% of global pharmaceutical R&D spend in 2023, with projected sales of $375bn by 2030, more than twice that of the next largest therapeutic area, immunology, at $165bn (Exhibit 1). Exhibit 1: Therapeutic area market size projections (2030) Source: Evaluate Pharma, Edison Investment Research Within oncology, IO has become a central pillar of R&D and commercial strategy. PD-(L)1 inhibitors have created a large, durable market, but the competitive dynamics have shifted from ‘who has a PD-1’ to ‘who has the best combination ecosystem and differentiated biology’. This matters for how value is likely to accrue. In the next phase, winners are likely to be those that can: (a) take immunotherapy into harder-to-treat tumours and patient subgroups; (b) move effective approaches earlier in the disease course (adjuvant/maintenance/minimal residual disease); and (c) reduce toxicity and delivery friction so that therapies can be used more widely and earlier. ICIs: Revolution and limitations What are ICIs? ICIs are immunotherapies or drugs that modulate immune ‘brakes’ that ordinarily prevent excessive immune activation, such as by T cells. Tumours exploit these brakes to avoid immune destruction. By blocking these inhibitory brakes, ICIs restore anti-tumour immune activity, thereby enabling the immune system to recognise and attack cancer cells (Exhibit 2). The two foundational inhibitory pathways to date have been PD-1/PD-L1 (dominant in the tumour microenvironment (TME); affects peripheral effector function) and CTLA-4 (more upstream; affects T-cell priming/activation in lymphoid tissues). By releasing these brakes, ICIs can convert an existing anti-tumour immune response into deep, durable remissions in a subset of patients, an outcome rarely achieved with historical cytotoxic treatments or reliably matched by targeted therapy. Exhibit 2: ICIs’ mechanism of action Source: Adapted from Poto R, Troiani T, Criscuolo G, Marone G, Ciardiello F, Tocchetti CG and Varricchi G (2022) Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events. Front. Immunol. 13:804597. (CC by 4.0)https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.804597/full Clinically, the impact has been most visible in immunogenic tumours (with multiple neoantigens; proteins exclusively expressed by cancer cells) and where a pre-existing anti-tumour immune response can be amplified (eg ‘hot’ tumours such as melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma and classical Hodgkin lymphoma). However, mechanistically this is not a simple ‘on/off’ switch: the effectiveness of ICIs depends on antigen presentation, T-cell trafficking and infiltration, TME suppressive factors and the dynamic expression of multiple immune checkpoints. Current ICI landscape limited to PD-(L)1s The current ICI market (Exhibit 3) has been dominated by PD-1 and PD-L1 inhibitors, which have achieved broad approvals, frequent label expansions and deep integration into treatment pathways, with Merck’s Keytruda (generic name: pembrolizumab) leading the pack with $31.7bn in annual sales in 2025 and approval across 20+ indications, with an additional 20+ indications in clinical development. CTLA-4 inhibition (BMS’s Yervoy) remains important in select high-intensity combinations. More recently, LAG-3 joined the approved checkpoint set through BMS’s Opdivo (nivolumab) + relatlimab fixed-dose combination, Opdualag, in melanoma (approved in 2022), the first successful next-generation checkpoint beyond CTLA-4. Opdualag’s approval validates the potential clinical relevance of additional checkpoints, in our view. Exhibit 3: Approved ICIs Source: Evaluate Pharma, Edison Investment Research According to Global Markets Insights, the global ICI market was valued at $66.2bn in 2025, with double-digit growth expected over the next decade, driven by earlier lines/adjuvant settings, new combinations and next-generation mechanisms that can extend benefit beyond today’s responder ceiling (discussed in further detail below). Limitations of current ICIs Hitting the biological ceiling: Despite transformative outcomes in some tumour types, only a minority of patients benefit from PD-(L)1 and CTLA-4 blockade, in what is termed a ‘biological ceiling’ issue. Large reviews commonly cite 20–40% of the patients benefiting across broad populations depending on tumour type, biomarker enrichment and treatment regimen. While response rates can vary, the key issue is that a large proportion of patients either do not respond at all or respond transiently before disease progression. This constrains the ceiling of benefit for monotherapy and forces the field toward combination strategies, better patient selection and immune priming approaches. Resistance mechanisms – innate and acquired resistance: The variability in ICI efficacy is fundamentally driven by tumour immune resistance mechanisms, which can be broadly classified as innate (primary) or acquired (secondary). In primary resistance, tumours lack the biological prerequisites for response, including effective antigen presentation, baseline immune activation and pre-existing T-cell infiltration. In acquired resistance, initial responders subsequently relapse as tumours undergo immune editing, downregulate antigen presentation, activate alternative inhibitory checkpoints or remodel the TME to exclude effector T cells. Together, these adaptive escape processes cap response rates and durability. Haematological malignancy limitations: While ICIs have transformed outcomes in multiple solid tumours, their performance has often been more variable in haematological cancers. Many haematological malignancies have lower levels of tumour-specific mutations (so the immune system has fewer abnormal targets to recognise) and exist in the bone marrow and lymph node environment, which is naturally immunosuppressive and can physically limit effective T-cell activity. As a result, releasing a single immune brake is often not enough to generate a meaningful anti-tumour response. The key exception is classical Hodgkin lymphoma, where the PD-1 pathway is genetically overactive, making it particularly sensitive to checkpoint blockade. This has created space for other immunotherapy modalities (including cellular therapies and vaccines) to become central to innovation and value creation in haematology. Toxicity and immune-related adverse events: ICIs work by activating the immune system, but this broad activation can also cause the immune system to attack normal healthy tissues, leading to immune-related adverse events (irAEs). These side effects can affect multiple organs (most commonly the skin, gut, liver, lungs and hormone-producing glands) and range from mild inflammation to, in rare cases, severe or life-threatening complications. In clinical practice, most irAEs are manageable with early detection and immunosuppressive treatment, but they remain a key factor in treatment selection and in the design of next-generation IO combinations. TME complexity: ICIs are also less effective in many cancers because of the complex TME (the community of non-cancer cells, blood vessels and signalling molecules that surround the tumour). In some tumours, this environment acts like a protective shield, keeping cancer-killing immune cells out, switching them off, or flooding the area with signals that suppress immune activity. This means that even if an ICI releases the ‘brakes’ on the immune system, the T cells either cannot reach the tumour or cannot function properly once they get there. As a result, the treatment has little effect. Overcoming this barrier is a major focus for next-generation IO, with new strategies aimed at making these tumours more immune-friendly (such as intratumoral therapies, vaccines and myeloid-targeting approaches) so checkpoint inhibitors can work more effectively. Cold tumours (eg pancreatic, prostate, ovarian, colorectal cancer): ICIs tend to work best when there is already an active immune response against the tumour. In so-called ‘cold’ tumours, this immune activity is largely absent (there are very few cancer-fighting T cells in or around the tumour), and the cancer often does not produce enough abnormal signals to attract them. As a result, giving an ICI is like releasing the brakes on a car that has no engine running – the drug removes the immune block, but there are not enough immune cells present to attack the cancer. In addition, these tumours often create a strongly suppressive environment that keeps immune cells out. To address this, a key focus of current research is on combination approaches that first ‘heat up’ the tumour by bringing immune cells in, and then use ICIs to activate them. Upcoming newer generation ICI strategies To transcend current limitations, the field is aggressively exploring novel immune checkpoints and innovative modalities, with the goal of improving response rates, overcoming resistance and broadening benefit to more tumour types and patients. Expansion into earlier treatment lines: One of the key commercial upsides for ICIs will come from increasing use in the adjuvant, peri-operative and minimal residual disease (MRD) settings, where patient numbers are higher, treatment duration is longer and curative intent supports premium pricing. This is already evident with pembrolizumab in adjuvant melanoma and peri-operative NSCLC (KEYNOTE-671), nivolumab in adjuvant melanoma and resected oesophageal/gastroesophageal junction (GEJ) cancer (CheckMate-577) and atezolizumab in adjuvant NSCLC (IMpower010). With metastatic markets largely penetrated, future growth and blockbuster potential for next-generation IO will depend on demonstrating meaningful benefit in earlier-stage disease. New-generation checkpoint targets – LAG-3, TIGIT, TIM-3, VISTA: Most solid tumours can express multiple inhibitory checkpoints at the same time, often five to 10 or more across tumour cells, building the biological basis for a ‘multiple brakes’ concept and for the move toward dual- and multi-checkpoint strategies. Beyond PD-(L)1 and CTLA-4, multiple inhibitory pathways have emerged as potential levers to overcome resistance and improve response. However, translating target biology into consistent clinical benefit has been uneven. Combination treatments – two better than one?: With growing proof of the ability of tumours to activate multiple immune ‘brakes’ simultaneously, combination checkpoint strategies are increasingly being evaluated. These aim to widen the responder pool by targeting complementary resistance pathways, deepen responses by enhancing T-cell activation and reduce the likelihood of tumour escape via single-pathway adaptation. One thing is clear from the above – to win adoption, combinations need either a clear efficacy step-up (eg overall survival benefit) or a tolerability/convenience advantage that enables broader eligible populations. Bispecific and multi-specific agents: Bispecific and multi-specific agents attempt to integrate the aforementioned combination logic into a single molecule, potentially improving pharmacology and co-targeting engagement, convenience of administration and intellectual property differentiation. These agents can be designed to simultaneously block multiple inhibitory pathways, bring immune effector cells into proximity with tumours, or combine inhibitory checkpoint blockade with immune stimulation. Early clinical and regulatory validation is emerging, with PD-1 × CTLA-4 bispecifics such as Akeso’s cadonilimab approved in China in first-line treatment in gastric/GEJ cancer in combination with chemotherapy. PD-1 × LAG-3 bispecifics represent a mechanistically validated optionality following Opdualag, with assets such as EpimAb/BeiGene’s EMB-02, aiming to co-target the commonly co-expressed pathways and show activity in PD-1–refractory disease. However, challenges remain, as evidenced by the clinical discontinuations of MacroGenics’s tebotelimab and Roche’s tobemstomig, underscoring execution risk. PD-1 × TIGIT formats, led by AstraZeneca’s rilvegostomig, are higher risk but offer potential upside if bispecific architecture can outperform prior TIGIT monoclonal antibodies. The challenge will be to demonstrate meaningful differentiation, efficacy or tolerability versus simply co-administering two agents, while maintaining manufacturability and safety. More recently business development activity in ICI bispecifics has increasingly converged on the PD-(L)1 × VEGF axis, which has emerged as one of the most competitive post-PD-1 backbone strategies. VEGF (vascular endothelial growth factor) is a key signalling protein that tumours use to stimulate the formation of new blood vessels (angiogenesis). VEGF-targeted therapies disrupt this process, effectively starving the tumour and normalising its abnormal vasculature. By simultaneously blocking immune checkpoints and normalising tumour vasculature, these agents may help address two of the key limitations of first-generation PD-1 therapy: poor T-cell infiltration and an immunosuppressive microenvironment. A series of large transactions, including multi-billion-dollar collaborations, the largest being the $11.1bn deal between BMS and BioNTech (for pumitamig) in June 2025, highlights big pharma’s urgency to secure next-generation platforms that combine immune activation with TME normalisation. Exhibit 4 lists the major ICI bispecific licensing deals since 2022, the largest volume and value of which have been in PD-1 x VEGF bispecifics. Exhibit 4: Major ICI bispecific licensing deals Source: Edison Investment Research, Evaluate Pharma Value in the ICI space is shifting from new PD-1 monotherapies to combination-enabling assets that expand responder populations, overcome resistance and move treatment into earlier lines. The biological ceiling creates strong partnering demand for next-generation checkpoints, TME modulators and immune-priming approaches. Bispecific deal activity highlights big pharma’s urgency to secure differentiated, franchise-extending platforms. Therapies that demonstrate additive efficacy with manageable toxicity and clear biomarker strategy are most likely to achieve premium valuations and early monetisation. Cancer vaccines: From disappointment to resurgence Unlike traditional preventative vaccines, therapeutic cancer vaccines are designed to treat patients who already have cancer by training the immune system to recognise and attack tumour-specific targets, mainly by activating cancer-killing T cells. This is more challenging because cancer comes from the body’s own cells and often hides from the immune system, but the same fact also makes these vaccines a strong partner for checkpoint inhibitors. The vaccine helps create more tumour-fighting immune cells, and the checkpoint drug keeps them active. Earlier-generation cancer vaccines delivered only modest clinical benefit and struggled commercially due to weak immunogenicity, suboptimal antigen selection and deployment in late-stage disease, where immune dysfunction is profound. However, recent randomised clinical data provide the first clear evidence that newer-generation vaccines can significantly reduce recurrence risk when used in the early or minimal residual disease setting and/or in combination with PD-1 inhibitors. This represents a fundamental shift in how the modality is positioned: not as a monotherapy for metastatic disease, but as an immune-priming platform capable of inducing durable, tumour-specific T-cell responses. Historical clinical development and limited early impact First-generation cancer vaccines were based on several technological approaches, including peptide vaccines, whole-cell tumour vaccines and autologous dendritic cell therapies. While these strategies demonstrated proof of principle that immune responses could be generated against cancer, they failed to produce consistent and clinically meaningful tumour regression. The approval of Dendreon Corp’s sipuleucel-T (Provenge) in 2010 for metastatic castration-resistant prostate cancer represented a landmark for the field, as it showed an overall survival benefit in a randomised trial. However, the absence of objective tumour responses, the complexity of autologous manufacturing, high cost of goods and logistical challenges limited physician adoption and ultimately constrained commercial success. More broadly, these early programmes suffered from a lack of biomarker-driven patient selection (such as MSI-H/dMMR), poor antigen immunogenicity due to immune tolerance and clinical trial designs that evaluated vaccines in heavily pre-treated metastatic patients with advanced immune dysfunction. Collectively, these factors led to the perception that cancer vaccines were biologically interesting but clinically impractical. Core scientific and clinical limitations of earlier approaches Antigen selection (shared TAAs) and immune tolerance: Most first-generation therapeutic cancer vaccines were built around shared tumour-associated antigens (TAAs), proteins overexpressed in cancer cells but also present at low levels in normal tissues. Because the immune system is trained to tolerate self-antigens, these targets had limited capacity to generate strong cytotoxic T-cell responses. This biological constraint was reflected in several high-profile late-stage failures including GSK’s MAGE-A3 programme (in melanoma and NSCLC), Merck KGaA’s tecemotide (L-BLP25), which targeted the MUC1 glycoprotein in NSCLC, and Bavarian Nordic’s PROSTVAC, a PSA-targeted viral vaccine for prostate cancer. TME and immune escape: A second major limitation was the inability of early vaccine strategies to overcome the TME. First-generation cancer vaccines were commonly administered as monotherapies in patients with advanced metastatic disease, where tumour burden is high and immunosuppressive signalling is well established. Even when tumour-specific T cells were successfully generated in the periphery, their infiltration and cytotoxic function within the tumour were actively inhibited by a complex network of suppressive signals. This included upregulation of immune checkpoints such as PD-L1, recruitment of regulatory T cells and myeloid-derived suppressor cells (MDSCs) and secretion of inhibitory cytokines such as TGF-β and IL-10. Disease setting and tumour burden: Clinical positioning was another critical determinant of failure. Early vaccine trials were conducted predominantly in late-stage, heavily pre-treated patients with high tumour burden and often impaired immune function. In this context, the time required to generate an adaptive immune response, typically several weeks to months, is biologically and clinically mismatched with the rapid disease progression typical of advanced cancer. In contrast, it is now widely recognised that cancer vaccines are most effective in the minimal residual disease or adjuvant setting, where tumour burden and subclonal diversity are lower and immune competence is relatively preserved. Platform and delivery limitations: Many peptide-based vaccines lacked sufficiently potent or appropriately tailored adjuvants to stimulate dendritic cell maturation and effective cross-presentation through MHC Class I pathways, which is essential for generating CD8+ cytotoxic T-cell responses. Without robust innate immune activation, adaptive responses remained quantitatively and qualitatively inadequate. Modern platforms, including mRNA, viral vectors and next-generation dendritic cell approaches (Exhibit 5) are specifically designed to address this limitation by integrating antigen delivery with strong innate immune stimulation. Exhibit 5: Different types of therapeutic cancer vaccines Source: mRNA vaccines for cancer immunotherapy, Yashavantha Vishweshwaraiah, Nikolay Dokholyan. 2022. Frontiers of Immunology Field at an inflection point The resurgence of cancer vaccines is not driven by a single breakthrough but by the convergence of multiple enabling technologies. Neoantigen targeting – moving beyond shared self-antigens: Next-generation cancer vaccines prioritise tumour-specific neoantigens rather than shared TAAs, avoiding central immune tolerance and enabling high-avidity cytotoxic T-cell responses. This shift materially improves the probability of meaningful tumour control, as neoantigens are recognised as non-self and can drive polyclonal immune activation through multi-epitope designs. Clinical validation is emerging across multiple platforms. Moderna/Merck’s V940 has demonstrated a significant reduction in melanoma recurrence in the adjuvant setting in a randomised Phase IIb trial, while BioNTech/Genentech’s autogene cevumeran has generated strong neoantigen-specific T-cell responses in pancreatic cancer. Viral and epitope-based approaches from Nouscom (NOUS-PEV), OSE Immunotherapeutics (Tedopi) and Transgene (TG4050) further underscore the central importance of antigen selection, alongside optimised delivery technologies, in driving immunogenicity and clinical activity. Genetic delivery platforms – mRNA and DNA as scalable backbones: New-generation cancer vaccines are increasingly using genetic material, such as mRNA or DNA, to instruct the body’s own cells to produce tumour antigens, rather than introducing the antigens directly as proteins or peptides. This approach helps the immune system recognise the targets more effectively and generates both killer (CD8+) and helper (CD4+) T cell responses. It also naturally activates the early immune signals needed for a strong and durable reaction, reducing the need for additional adjuvants. Moderna’s personalised mRNA vaccines and BioNTech’s personalised and shared antigen programmes (including BNT111) highlight the speed and flexibility of this technology, while Scancell’s DNA ImmunoBody platform (iSCIB1+) shows how a potent off-the-shelf option can be combined with checkpoint inhibitors. Designed for checkpoint inhibitor synergy: Newer cancer vaccines are also being positioned as immune primers for checkpoint blockade rather than as standalone therapies. The vaccine trains the immune system to recognise the tumour and brings T cells into the tumour, while drugs such as PD-1, PD-L1 or CTLA-4 inhibitors stop those T cells from being switched off. Together, this helps overcome two key problems: many tumours do not already have tumour-fighting T cells, and the tumour environment suppresses immune activity. The positive data for V940 with pembrolizumab show this approach can work in practice. Similar combination strategies, including Scancell’s iSCIB1+ with dual checkpoint blockade, also make it easier for vaccines to fit into current treatment pathways. Earlier disease settings – MRD, adjuvant and maintenance therapy: Cancer vaccine development is moving away from use in very late-stage disease and focusing instead on earlier settings, such as after surgery or when only small amounts of cancer remain (minimal residual disease). At this stage, the immune system is stronger and the tumour burden is low, giving vaccine-activated T cells a better chance to clear remaining cancer cells and provide long-term protection. This also fits better with how vaccines work, as they need time to build an immune response and are less effective in fast-growing metastatic disease. Mendus’s vididencel in acute myeloid leukaemia (AML) after remission and V940 in post-surgery melanoma are good examples. Earlier use also means larger patient populations and longer treatment duration, which improves commercial potential. Exhibit 6 presents a list of the most clinically advanced cancer vaccine programmes in development. Exhibit 6: Selection of ongoing clinical-stage cancer vaccine programmes Source: Edison Investment Research, Evaluate Pharma Deal activity in cancer vaccines is re-accelerating after a prolonged period of limited partnering, reflecting renewed confidence in the modality as clinical data and platform maturity improve. The c $1.25bn BioNTech acquisition of German mRNA vaccine developer CureVac in December 2025 is a clear inflection point. This follows earlier large platform alliances such as BioNTech-Genentech and Moderna-Merck and signals that large pharma now views cancer vaccines as a core long-term pillar of IO. For the broader sector, the transaction raises the strategic value of companies with validated antigen-selection technologies, combination data with checkpoint inhibitors and scalable manufacturing infrastructure, and points to a more competitive partnering and M&A environment. Cancer vaccines are transitioning from a historically high-risk modality to a combination-driven, platform opportunity, supported by randomised clinical validation in the adjuvant and MRD settings. The shift to neoantigen targeting, genetic delivery and PD-1 synergy materially improves probability of success and commercial scalability. Earlier-line positioning expands patient populations and treatment duration, while recent large-scale transactions signal renewed big pharma appetite. Companies with biomarker-led development, checkpoint-combination data and scalable manufacturing are therefore best placed to secure premium partnering and valuation re-rating. CAR-Ts: Expanding beyond first-generation constraints CAR-Ts – mechanism and therapeutic concept Chimeric antigen receptor-T cell therapies (CAR-Ts) are a form of adoptive cell therapy in which a patient’s immune cells are genetically engineered to recognise and kill cancer cells. The process begins with the collection of T cells from the patient, which are then modified ex vivo to express a synthetic receptor, the chimeric antigen receptor, that binds to a specific tumour surface antigen independently. These engineered cells are expanded and reinfused into the patient, where they proliferate, directly eliminate antigen-expressing tumour cells and can persist as a living drug capable of long-term immune surveillance (Exhibit 7). Exhibit 7: How CAR-Ts work Source: Zhou Y, Wei S, Xu M, Wu X, Dou W, Li H, Zhang Z and Zhang S (2024) CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges. Front. Immunol. 15:1489649. (CC BY 4.0) https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1489649/full Limitations and next-generation solutions Curative potential but concentrated to haematology: To date, CAR-Ts have been applied in the treatment of haematological cancers by targeting the CD19 and BCMA antigens. Approved CAR-T therapies from companies such as Gilead/Kite (Yescarta, Tecartus), BMS (Breyanzi, Abecma) and Johnson & Johnson/Legend (Carvykti) have transformed outcomes in relapsed or refractory B-cell malignancies and multiple myeloma, delivering deep and durable responses in heavily pre-treated patients (Exhibit 8). This success stems from several structural advantages over conventional therapies: high target specificity, in vivo expansion after infusion and the potential for durable remission following a single treatment. However, the treatment is also associated with unique immune-mediated toxicities. Complex autologous manufacturing and the need for specialised centres for treatment delivery currently limit scalability. More importantly, clinical activity in solid tumours has been modest (due to tumour heterogeneity), highlighting that first-generation autologous CAR-T designs are highly effective in liquid cancers but not yet broadly applicable across oncology. Exhibit 8: FDA-approved CAR-T therapies Source: Edison Investment Research Antigen escape – The shift to multi-target constructs: Antigen escape in CAR-T cell therapy is a mechanism of treatment resistance where tumour cells evade destruction by losing or reducing the specific surface protein (antigen) that the CAR-T cells are engineered to recognise. Relapse driven by antigen loss is a major limitation of single-target CAR-Ts. Dual and multi-antigen targeting is now a central development focus, designed to address this limitation by simultaneously recognising more than one tumour antigen, reducing the probability of immune evasion and improving depth and duration of response. Academic and China-based programmes evaluating dual CD19/CD22 CAR-Ts, as well as BCMA/CD19 constructs being explored by multiple developers, exemplify this strategy. In parallel, next-generation single-target approaches such as Autolus’s obe-cel (Aucatzyl), approved by the FDA in November 2024 for adults with relapsed/refractory B-cell precursor ALL, use a fast off-rate CD19 binder to enhance T-cell persistence and reduce exhaustion, representing an alternative strategy to improve durability of response. This strategy is particularly relevant in B-cell malignancies and multiple myeloma, where antigen downregulation is well documented. These designs are expected to become increasingly important as CAR-Ts move into earlier lines of therapy where durability requirements are higher. Toxicity and safety – Enabling broader adoption: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain key barriers to treatment in community settings Engineering approaches to reduce tonic signalling and control CAR activation are being pursued by Autolus and Allogene, while pharmacological strategies targeting inflammatory pathways are emerging as a complementary solution. In parallel, adjunctive therapies specifically targeting CRS are being developed. A notable example is Poolbeg Pharma’s POLB-001, an oral p38 MAP kinase inhibitor, being developed to prevent CRS associated with CAR-T and bispecific antibodies. The asset has completed Phase I human challenge work demonstrating broad cytokine suppression and is now entering a Phase IIa (TOPICAL) proof-of-concept study in r/r multiple myeloma patients receiving the bispecific T-cell engaging antibody teclistamab, with interim data expected in summer 2026. The programme has received FDA Orphan Drug Designation for CRS prevention, positioning it as a potential first-in-class prophylactic that could enable outpatient delivery and broader adoption of cell and T-cell-redirecting therapies. Manufacturing bottlenecks – the move to allogeneic, off-the-shelf platforms: Off-the-shelf (allogeneic) CAR-T therapies use pre-made immune cells from healthy donors instead of creating a custom product for each patient. This could allow treatment to be given much faster, at lower cost and with more consistent quality. Gene editing removes the donor cell’s natural receptor so it does not attack the patient and is less likely to be rejected, an approach being developed by companies such as Allogene and Cellectis. Newer ‘immune-cloaked’ versions use CRISPR to help the cells stay in the body longer, which is important for long-lasting benefit. Another step forward is induced pluripotent stem cell (iPSC)-derived CAR-Ts, where stem cells are used to produce a large, standardised supply. If these therapies work as well as current CAR-T therapies, they could be delivered more widely and earlier in treatment. Alternative effector cells: CAR-NK and CAR-iNKT: Other immune cells such as natural killer (NK) cells and invariant natural killer T (iNKT) cells offer several structural merits over conventional CAR-T cells. They are inherently allogeneic, have a lower risk of graft-versus-host disease and appear to produce less severe CRS. Nkarta and Fate Therapeutics are advancing CAR-NK programmes in both haematological and solid tumours, while Arovella Therapeutics is developing CAR-iNKT therapies, with encouraging early data. These platforms may be particularly important for solid tumours and outpatient delivery models. A key current limitation however is the relatively short in-vivo persistence and limited clinical durability particularly for CAR-NK approaches, which may necessitate repeat dosing to match the long-term efficacy achieved with autologous CAR-T therapies. CAR-T for solid tumours – the largest expansion opportunity: Extending CAR-T therapies into solid tumours represents the biggest long-term growth opportunity for the modality, but also the most complex biologically due to the immunosuppressive TME and heterogeneous antigen expression. Armoured CAR-T cells, designed to secrete stimulatory cytokines such as IL-12 or IL-15, aim to remain active within this hostile environment and recruit other immune cells; this approach is being explored in multiple early-stage clinical and academic–industry programmes. To improve tumour specificity and safety, logic-gated CAR designs that require the presence of more than one tumour antigen for activation are also under development. Modular adaptor CAR platforms, such as Prescient Therapeutics’ OmniCAR, provide an alternative strategy by enabling controllable and retargetable tumour recognition. Most of these approaches remain in early phases of clinical development. Expanding beyond oncology: CAR-T therapies are emerging as a potentially transformative modality in autoimmune disease by delivering deep and durable depletion of pathogenic B cells, creating the possibility of a one-time immune reset rather than chronic immunosuppression. Early academic CD19 CAR-T studies in systemic lupus erythematosus have demonstrated drug-free remissions, catalysing rapid industry investment. A key requirement for broader adoption in immunology is an improved safety and tolerability profile suitable for outpatient use. Immix Biopharma’s NXC-201, a BCMA-targeted CAR-T in Phase Ib/II for AL amyloidosis with registrational intent, uses a sterically optimised design that has shown low neurotoxicity and short-duration CRS. This profile underpins planned expansion into B-cell-driven non-oncology indications, where risk tolerance is lower but the commercial opportunity is significantly larger. In-vivo CAR-T: Next-generation cell therapy without ex-vivo manufacturing: An area of development that has been gaining increasing interest is in-vivo CAR-T therapy, an emerging approach in which a patient’s T cells are genetically programmed directly inside the body using targeted delivery technologies such as lipid nanoparticles or viral vectors, removing the need for complex ex-vivo cell processing. This has the potential to significantly reduce manufacturing time, lower cost of goods and enable treatment in outpatient or community settings, addressing key access and scalability barriers associated with current autologous CAR-T therapies. The modality may also allow repeat dosing and more controlled cell expansion, although this remains to be demonstrated clinically. This field has seen increasing M&A and licensing activity in the past year and is becoming one of the most commercially attractive areas of development within the cell therapy space. Exhibit 9 highlights some of the major deals in this space, the most recent being the acquisition of Orna Therapeutics by Eli Lilly for up to $2.4bn in February 2026. Exhibit 9: Recent in-vivo CAR-T deals Source: Edison Investment Research, Evaluate Pharma Competitive pressure from bispecific antibodies: Bispecific T-cell engagers from companies such as Amgen (Blincyto), Regeneron and Roche are achieving high response rates in haematological malignancies with an off-the-shelf format, creating both a competitive threat and a complementary treatment option. Their ease of administration and lower upfront cost are accelerating adoption, particularly in earlier lines of therapy. As a result, CAR-T developers are increasingly focused on demonstrating superior durability and curative potential to maintain differentiation. The long-term value of CAR-T therapy will depend on its evolution from an autologous, late-line therapy into a scalable, earlier-line treatment modality. Off-the-shelf manufacturing, improved safety profiles and expansion into solid tumours are the key inflection points. Companies that can demonstrate durable responses with faster delivery and outpatient administration are likely to capture a disproportionate share of future growth. Other promising treatment modalities Emerging intratumoural modalities Intratumoural delivery is gaining traction as a strategy to activate the anti-tumour immune response directly at the tumour site while minimising systemic toxicity. By converting immune-cold lesions into inflamed, T cell-infiltrated tumours, these approaches can generate systemic immunity and improve responses to checkpoint inhibitors. Rather than competing with established backbones, most intratumoural therapies are being developed as immune-priming combination partners, with their greatest potential in accessible solid tumours and earlier treatment settings where immune function is less compromised. Immuno-modulatory antibodies – reprogramming the TME Immuno-modulatory antibodies are an emerging class of IO agents that work by changing the tumour’s immune environment rather than attacking cancer cells directly. They act on both the innate and adaptive immune system to improve antigen presentation, boost antibody-driven tumour killing and help overcome resistance to PD-1 inhibitors and other targeted antibodies, making them important combination partners. BioInvent’s BI-1206, a first-in-class FcγRIIB-blocking antibody in Phase I/II, is a key example, restoring sensitivity to rituximab in lymphoma with early signs of re-sensitising tumours to pembrolizumab in solid tumours. Overall, these therapies act as immune amplifiers that increase response rates to established checkpoint backbones and are an important source of the next wave of IO value. Pharma patent cliff – implications The healthcare sector is approaching an unprecedented loss-of-exclusivity cycle, with >$200bn of branded drug revenue at risk by 2030 (Exhibit 10). The concentration of exposure in a small number of megabrands means the impact will be both financially material and strategically disruptive for large pharma, which will be looking to acquire new assets to replenish pipelines and future revenues. Exhibit 10: Worldwide sales at risk from patent expiration (2025–30) Source: Edison Investment Research, Evaluate Pharma The notable event in this cycle is the expected biosimilar exposure of Merck’s Keytruda from 2028, currently the world’s largest oncology drug with c $31.7bn in sales in 2025. BMS’s Opdivo, with over $10bn in revenue in 2025, faces a similar timeline. Together, these two PD-1 inhibitors account for over $40bn of at-risk revenue, making IO one of the largest contributors to the late-decade patent cliff. This is structurally different from previous cycles because PD-1 therapy is not a single indication franchise, but a treatment backbone across multiple tumour types and lines of therapy. What it means for the biotech sector Lifecycle management is necessary but not sufficient: Large pharma is already implementing lifecycle strategies to defend these franchises, most visibly through subcutaneous formulations of PD-1 antibodies such as Keytruda and Opdivo. However, lifecycle management alone is unlikely to offset the scale of the revenue decline. The more durable strategy is to build proprietary combination regimens that extend the clinical relevance of the checkpoint backbone, which in turn increases reliance on external innovation. Combination-driven innovation – a structural tailwind for biotechs: The Merck-Moderna collaboration around the personalised cancer vaccine V940 illustrates how the patent cliff is reshaping deal-making. Positive Phase II melanoma data in combination with Keytruda led to a global profit-share agreement, reflecting the value of assets that increase responder rates and enable earlier-line use. BioNTech’s neoantigen vaccine partnership with Genentech follows the same logic. These therapies do not compete with PD-1; they expand its addressable population, which makes them strategically attractive and allows smaller companies to monetise early clinical proof of concept. Cell therapy/CAR-T platform acquisitions and modality leadership: A similar dynamic is evident in cell therapy, where the focus has shifted to scalable next-generation platforms. AbbVie’s acquisition of Capstan for up to $2.1bn, AstraZeneca’s purchase of EsoBiotec for up to $1bn and Gilead/Kite’s acquisition of Interius for $350m all target in-vivo cell-engineering technologies that remove the manufacturing bottlenecks of autologous CAR-T therapies. Eli Lilly’s recent acquisition of Orna for up to $2.4bn reinforces the strategic importance of programmable immune-engineering platforms. These transactions show that modality leadership alone can crystallise significant value for small biotechs, often before pivotal data. Targeting resistance – the rise of immune-modulatory combinations: Overcoming resistance to PD-1 and other targeted therapy is another major investment theme. BioInvent’s BI-1206, which restores sensitivity to rituximab and pembrolizumab by targeting FcγRIIB. CD47/SIRPα programmes, including assets originating from Trillium (Pfizer) and the AbbVie/I-Mab collaboration, aim to enhance macrophage-mediated tumour cell clearance, although recent clinical setbacks across the class have increased the focus on differentiated safety and combination positioning. By increasing response rates rather than competing with established backbones, these therapies extend the commercial lifespan of PD-1 and are therefore highly attractive combination partners. From single-asset licensing to platform consolidation: The urgency to replace multi-billion-dollar revenues is also changing the structure of deal-making. Large pharma is increasingly acquiring entire technology platforms, as seen in BioNTech’s $1.25bn acquisition of CureVac and Eli Lilly’s acquisition of Orna. Owning the underlying technology allows rapid generation of multiple clinical assets and shortens time to impact. For small biotechs, this creates an opportunity to monetise platform value earlier and reduces dependence on late-stage, capital-intensive development. Financing and valuation implications for the biotech sector: The patent cliff creates a multi-year period of structural demand for external innovation. Assets that demonstrate clear synergy with PD-1, durable responses, or the ability to move into earlier lines of therapy are likely to attract partnering interest earlier, at Phase I or II, bringing forward value inflection points. At the same time, the bar for differentiation is rising, with increasing emphasis on biomarker selection, durability and health-economic benefit. Tougher evidence bar and payer friction post-loss of exclusivity: As pricing dynamics intensify around megabrands, payers will push harder on incremental benefit. Biotechs should expect increasing emphasis on: clear biomarkers, durable endpoints, health-economic outcomes (reduced hospital time, fewer cycles) and differentiated safety/route of administration. In the US, the Inflation Reduction Act and Medicare price negotiation for high-spend biologics further increase long-term pricing pressure, reinforcing the need for clinically differentiated, earlier-line and combination-driven strategies to sustain premium reimbursement. What it means for investors Lower commercial risk: From an investor standpoint, IO remains one of the most compelling areas in biotechnology because it combines large commercial markets, multiple value-creation inflection points and strong strategic demand from large pharma. Unlike many therapeutic areas where new entrants must displace entrenched standards of care, most next-generation IO assets are largely developed as combination partners to existing treatments. This significantly lowers commercial adoption risk and increases the probability of partnering at an early clinical stage. For investors, this creates a model in which Phase I/II proof-of-concept data can drive disproportionate valuation re-rating, well ahead of registrational timelines. Pipeline-in-a-product optionality: Many IO modalities are inherently modular and can be expanded across multiple tumour types and treatment settings. Personalised cancer vaccines, cell therapies and immune-modulatory antibody platforms can generate several clinical programmes from a single technology base. This supports higher risk-adjusted valuations, multiple deal opportunities and lifecycle expansion, which is particularly valuable for small and mid-cap companies. Accelerated development pathways: IO assets often target high-unmet-need or biomarker-selected populations, making them well suited for expedited regulatory pathways and smaller, faster clinical trials. The use of durable endpoints such as long-term survival or MRD clearance can shorten development timelines and reduce funding requirements, improving the return profile for investors. Premium pricing: Therapies that deliver deep and durable responses, particularly those with curative potential, can command premium pricing despite high upfront costs. This is already evident in the CAR-T space (eg Kymriah and Yescarta come with list price of $47k and $373k, respectively) and is likely to extend to immune-reset approaches in both oncology and autoimmune disease. Strong pricing power translates into attractive peak-sales potential and supports higher valuation multiples. Structural deal flow driven by the patent cliff: The loss of exclusivity for major ICIs is creating a multi-year need for revenue replacement among large pharmaceutical companies. This is accelerating licensing and M&A activity for assets that can expand the PD-1 ecosystem or overcome resistance. For investors, this provides a clear and recurring exit pathway through strategic transactions. Multiple value inflection points across the development cycle: IO programmes typically generate several catalysts, including early immune-response readouts, combination data, expansion into new indications and regulatory designations. This steady flow of milestones supports sustained investor engagement and allows value to be realised progressively rather than only at approval. From a capital markets perspective, IO offers earlier value inflection than most therapeutic areas. Immune-response readouts, durability signals and initial combination data can drive meaningful re-rating well ahead of approval, while sustained M&A demand provides a clear monetisation pathway. Risk-reward considerations Investment risks Despite its transformational clinical impact and strong deal activity, immuno-oncology investments continue to carry meaningful risk. Clinical development risks: Commercial risks: Company-specific risks: Mitigating factors Several factors help mitigate traditional IO investment risks. Strong external demand for innovation Increasingly validated biology Large and durable market opportunity Platform and lifecycle optionality Investment conclusions The IO landscape represents one of the most compelling long-term investment themes in healthcare today, driven by scientific validation, platform technologies and the need to replace multibillion-dollar checkpoint revenues. The shift from monotherapy checkpoints to combination-based, immune-ecosystem control marks the next phase of value creation. Several factors make the current investment environment particularly attractive. The upcoming PD-1 patent cliff is accelerating external innovation and increasing partnering appetite for assets that expand responder populations or overcome resistance. At the same time, advances in biomarker-driven development, cell-engineering, mRNA and in-situ tumour-priming approaches are improving clinical success probabilities and shortening development timelines. The commercial opportunity remains substantial. Oncology continues to be the largest therapeutic area globally, with immuno-oncology capturing a disproportionate share of drug spending. Movement into earlier lines of therapy, adjuvant and MRD settings is expanding the addressable population, while durable responses and treatment-free remission support premium pricing and strong pharmacoeconomic value. For investors, immuno-oncology offers multiple avenues for exposure. Large-cap pharmaceutical companies provide franchise stability and lifecycle management of checkpoint backbones, mid-cap innovators offer focused exposure to next-generation modalities and small-cap platform companies present the most asymmetric risk-reward, particularly where early data can unlock partnering or acquisition. The companies highlighted in this report reflect the breadth of innovation across the field. From personalised cancer vaccines and next-generation cell therapies to immune-modulatory antibodies and intratumoural immune-priming approaches, these platforms are designed to extend the PD-1 ecosystem rather than compete with it, which lowers commercial adoption risk. Risk mitigation comes from the structural demand for external innovation and the modular nature of many IO technologies. Multiple value inflection points, accelerated regulatory pathways and the ability to monetise assets at Phase I/II through partnerships help offset traditional biotech funding and development risks. As this next phase of immuno-oncology unfolds, investors who position themselves early in differentiated platforms and combination-relevant assets are likely to benefit from sustained deal flow and valuation re-rating. The sector combines a large market opportunity, strong strategic buyer demand and scalable technologies, creating a highly attractive long-term investment landscape. Appendix: Company showcase The following companies represent a selection of the most innovative approaches across the immuno-oncology landscape, each targeting a key biological or commercial bottleneck such as responder expansion, resistance reversal, immune priming or scalable cell therapy delivery (Edison clients are indicated with an asterisk). BioInvent International BioInvent International AB (Nasdaq Stockholm: BINV) is a clinical-stage biotech focused on developing first-in-class immune-modulatory antibodies to address key limitations in cancer immunotherapy, particularly treatment resistance and low response rates. Its antibodies target immune checkpoints and tumour microenvironment biology to unlock new mechanisms of action. The company’s discovery engine is built on its proprietary F.I.R.S.T platform, which enables the simultaneous identification of novel targets and corresponding antibodies directly from patient-derived tumour material. This is complemented by the n-CoDe antibody library, supporting rapid generation of differentiated candidates. Following a strategic portfolio prioritisation in August 2025, BioInvent is focusing resources on its two lead assets, BI-1206 and BI-1808. BI-1206 (anti-FcγRIIB) is designed to restore sensitivity to anti-CD20 therapies in non-Hodgkin’s lymphoma and enhance responses to PD-1 inhibitors in solid tumours. In a Phase I/IIa trial with rituximab and acalabrutinib, early data from the triple-combination arm showed 100% disease control and a 63% objective response rate. Subsequent data for the Phase IIa safety run-in (n=15) showed an overall response rate of 80%, with 47% achieving complete responses. The disease control rate was 100%. A second Phase IIa study combining BI-1206 with pembrolizumab in first-line NSCLC and uveal melanoma marks its entry into treatment-naïve settings. The asset has also been reformulated for subcutaneous delivery to improve convenience, safety and durability. BI-1808 targets TNFR2 to counter tumour immune evasion by depleting regulatory T cells and expanding CD8+ T cells. In Phase IIa cutaneous T-cell lymphoma, it has demonstrated strong immune engagement with 100% disease control and a 45% response rate, alongside ongoing evaluation in combination with pembrolizumab in solid tumours. Both programmes have received supportive FDA designations, including Orphan Drug and Fast Track status, highlighting their potential in high-unmet-need indications. BioInvent’s integrated GMP manufacturing provides scalable, cost-efficient biologics production and ensures reliable global clinical supply, strengthening its operational and partnering position. Immix Biopharma* Immix Biopharma (NASDAQ: IMMX) is a clinical-stage company focused on advancing next-generation CAR-T therapies for patients with relapsed/refractory AL amyloidosis, a rare plasma cell disorder characterised by rapid organ deterioration and poor outcomes with conventional treatments. Its lead and wholly owned programme, NXC-201, is a BCMA-directed autologous CAR-T therapy designed with the objective of inducing deep haematologic responses and enabling meaningful and potentially durable organ recovery. Clinical data generated to date highlight compelling efficacy in a heavily pretreated patient population, including high overall and complete response rates and early signals of organ improvement. Recent interim data (20 patients) presented from the ongoing Phase Ib/II NEXICART-2 trial (n=40) showed a 75% complete response (CR) rate, with 15/20 patients achieving deep haematological responses. Of the five patients without a CR, four were MRD negative. Importantly, NXC-201 has demonstrated a favourable safety and tolerability profile, with low rates of high-grade CRS and neurotoxicity, a critical consideration in AL amyloidosis patients who are often frail and ineligible for intensive therapies. This safety profile, combined with rapid manufacturing turnaround and reliable product delivery, supports the potential use of NXC-201 in a broader treatment setting and in patients with significant organ involvement. The ongoing US-based NEXICART-2 study is intended to support a registrational pathway for AL amyloidosis with a biologics licence application planned before end-FY26. The company was recently granted the Breakthrough Therapy Designation for NXC-201 by the FDA based on the strength of the interim data. NXC-201 also holds the Regenerative Medicine Advanced Therapy designation by the US FDA and Orphan Drug Designation by FDA and the EMA. With CAR-T increasingly recognised as a transformative modality in non-oncology indications, NXC-201 is positioned to address a critical gap for AL amyloidosis patients who have limited therapeutic options and poor prognosis following relapse. Immutep Immutep (ASX: IMM) is a late-stage biotechnology company and a pioneer in therapies targeting the MHC Class II and LAG-3 pathways for cancer and autoimmune diseases. Its scientific leadership is rooted in the discovery of LAG-3 by CSO Dr Frédéric Triebel, positioning the company at the forefront of this immune checkpoint field. Immutep’s approach focuses on modulating key regulators of the immune response to enhance anti-tumour activity and improve outcomes for patients who derive limited benefit from existing immunotherapies. The oncology pipeline is anchored by two clinical-stage assets that employ complementary strategies to stimulate anti-cancer immunity. Efti (eftilagimod alpha) is a first-in-class MHC Class II agonist that directly activates antigen-presenting cells (APCs), including dendritic cells and monocytes. By engaging this central immune control point, efti drives a broad and durable immune response, priming CD8+ cytotoxic T cells and expanding multiple immune effector populations. This mechanism has demonstrated strong synergy with anti-PD-(L)1 therapy, chemotherapy and radiotherapy, alongside a favourable safety profile across combinations. Efti is currently being evaluated in TACTI-004 (KEYNOTE-F91), a pivotal Phase III trial in partnership with MSD (n=750), in combination with pembrolizumab and chemotherapy as first-line treatment for advanced/metastatic NSCLC (50% enrolment completed). The study builds on positive data from TACTI-002 and INSIGHT-003 (>165 patients), which showed high response rates and encouraging survival outcomes. Notably, efficacy has been observed across the full PD-L1 expression spectrum, including the large low/negative PD-L1 population with significant unmet need. Efti is also being explored in multiple additional solid tumours, including head and neck, urothelial, breast cancer and soft tissue sarcoma. Immutep’s second clinical asset, LAG525 (ieramilimab), the first anti-LAG-3 antibody, is out-licensed to Novartis, validating the company’s leadership in LAG-3 biology. Earlier-stage programmes include a small-molecule LAG-3 inhibitor and IMP761, the first LAG-3 agonist antibody for autoimmune disease, which has generated promising initial Phase I data (single ascending dose part completed). Lytix Biopharma Lytix Biopharma (Euronext Growth Oslo: LYTIX) is developing a novel class of oncolytic immunotherapies designed to harness the full potential of the immune system by directly reprogramming the tumour microenvironment. Its lead asset, ruxotemitide (LTX-315), is a first-in-class intratumoral therapy that rapidly disrupts tumour cell membranes, releasing a broad repertoire of tumour antigens and danger signals that drive immune activation. By initiating immune recognition rather than relying on pre-existing anti-tumour immunity, the approach is positioned to convert immunologically ‘cold’ tumours into ‘hot’ tumours and expand the benefit of checkpoint inhibitors beyond current responder populations. This mechanism enables broad T-cell priming and durable systemic immune responses, providing a strong biological rationale for combination with PD-1/PD-L1 inhibitors in indications where response rates to checkpoint blockade alone remain limited. Clinically, the company is prioritising injectable and resectable solid tumours, where intratumoral delivery is both feasible and therapeutically meaningful. In partnership with Verrica Pharmaceuticals, ruxotemitide has completed a Phase II study in non-metastatic skin cancer, demonstrating a 97% objective response rate, 51% pathological complete responses and an 86% mean tumour reduction across treated lesions, alongside a favourable safety profile with no serious adverse events. Based on these data and FDA alignment on trial design, Verrica is preparing a pivotal Phase III programme in basal cell carcinoma. Lytix retains rights in metastatic and neoadjuvant settings, including melanoma, triple-negative breast cancer and Merkel cell carcinoma, where combination strategies with checkpoint inhibitors represent a key value driver. The pipeline also includes LTX-401, an oncolytic candidate targeting liver metastases, extending the platform to deep-seated tumours. With a validated mechanism, encouraging clinical activity and a flexible partnering strategy, Lytix is positioning intratumoral immunotherapy as a complementary modality within the immuno-oncology landscape, aimed at delivering a durable systemic benefit for patients underserved by current treatments. Mendus* Mendus (OMX: IMMU) is a clinical-stage immuno-oncology company developing off-the-shelf cellular cancer vaccines designed to induce durable, tumour-specific immune responses and reduce relapse in haematological malignancies and solid tumours. Its lead programme, vididencel, is an allogeneic dendritic cell-based therapy aimed at establishing long-term immune surveillance in patients with AML and CML. By priming and expanding tumour-specific T cells, vididencel is intended to eliminate residual malignant cells and deliver sustained disease control without the toxicity associated with intensive consolidation treatments. The off-the-shelf format enables rapid treatment, scalable manufacturing and favourable logistics compared with autologous cell therapies. Clinical data to date from the ADVANCE II trial has demonstrated encouraging immune responses, a favourable safety profile and signals of relapse reduction in AML patients following first line intensive induction chemotherapy. The programme is now being repositioned to address a broader AML population, including ‘chemo-unfit’ patients receiving venetoclax-based regimens, with new studies (CADENCE and DIVA) expected to inform the design of a potential global registrational trial. Mendus is also expanding into CML, where vididencel is being developed as a potential treatment-free remission, enabling therapy for patients on long-term TKI therapy, representing a large and well-defined commercial opportunity. Vididencel is also being explored in ovarian cancer and has potential applicability in additional tumour settings where immune priming in the minimal residual disease setting could improve long-term outcomes. Manufacturing is supported through a dedicated GMP partnership with NorthX Biologics, providing scalable, commercial-ready production capabilities and strengthening the pathway to late-stage development and potential out-licensing. The company is funded into 2027 and is seeking partnerships to support late-stage development and maximise the platform’s potential. See below for our most recently conducted Edison TV executive interview with Mendus. Exhibit 11: Executive interview with Erik Manting, CEO of Mendus, and Tariq Mughal, CMO Source: Edison Investment Research OSE Immunotherapeutics* OSE Immunotherapeutics (PAR: OSE) is a clinical-stage biotechnology company developing first-in-class immunotherapies across oncology and immuno-inflammation, with a strategy centred on biomarker-driven precision medicine and differentiated T-cell modulation. Its lead oncology programme, Tedopi, is an off-the-shelf, multi-epitope therapeutic cancer vaccine designed to induce tumour-specific cytotoxic T-cell responses in HLA-A2–positive patients and address resistance to ICIs. Tedopi is being advanced in NSCLC after ICI failure, a setting with high unmet need and limited treatment options. The vaccine targets five tumour-associated antigens and is engineered to generate durable CD8+ T-cell immunity with a favourable tolerability profile compared with chemotherapy. In the Phase III ATALANTE-1 study, Tedopi demonstrated a clinically meaningful survival benefit versus standard chemotherapy in the ICI-resistant population, establishing proof of concept and supporting its ongoing registrational strategy. The confirmatory ARTEMIA Phase III trial, comparing Tedopi with docetaxel, represents the final step toward potential approval, with a futility analysis expected in 2026. Beyond oncology, OSE’s immunology pipeline provides additional value creation and partnering optionality. The most advanced asset, lusvertikimab (anti-IL-7R), targets a central pathway in T-cell expansion and is being developed in chronic inflammatory diseases (ulcerative colitis, chronic pouchitis and hidradenitis suppurativa) offering a complementary and potentially less capital-intensive route to late-stage development through partnerships. See below for our most recently conducted Edison TV executive interview with OSE Immunotherapeutics. Exhibit 12: Executive interview with Silvia Comis MD, chief clinical and medical research officer at OSE Immunotherapeutics Source: Edison Investment Research Percheron Therapeutics* Percheron Therapeutics (ASX: PER) is a clinical-stage immuno-oncology company developing next-generation checkpoint inhibitors to address resistance to PD-1/PD-L1 therapies. Its lead asset, HMBD-002, targets VISTA (V-domain Ig suppressor of T-cell activation), an emerging immune checkpoint strongly associated with poor response to existing immunotherapies and with tumours that remain largely unresponsive to current treatment, including pancreatic, ovarian and prostate cancers. By expanding the number of patients who can benefit from checkpoint blockade, VISTA inhibition represents a key opportunity in the evolution of the IO landscape. HMBD-002 is differentiated by its IgG4 backbone, the same isotype used in pembrolizumab and nivolumab, which is designed to minimise unwanted immune activation and improve tolerability, an important advantage in a class where earlier candidates have been limited by toxicity. Preclinical studies have demonstrated broad anti-tumour activity both as monotherapy and in combination with PD-1 inhibitors, including in triple-negative breast cancer models (UT Southwestern) and in radiotherapy combinations in head and neck cancer (Stanford), supporting a strong biological rationale for use in CPI-resistant disease. The completed US Phase I study (n=48) showed an excellent safety profile across doses from 20–1,400mg, with no maximum tolerated dose reached due to the low incidence of dose-limiting toxicities. Early signs of clinical activity included tumour shrinkage and durable stable disease in heavily pre-treated patients, supporting advancement into later-stage trials. A modular Phase II study is expected to commence within 2026. See below for our most recently conducted Edison TV executive interview with Percheron Therapeutics. Exhibit 13: Executive interview with Percheron Therapeutics CEO, Dr James Garner Source: Edison Investment Research Poolbeg Pharma Poolbeg Pharma (LSE: POLB) is developing POLB 001, a first-in-class, orally administered p38 MAPK inhibitor designed to prevent cancer immunotherapy-induced CRS, one of the most serious and resource-intensive toxicities associated with T-cell-engaging bispecific antibodies and CAR-T therapies. CRS affects more than 70% of patients receiving certain T-cell-redirecting treatments and currently necessitates administration in specialised centres, leading to prolonged hospitalisation, high healthcare utilisation and constrained patient access. With no approved preventative therapies, POLB 001 is positioned to address a critical bottleneck in the delivery and scalability of next-generation immuno-oncology treatments. By selectively modulating excessive inflammatory signalling without causing broad immunosuppression, POLB 001 aims to improve the safety profile of T-cell-engaging therapies while preserving anti-tumour immune function, an important consideration in heavily pre-treated cancer populations. Enabling safer outpatient or community-hospital administration could significantly expand treatment capacity, improve patient quality of life and unlock additional commercial value across the rapidly growing cell therapy and bispecific antibody markets. The initial commercial opportunity, focused on multiple myeloma and diffuse large B-cell lymphoma, is estimated to exceed US$10bn, with further upside as T-cell-engaging therapies move into earlier lines of treatment and into solid tumours. The programme has demonstrated a favourable safety and pharmacodynamic profile in preclinical studies and in a human lipopolysaccharide (LPS) challenge model, providing important translational validation ahead of patient studies. The Phase IIa open-label, single-arm trial is in advanced preparation and will evaluate POLB 001 in approximately 30 relapsed/refractory multiple myeloma patients receiving an approved bispecific antibody (teclistamab), with interim data expected in summer 2026. The study is being led by The Christie NHS Foundation Trust and the Accelerating Clinical Trials network. FDA Orphan Drug Designation provides additional regulatory validation and commercial optionality. On positive data, Poolbeg expects to pursue a partnering strategy, positioning POLB 001 as a potential enabling therapy for the broader immuno-oncology ecosystem. Scancell Scancell (LSE: SCLP) is a clinical-stage immuno-oncology company developing targeted active immunotherapies designed to generate durable, tumour-specific T-cell responses and address the large proportion of patients who fail to benefit from checkpoint inhibitors (ICIs). With approximately half of patients not responding to ICIs and five-year survival in stage IV melanoma below 23%, Scancell’s off-the-shelf platforms aim to enhance efficacy without adding toxicity while improving accessibility versus personalised approaches. The lead asset, iSCIB1+ (DNA Immunobody), is a needle-free DNA vaccine that induces high-avidity T cells against gp100 and TRP-2 melanoma antigens, selected from patients with spontaneous tumour regression. In the Phase II SCOPE study (n=140), iSCIB1+ in combination with ICIs has demonstrated clinically meaningful improvements over historical CPI outcomes. Progression-free survival in the target HLA population reached 78% at 11 months versus ~46% for nivolumab/ipilimumab, with 69% PFS at 22 months across cohorts. Updated data remained encouraging with PFS of 74% at 16 months in the target population. These data support the potential to establish a new standard of care in advanced melanoma. With FDA IND clearance in place, development is being accelerated towards a randomised registrational study in 2026, likely incorporating a precision biomarker. A commercial-scale GMP manufacturing process with strong stability has already been established, supporting future scalability. The second clinical programme, Modi-1 (Moditope), is a peptide-based active immunotherapy targeting post-translationally modified tumour antigens and is currently in Phase II evaluation in hard-to-treat solid tumours, including head and neck cancer, with further data expected in early 2026. Beyond vaccines, Scancell’s GlyMab platform, developed within its Glymab Therapeutics subsidiary, generates high-affinity antibodies against tumour-specific glycans, with two assets already licensed to Genmab, providing external validation and potential non-dilutive value. See below for our recent Edison TV executive interview with Scancell. Exhibit 14: Executive Interview with Scancell Holdings’ chief medical officer, Dr Nermeen Varawalla Source: Edison Investment Research Transgene Transgene (FRA: TNG) is a clinical-stage biotechnology company developing virus-based immunotherapies, with a strategic focus on individualised neoantigen therapeutic vaccines (INTVs) to prevent cancer relapse in early-stage disease. Its lead programme, TG4050, is based on the proprietary myvac platform and is currently being evaluated in the randomised Phase II part of a Phase I/II trial in operable head and neck cancer (HNSCC). The myvac platform integrates viral vector engineering, artificial intelligence and translational data to deliver precision immunotherapy at clinically relevant timelines. Using a Modified Vaccinia Ankara (MVA) vector, TG4050 encodes patient-specific neoantigens identified through AI-driven algorithms developed with NEC. This approach is designed to generate potent and durable CD8+ T-cell responses against tumour mutations unique to each patient, with the aim of establishing long-term immune surveillance following surgery and standard-of-care treatment. A digitalised, in-house GMP manufacturing process supports scalable production within a timeframe compatible with routine clinical practice. Clinical data presented at ASCO 2025 demonstrated the feasibility, safety and strong immunogenicity of TG4050, with 100% disease-free survival at a median 30-month follow-up (n=32). Neoantigen-specific CD8+ T-cell responses persisted for more than two years and showed effector and memory phenotypes consistent with durable protection against relapse. Additional translational analyses presented at SITC 2025 confirmed the induction of polyclonal cytotoxic T cells, expansion of both de novo and pre-existing tumour-reactive clones and the development of tissue-resident immune populations, highlighting the potential to overcome resistance in immunologically ‘cold’ tumours. With proof of concept established, Transgene is advancing TG4050 towards a registrational pathway and exploring expansion into additional early-stage solid tumours. More broadly, myvac represents a scalable platform for a pipeline of individualised vaccines, positioning the company at the forefront of next-generation precision immuno-oncology.

Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules. 2022 Sep 5;27(17):5730. doi: 10.3390/molecules27175730. PMID: 36080493; PMCID: PMC9457814. 前列腺癌是影响男性的恶性肿瘤之一，在全球范围内显着增加男性死亡率。受前列腺癌影响的患者表现为局部或晚期疾病。在这篇综述中，我们旨在提供前列腺癌的整体概述，包括疾病的诊断、导致疾病发作和进展的突变以及治疗方案。前列腺癌诊断包括直肠指检、前列腺特异性抗原分析和前列腺活检。某些基因的突变与癌症的发生、进展和转移有关。局限性前列腺癌的治疗包括主动监测、消融放疗和根治性前列腺切除术。复发或出现转移性前列腺癌的男性接受雄激素剥夺疗法 (ADT)、挽救性放疗和化疗。目前，可用的治疗方案在用作联合疗法时更有效；然而，尽管有可用的治疗选择，前列腺癌仍然无法治愈。一直在进行研究，寻找和确定其他治疗方法，例如使用传统医学、纳米技术的应用和基因疗法来对抗前列腺癌、耐药性，以及减少当前治疗方案带来的不利影响. 在这篇文章中，我们总结了与前列腺癌有关的基因、可用的治疗方案以及目前对替代治疗方案的研究。当作为联合疗法使用时，可用的治疗方案更有效；然而，尽管有可用的治疗选择，前列腺癌仍然无法治愈。一直在进行研究，寻找和确定其他治疗方法，例如使用传统医学、纳米技术的应用和基因疗法来对抗前列腺癌、耐药性，以及减少当前治疗方案带来的不利影响. 在这篇文章中，我们总结了与前列腺癌有关的基因、可用的治疗方案以及目前对替代治疗方案的研究。当作为联合疗法使用时，可用的治疗方案更有效；然而，尽管有可用的治疗选择，前列腺癌仍然无法治愈。一直在进行研究，寻找和确定其他治疗方法，例如使用传统医学、纳米技术的应用和基因疗法来对抗前列腺癌、耐药性，以及减少当前治疗方案带来的不利影响. 在这篇文章中，我们总结了与前列腺癌有关的基因、可用的治疗方案以及目前对替代治疗方案的研究。一直在进行研究，寻找和确定其他治疗方法，例如使用传统医学、纳米技术的应用和基因疗法来对抗前列腺癌、耐药性，以及减少当前治疗方案带来的不利影响. 在这篇文章中，我们总结了与前列腺癌有关的基因、可用的治疗方案以及目前对替代治疗方案的研究。一直在进行研究，寻找和确定其他治疗方法，例如使用传统医学、纳米技术的应用和基因疗法来对抗前列腺癌、耐药性，以及减少当前治疗方案带来的不利影响. 在这篇文章中，我们总结了与前列腺癌有关的基因、可用的治疗方案以及目前对替代治疗方案的研究。 前列腺癌影响 45 至 60 岁的中年男性，是西方国家癌症相关死亡率的最高原因 [ 1]. 许多患有前列腺癌的男性是通过前列腺活检和分析、前列腺特异性抗原 (PSA) 检测、直肠指检、磁共振成像 (MRI) 或健康筛查确诊的。与前列腺癌相关的危险因素包括家庭风险、种族、年龄、肥胖和其他环境因素。前列腺癌是一种基于流行病学和遗传学的异质性疾病。遗传学、环境影响和社会影响之间的相互作用导致种族特异性前列腺癌存活率估计值下降，从而导致不同国家前列腺癌流行病学观察到的差异 [ 2 ]]. 有文件证明遗传对前列腺癌有贡献。遗传性前列腺癌和前列腺癌的遗传成分易感性已研究多年。前列腺癌最易患的遗传风险因素之一是家族遗传。双胞胎研究和流行病学研究均证明了遗传性前列腺癌的作用 [ 3 ] 。许多研究人员已经研究了遗传变异在雄激素生物合成和代谢中的可能作用，以及雄激素的作用 [ 4、5 ]。基因组学研究已经确定了导致某些癌症发展的分子过程，例如染色体重排 [ 2 ]。 一般来说，基因突变是癌症的普遍原因。前列腺癌易感性的候选基因是参与雄激素途径和睾酮代谢的基因。前列腺上皮和前列腺癌细胞的发育依赖于雄激素受体信号通路和睾酮 [ 6 ] 。癌症生物标志物的鉴定和特定基因突变的靶向可用于前列腺癌的靶向治疗。可用于靶向治疗的生物标志物有DNA肿瘤生物标志物、DNA生物标志物和一般生物标志物[ 7 ]。 前列腺癌可分为雄激素敏感型或雄激素不敏感型，后者是睾酮刺激的指标和可能的治疗选择 [ 8 ]。前列腺癌可用的治疗方案包括主动监测、化学疗法、放射疗法、激素疗法、手术和冷冻疗法。提供给患者的治疗方案取决于肿瘤的性质、PSA 水平、分级和分期以及可能的复发。例如，根治性前列腺切除术是一种手术选择，涉及切除前列腺和附近的组织，与放射疗法结合用于治疗低风险前列腺癌 [ 9 ]]. 对于已经扩散到前列腺以外并复发的癌症，推荐使用雄激素剥夺疗法，也称为激素疗法 [ 1 ]。每种治疗都与严重的副作用有关，例如毒性和白细胞和红细胞计数减少，这会导致疲劳、脱发、周围神经病变、勃起失禁和功能障碍、转移，最后对初始治疗产生耐药性。可用的治疗方案很昂贵并且会造成严重的副作用。有必要发现具有很少或没有副作用和更高疗效的新的具有成本效益的化疗药物 [ 3]. 在这篇综述中，我们提供了前列腺癌的整体概述，包括疾病的诊断、导致疾病发作和进展的基因和突变、治疗方案和替代治疗方案。2.1. 前列腺癌的流行病学 2.1.1. 全球范围内 前列腺癌是全世界男性最常见的恶性肿瘤之一 [ 10 ]。2018 年，GLOBOCAN 报告了全球约 1,276,106 例前列腺癌新发病例，导致约 358,989 例死亡，发达国家的患病率更高。平均而言，全世界每年有 190,000 例新的前列腺癌病例出现，每年约有 80,000 例死亡 [ 11 ]。前列腺癌的全球发病率因不同地理区域和种族群体而异。在世界上，黑人男性的前列腺癌发病率最高 [ 12]. 美国黑人的发病率比美国白人男性高约 60%。最高记录的前列腺癌发病率出现在发达国家，那里对前列腺癌有认识，并且前列腺特异性抗原 (PSA) 检测是一种普遍的筛查做法 [ 13 ]。GLOBOCAN 的 PSA 检测报告表明，2012 年澳大利亚（每 100,000 人 111.6 人）和美国（每 100,000 人 97.2 人）的发病率很高 [ 14 ]。在全球范围内，预计到 2030 年前列腺癌新发病例将增加到约 170 万，死亡人数将达到 499,000 人，原因是人口呈指数级增长，并且 65 岁及以上的男性人口众多 [ 15 ]。 2.1.2. 本地规模 非洲国家对前列腺癌知之甚少。使用 PSA 测试或直肠指检进行前列腺癌筛查在非洲并不是一种成熟的做法。与北非相比，南部非洲男性的前列腺癌发病率更高 [ 16 ]。在南非，前列腺癌是全国男性中诊断最多的癌症之一。根据南非国家癌症登记处的记录，2007 年前列腺癌的发病率为每 100,000 名男性中有 29.4 例。2012 年，发病率增至每 100,000 名男性中有 67.9 人 [ 15 ]。2.2. 前列腺癌的筛查和诊断 在疾病的成熟阶段诊断前列腺癌和治疗失败是导致死亡率增加的主要因素。没有针对前列腺癌的单一、特异性测试；然而，它通常通过直肠指检 (DRE) 进行诊断，将戴手套的手指插入患者的直肠以评估前列腺的大小和任何异常情况。然而，前列腺特异性抗原 (PSA) 测试仍然是前列腺癌筛查的基石 [ 17 ]。PSA是由前列腺上皮细胞分泌的糖蛋白。它通常存在于精液中，但也存在于血液中 [ 18]. 在 PSA 测试期间，采集血液样本以测试 PSA 水平。然后，在 4 ng/mL 的 PSA 截止点分析血样。PSA 水平高于 4 ng/mL 表明患者需要进一步检测 [ 19 ]。PSA 水平在 4 ng/mL 和 10 ng/mL 之间的患者患前列腺癌的几率约为四分之一。如果 PSA 超过 10 ng/mL，则患前列腺癌的可能性超过 50% [ 20]. PSA 是前列腺特异性的，而不是前列腺癌特异性的；因此，前列腺特异性抗原水平可以指示良性病变，例如良性前列腺增生 (BPH) 和前列腺炎，而不是前列腺癌，据报道，未患前列腺癌的男性 PSA 水平升高。通常进行前列腺组织活检以确认癌症的存在 [ 21 ]。 活组织检查是一种医疗程序，其中使用细空心针从前列腺收集小组织样本，以便在显微镜下观察。活检可通过肛门和阴囊之间的皮肤或直肠壁进行（称为经直肠活检）[ 22 ]。在活组织检查期间，前列腺通常通过磁共振成像 (MRI) 和经直肠超声 (TRUS) 等设备定位。MRI 扫描仪使用强磁场和无线电波创建身体组织的详细图像 [ 23 ]。MRI 阳性结果可用于在活检期间专门针对前列腺的异常区域 [ 24]. 如果 DRE、PSA 测试和 MRI 的结果均为阴性，则多参数 MRI 也可以是在没有活检的情况下进行的分类测试。TRUS 是一种放置在患者直肠中的小型探针。探头发出的声波穿过前列腺并产生回声。然后探头识别并读取回声，计算机系统将它们转换为器官的黑白图像 [ 25 ]。 活检分析是最可靠的前列腺癌诊断方法之一。活组织检查的组织样本在实验室中使用显微镜进行研究和分析。还可以分析细胞以确定癌症扩散的速度。活检结果通常报告如下： 前列腺癌呈阴性，活检样本中未检测到癌细胞。 前列腺癌呈阳性，在活检样本中检测到癌细胞。 存在可疑的异常细胞，但可能不是癌细胞 [ 26 ]。 然而，人工智能 (AI) 和机器学习算法最近取得了进步，导致了前列腺癌的新分类。近年来，新型分子标记的可用性以及多参数磁共振成像 (mpMRI) 和前列腺特异性膜抗原正电子发射断层扫描 (PSMA-PET) 扫描等先进成像技术的引入已经改变了前列腺的范式癌症筛查、诊断和治疗转向更加个体化的方法 [ 27 ]。根据最新指南，任何有患前列腺癌风险的男性都应该在进行前列腺活检之前进行前列腺 MRI 检查 [ 28 ]]. 这有助于最大限度地减少并发症，例如下尿路症状、血尿和暂时性勃起功能障碍。此外，获得的活检针芯数量与直肠出血、血精症、出血问题和急性尿潴留等并发症的风险较高有关 [ 29 ]。因此，放射组学有助于前列腺体积的选择和分割；前列腺癌 (PCa) 筛查、检测和分类；以及风险分层、治疗和预后（表格1).表格1 与实际前列腺癌风险分层管理相比，放射基因组学的优缺点。放射基因组学优点限制 可以提供比基因检测更便宜的精确成像指标。缺乏前瞻性研究 人工智能和深度学习被用于生产用于临床实践翻译的计算机辅助工具，使用包含基因组和成像信息的大型公共数据库。用于定义和勾画感兴趣区域的图像采集需要放射科专家 计算机设计的软件，包括自动和半自动，用于消除缺点（缺乏标准化、成像和报告协议，这些协议在机构之间存在显着差异）。大量时间用于正确的手动描绘 放射组学/放射基因组学生物标志物可用于定制治疗方案并预测风险和结果。阅读和分割感兴趣的区域有很多观察者间的可变性 需要活检来深入了解肿瘤基因组，这是一种侵入性技术，可能会增加患者的发病率。可以使用放射基因组学预测肿瘤遗传变化。不同的采集技术、扫描仪和放射组学研究，以及由于缺乏标准化而缺乏可重复性和再现性 全肿瘤数据可通过基于放射组学的方法获得，该方法可以提供预测和预后信息。由于患者特征和成像技术的差异，将全基因组测序数据与成像数据进行匹配存在问题2.3. 前列腺癌与遗传学基因遗传 近亲血统是前列腺癌的主要危险因素。与没有前列腺癌家族史的男性相比，有近亲被诊断出患有前列腺癌的男性患癌症的风险为 50% [ 26 ]。连续几代诊断出前列腺癌的一级亲属通常患有早发性前列腺癌 [ 31 ]。流行病学研究表明前列腺癌易感基因具有遗传性。病例对照、双胞胎和家庭研究的分析得出结论，前列腺癌风险可能是遗传因素的结果。研究表明遗传性前列腺癌中存在特定基因突变，并报告说患有这些突变的患者患该病的风险增加 [ 4 ]]. 在遗传的遗传评估中，科学家对诊断出患有前列腺癌的男性以及患癌症的高风险男性进行多基因测序。这些男性中约有 5.5% 的 DNA 修复基因（例如ATM、BRCA1和BRCA2基因）存在可检测到的突变。非洲男性有某些使他们易患前列腺癌的基因突变；因此，种族和环境条件（例如迁移和食物饮食）被认为是促成因素 [ 21 ]。 癌症的发生是由于点突变、单核苷酸多态性 (SNP) 和体细胞拷贝数改变 (SCNA) 等突变引起的 DNA 序列变化 [ 31 ]。突变可通过关闭肿瘤抑制基因并开启致癌基因而导致前列腺细胞发生癌变 [ 32 ]。这通常会导致不受控制的细胞分裂。基因突变可以代代相传或由个体获得。获得性突变通常发生在细胞核中的 DNA 复制过程中 [ 33 ]。用作前列腺癌生物标志物的常见基因是 BRCA 基因、HOX 基因、ATM 基因、RNase L（HPC1、lq22）、MSR1 (8p) 和 ELAC2/HPC2 (17p11)。表 2显示了大多数用作前列腺癌生物标志物的基因。表 2 前列腺癌基因用作该疾病的生物标志物。基因基因描述诊断/预后或预测BRCA基因BRCA1 基因携带者在 65 岁时患前列腺癌的相对风险是 1.8-4.5 倍，而BRCA2基因携带者是 2.5-8.6 倍 [ 31 , 34 ]。BRCA 基因突变会抑制导致前列腺癌的 DNA 修复 [ 35 ]。诊断预测 [ 36 ]RNASEL核糖核酸酶 L ( RNase L ) 基因突变与前列腺癌有关 [ 37 ]。发现的突变可以使RNase L基因失活，使前列腺癌不易感 [ 38 ]。RNase L 是一种内切核糖核酸酶，在干扰素作用途径中发挥作用，可防止病毒感染 [ 35、39 ]。预测 [ 40 ]HOXB13HOXB13可降低前列腺癌的生长和激素介导的雄激素受体活性[ 41、42 ]。(rs339331) 多态性增加了HOXB13与转录增强子的结合，从而导致上调。大多数HOXB13突变与侵袭性和早发前列腺癌的风险相关 [ 43 ]。预测 [ 44 ]ATM基因ATM 蛋白控制细胞分裂和生长。它还会导致某些身体系统的发育，并帮助细胞识别受损的 DNA。种系 ATM 突变与早期转移和较低的前列腺癌存活率有关[ 45、46 ]。预后 [ 47 ]HPC2或ELAC2基因HPC2（遗传性前列腺癌基因2）和ELAC2（elaC同系物2）是遗传性前列腺癌的候选基因。与HPC1一样，与前列腺癌相关的突变是错义突变 [ 48 ]。预测 [ 40 ]MSR1基因MSR1 （巨噬细胞清道夫受体 1）位于遗传性前列腺癌 (HPC) 基因座的8p22–23，并且与该基因相关的突变与前列腺癌相关 [ 49、50 ]。预测 [ 40 ]ANXA7ANXA7是一种前列腺癌预后因子，显示出与肿瘤进展的双峰相关性 [ 51、52 ]。对前列腺肿瘤微阵列中 ANX7 蛋白的分析表明，与原发性肿瘤相比，激素难治性前列腺癌的复发和转移中 ANX7 表达的减少率增加 [ 53 ]。预后 [ 51 ]( ATBF1 )-一个AT 基序结合因子 1 ( ATBF1 ) -A因其在细胞抑制和高突变率方面的功能而成为前列腺癌肿瘤抑制的候选者。ATBF1-A mRNA 水平的降低与较差的诊断有关。ATBF1抑制细胞增殖；因此， ATBF1的丢失会导致不受控制的细胞生长 [ 54、55 ]。预测 [ 41 ]CDKN1BCDKN1B 的主要功能是细胞周期把关。研究表明，CDKN1B 基因是前列腺癌中重要的抑癌基因。CDKN1B 基因 (12p13) 的位置与不同人群对前列腺癌的易感性之间存在相关性[ 56、57 ]。预后 [ 58 ]( KLF6 ) 基因Kruppel 样因子 6 ( KLF6 ) 是一种抑癌基因和锌指转录因子。在 Narla 等人于 2008 年开展的一项研究中，77% 的前列腺肿瘤中KLF6基因的一个等位基因被删除，正常的 KLF6 基因上调 p21 (WAF1/CIP1) 并减少细胞增殖。KLF6-SV1 突变过表达会增加转移[ 59、60 ]。预测 [ 60 ]MYC基因MYC 原癌基因，BHLH 转录因子编码转录因子，促进前列腺癌的肿瘤发生。研究表明，前列腺癌肿瘤灶表现出 MYC 和蛋白质的过度表达，这与癌症的严重程度有关。由 MYC 突变引起的 TMPRSS2-ERG 基因融合与前列腺癌的侵袭性有关，在 60% 的患者中可见 [ 61 , 62 , 63 ]。预测 [ 63 ]NK321NK3 同源框 1 (Nkx3.1) 基因表达通常在人类和小鼠模型的前列腺癌发生和生长过程中丢失。发现 Nkx3.1 表达的缺失通过 11 kb 区域干预转录阶段 [ 64 , 65 ]。诊断 [ 64 ]PON1对氧磷酶 1 (PON1) 是一种蛋白质编码基因。该基因可减少氧化应激，从而导致癌症的发展 [ 66 ]。Stevens 等人于 2008 年开展的一项研究调查了 SNP（Q192R 和 L55M）与前列腺癌之间的关系。结果表明，在 Q192R 和 L55M SNP 中发现的变异等位基因的存在与侵袭性前列腺癌的风险增加有关 [ 67 ]。预后 [ 66 ]PTEN磷酸酶和张力蛋白同系物PTEN的缺失在雄激素非依赖性前列腺癌中很常见 [ 68 , 69 ]。PTEN基因功能的丧失与不规则的细胞增殖有关。研究表明，PTEN基因的突变在前列腺癌发生中发挥作用 [ 70 ]。PTEN基因在前列腺细胞系 LNCaP、PC3 和 DU145 以及前列腺癌异种移植物中发生突变 [ 71 ]。预后[ 70 ]线粒体DNA线粒体 DNA 有 16,569 个碱基，编码 37 个基因。已发现线粒体 DNA 基因中的突变会导致前列腺癌 [ 72 ]。在一项关于 mtDNA 基因的研究中，大约 12% 的患者在细胞色素氧化酶亚基 I (COI) 中存在突变 [ 73 ]。预后 [ 73 ]RAS大鼠肉瘤病毒 (RAS) 是由 N-RAS H-RAS 和 K-RAS 组成的基因家族的一部分，它们在细胞信号传导中很重要。在家族基因的密码子 12、13 或 61 处发生的点突变允许原癌基因被翻译成 RAS 癌基因 [ 74 ]。诊断[ 75 ] 生物标志物显示出用于诊断程序、分期、评估疾病侵袭性和评估治疗过程的优势。通过分析技术取得了多项进展，包括指导诊断和精准医学的新型生物标志物。现代生物标志物，如前列腺健康指数 (PHI)、TMPRSS2-ERG 融合基因、4K 测试和 PCA3，已被证明可以提高 PSA 的特异性和敏感性，从而使患者避免活检并减少过度诊断 [ 76 ]。表3下面显示了不同的诊断生物标志物及其不同的测试和类别。表3 其他诊断生物标志物的例子分为基于血清、基于尿液和基于组织的生物标志物，用于前列腺癌 [ 77 ]。生物标志物测试类别前列腺特异性抗原PSA 计数 >4 ng/mL 的特异性为 94%，但在 PCa 检测中的灵敏度仅为 20%；只有四分之一的 PSA 升高的男性会被诊断出患有 PCa。基于血清的生物标志物标准前列腺癌筛查方法4K 评分激肽释放酶标记物4K 测试包括 PCa 诊断算法，该算法在血浆中包含四种激肽释放酶。分析包括 4K 面板 = 总 PSA (tPSA)、游离 PSA (fPSA)、完整 PSA 和人激肽释放酶 2 (hK2)。基于血清的生物标志物检测先前未筛查的 PSA 升高的男性中的高级 PCa前列腺健康指数 (PHI)PHI 结果 = (−2) (proPSA/fPSA) x √ tPSA)。首先，开发 PHI 测试来预测 PCa 的概率。使用截断值≥25 的 PHI 可以避免 40% 的活检。基于血清的生物标志物检测任何 PCaPHI 测试也可以在主动监测期间检查 PCa 进展的可能性SelectMDxHOXC6、KLK3、DLX1 mRNA 和 PSAdSelectMDx 测试分析 DRE 期间前列腺中风后获得的尿样。评估 HOXC6 和 DLX1 基因的存在，以评估活检期间任何 PCa 的风险，以及高级 PCa 的风险。基于尿液的生物标志物mpMRI 结果表明 SelectMDx 评分是一种很有前途的 PCa 检测工具TMPRSS2-ERG融合TMPRSS2-ERG 水平与去势抵抗性前列腺癌有关。融合跨膜丝氨酸蛋白酶 2 (TMPRSS2) 和 ERG 基因可在 50% 的 PCa 患者中检测到。基于尿液的TMPRSS2-ERG 低灵敏度PCA3 Progensa 前列腺癌抗原 3前列腺癌基因 3（PCA3 或 DD3）是一种特定的非编码 mRNA，它在超过 95% 的原发性前列腺肿瘤中过表达。 就预测价值和特异性而言，基于尿液的生物标志物PCA3 评分相对于 PSA 的敏感性较低ConfirmMDx GSTP1、APC 和 RASSF1 基因的高甲基化，PSA在初始活检阴性后筛查有 HG PCa 风险的患者。它经过临床验证，可检测 PCa 阴性活检组织中的 PCa。基于组织的生物标志物来自前列腺活检的组织 图1描述了前列腺癌的发展阶段 [ 78 ]。 图1 描绘前列腺癌发展的示意图。癌症发生和发展的阶段由在癌症的不同阶段中重要的分子过程、基因和信号通路指示。前列腺癌的第一个征兆是由于无法控制的细胞分裂而导致的前列腺炎症。这种无法控制的细胞分裂是由 DNA 受损引起的突变引起的。在染色体水平上，前列腺癌的发生始于染色体末端端粒酶的缩短。前列腺炎症引起的氧化应激可以缩短前列腺端粒 [ 78 ]。Nkx3.1研究同源盒基因显示了该基因对小鼠前列腺癌起始阶段的影响。没有肿瘤抑制基因被单独赋予在前列腺癌发生或进展中的作用。然而，一些基因如MYC、PTEN、NKX3.1和 TMPRSS2-ERG 基因融合与前列腺癌的发生有关。TMPRSS2-ERG 基因融合导致前列腺癌的主要分子亚型。基因融合激活了 ERG 致癌途径，这有助于疾病的发展。前列腺癌的转移是通过重新激活参与细胞分裂的途径来实现的，这会导致不受控制的细胞分裂和细胞增殖，从而导致癌症转移 [ 79 ]]. 基因表达谱分析结果表明转移性前列腺癌中存在 EZH2 mRNA 和蛋白质的过度表达。由于 EZH2 的功能涉及细胞凋亡和增殖，EZH2 是前列腺癌的新靶点 [ 80 ]。2.4. 前列腺癌精准医疗 精准医学是一个新兴领域，它代表了一种替代方法，对于一些患有晚期癌症的男性来说，可以找到针对前列腺癌的基因特异性治疗方法。它使用遗传学和环境生物标志物来确定诊断、患者的预后治疗选择以及准确的剂量。精准医学使用基因组测序对疾病进行分类，以确定肿瘤患者表现出可操作的目标，并促进更明智和准确的治疗决策 [ 81 ]。前列腺癌相关基因BRCA1和BRCA2的突变使患有 mCRPC 的男性适合使用 rucaparib 或 olaparib 以及其他对 olaparib 治疗反应良好的前列腺癌基因，包括ATM, CDK12 , CHECK2 , CHECK1 , PALB2 , PP2R2A和RAD54L [ 82]. 在一项包含 67 名 BRCA 突变携带者的 1302 名患者的研究中，调查了 BRCA 突变对治疗结果的影响。结果表明，与没有 BRCA 基因突变的患者相比，接受前列腺切除术或放疗的患者发生转移，生存期更短。这项研究还发现，BRCA1 基因比 BRCA2 基因多出 12%，后者仅占 2%。在最近于 2019 年进行的一项研究中，在一名接受放疗和 ADT 治疗的前列腺癌中国患者中发现了 BRCA 基因突变 (c.4211C > G)。该研究表明，具有这种特定突变的前列腺癌患者对 ADT 和放疗敏感，使治疗更有效 [ 83 ]]. 使治疗或设计有效 CRPC 变得困难的突变包括F876L突变，它改变了 AR 中的结合配体袋。同样，W741L/C 突变刺激特定的 AR 结合，能够将 AR 移动到其活性构象中。这种突变为设计有效的 CRPC 治疗创造了障碍 [ 84 ]。2.5. 前列腺癌的治疗和管理 包括初始 PSA 水平、临床 TNM 分期和 Gleason 评分在内的预后因素已与基线尿功能、合并症和年龄等其他因素一起作为前列腺癌治疗的选择 [ 85 ]。前列腺癌诊断和治疗的进步提高了临床医生按风险对患者进行分类并根据癌症预后和患者偏好提出治疗方案的能力 [ 86 ]]. 监测、前列腺切除术和放疗被公认为 I-III 期前列腺癌患者的标准治疗方法。通过手术或药物去势去除雄激素可以为所有 IV 期和高危 III 期患者带来持久缓解。在这种情况下，第一代抗雄激素药物如氟他胺和比卡鲁胺可以提供帮助。然而，IV 期总是出现以雄激素受体基因组突变为特征的去势抵抗，预后较差 [ 87 ]。表 4下面总结了前列腺癌的治疗选择及其副作用。表 4 常见的前列腺癌治疗选择和潜在的不良反应 [ 88 ]。治疗方案疾病进展潜在的不利影响主动监测本地化疾病不确定性根治性前列腺切除术本地化勃起功能障碍尿失禁外部光束辐射局部和晚期疾病尿急和尿频、排尿困难、腹泻和直肠炎勃起功能障碍尿失禁近距离放射治疗本地化尿急和尿频、排尿困难、腹泻和直肠炎勃起功能障碍尿失禁冷冻疗法本地化勃起功能障碍尿失禁和潴留直肠疼痛和瘘管荷尔蒙疗法先进的疲劳潮热和耀斑效应高脂血症胰岛素抵抗心血管疾病贫血骨质疏松症勃起功能障碍认知缺陷化疗先进的骨髓抑制超敏反应胃肠道不适周围神经病变 2.5.1. 主动监控 主动监测是一种结构化计划，它采用监测和预期干预作为前列腺癌管理的主要技术 [ 89 ]。对于低风险癌症患者或预期寿命较短的患者，主动监测已被认为是最佳选择。主动监测标准的建议通常基于以下因素：疾病特征、健康状况、预期寿命、副作用和患者偏好 [ 90 ]。PSA 水平、临床进展或组织学进展被用作前列腺癌的触发点 [ 91 ]。 主动监测的优点是保持勃起功能、降低治疗成本、避免对非活动性癌症进行不必要的治疗以及维持生活质量和正常活动。它的缺点包括治疗前癌症转移的可能性、错过补救的机会、需要对较大和侵袭性癌症产生副作用的复杂疗法、主要在手术后保留效力的机会减少、患者焦虑增加的机会以及频繁的医疗检查 [ 92 ]。2.5.2. 根治性前列腺切除术 根治性前列腺切除术是通过开放和/或腹腔镜手术从医学上去除前列腺的过程 [ 93 ]。该过程需要在腹部或通过会阴做小切口。 对于在接受外照射放射治疗、近距离放射治疗或冷冻治疗后没有转移但局部复发的患者，通常建议进行挽救性根治性前列腺切除术。然而，这可能导致发病率增加。年龄小于 70 岁的局限于器官的前列腺癌患者，预期寿命超过 10 年，几乎没有或没有合并症，最适合根治性前列腺切除术。但是，它的使用存在一些并发症。这些并发症包括手术损伤泌尿道括约肌和勃起神经引起的尿失禁和勃起功能障碍 [ 94 ]。2.5.3. 冷冻疗法 该方法涉及在超声引导下使用外科手术将冷冻探针插入前列腺。它涉及将前列腺冷冻至-100°C至-200°C的温度约10分钟。然而，有报道称使用这种方法会导致并发症，包括尿失禁和尿潴留、勃起功能障碍、瘘管和直肠疼痛 [ 95 ]。 2.5.4. 辐射 放射疗法被认为是使用高辐射杀死前列腺癌细胞的最有效疗法之一。辐射通过各种技术发送到癌细胞，例如近距离放射治疗（使用植入体内的种子）和外照射（能量通过皮肤投射）到癌变部位。放射治疗旨在专门将高能射线或粒子剂量直接转移到前列腺而不影响正常组织。这些剂量基于前列腺癌的水平。对于不适合外科手术的患者，这种治疗被认为是可接受的治疗 [ 96 ]。下面讨论各种放射治疗技术。 近距离放射治疗 近距离放射治疗包括在经直肠超声的引导下借助粒子、注射剂或导线将放射源直接放置到前列腺中。这通常涉及两种技术：低剂量和高剂量率。低剂量率是指粒子永久植入前列腺组织，逐渐失去放射性[ 97]，后者指的是向前列腺组织提供一定剂量的辐射，具有泄漏到其他周围器官的显着风险。近距离放射治疗的优点是可以在一天或更短时间内完成。之前没有经尿道前列腺切除术 (TURP) 的患者出现尿失禁的风险很小。勃起功能也不受影响。它的缺点通常是需要全身麻醉、急性尿潴留风险和持续的刺激性排尿症状 [ 98 ]。外照射放射治疗 外照射放射治疗 (EBRT) 是一种常用的治疗技术，涉及发射专门针对前列腺组织的强 X 射线束。它辐射更高的前列腺辐射剂量，对周围组织的辐射更少。当与雄激素剥夺疗法 (ADT) 一起使用时，放射疗法被认为是一种有效的中度风险和高风险前列腺癌治疗 [ 80 ]。它是减弱转移性癌细胞的合适疗法。这种技术比手术治疗更有优势。它可以治疗早期癌症，并且与出血、心肌梗塞、肺栓塞、尿失禁和勃起功能障碍等风险较低相关。它还可以缓解骨骼和关节疼痛等症状 [ 93]. 辐射的副作用包括尿急和尿频、勃起功能障碍、排尿困难、腹泻和直肠炎 [ 97 ]。2.5.5. 镭223疗法 镭 223 二氯化物 (Xofigo) 技术利用一种用于治疗对激素疗法有抵抗力的转移性前列腺癌患者的物质。它模仿钙的能力使二氯化镭 223 被骨组织中的癌细胞选择性吸收。据报道，这项技术对转移性前列腺癌患者的生存和康复有相当大的影响，可导致骨折和疼痛的延迟发作 [ 85 ]。2.5.6. 荷尔蒙疗法 激素疗法也称为雄激素剥夺疗法 (ADT)。该技术应用于晚期和/或转移性前列腺癌的治疗。其治疗机制基于阻断睾丸激素和其他雄性激素的产生，防止它们为前列腺癌细胞提供燃料。因此，显着降低的男性荷尔蒙水平是抑制雄激素对雄激素受体作用的原因[ 99]. 这通常是通过使用促黄体激素释放激素 (LHRH) 类似物或拮抗剂使用双侧睾丸切除术或药物阉割来实现的。LHRH 类似物主要通过刺激垂体受体来提高黄体生成素 (LH) 和促卵泡激素 (FSH)，从而使药物能够下调垂体受体，同时降低 LH 和 FSH 水平，从而抑制睾酮的产生。亮丙瑞林、戈舍瑞林、曲普瑞林和组瑞林是常见的 LHRH 激动剂。拮抗剂通过阻断垂体受体而引起作用，从而引发对睾酮合成的直接抑制 [ 100]. 然而，ADT 与急性和长期副作用相关，例如高脂血症、疲劳、潮热、耀斑效应、骨质疏松症、胰岛素抵抗、心血管疾病、贫血和性功能障碍 [ 101 ]。 氟他胺是一种非甾体类药物，是纯抗雄激素药物，缺乏激素激动剂活性。氟他胺是雄激素依赖性附属生殖器的抗雄激素。其生物活性基于 2-羟基氟他胺。用氟他胺和一种 (LHRH) 激动剂治疗前列腺癌已产生可喜的结果。氟他胺的体内研究表明，它在腹侧前列腺和雄激素依赖性精囊中具有某些拮抗剂 [ 102、103 ]。已知氟他胺会导致肝功能障碍；然而，一项抗雄激素疗法 (AAT) 联合氟他胺的研究表明，在治疗期间定期进行肝功能检测时，氟他胺可能会取得成功 [ 104 ]]. 使用氟他胺作为二线激素疗法的最大雄激素阻断 (MAB) 可产生前列腺特异性抗原反应而无副作用，这使其成为无骨转移或癌症进展超过一年的 HRPC 患者的可能治疗选择一线治疗后 [ 105 ]。 Chlormadinone acetate (CMA) 是一种口服类固醇抗雄激素药物。Chlormadinone 已被证明具有抗癌活性。类似于日本最大雄激素阻断 (MAB) 疗法以及前列腺癌单一疗法中使用的黄体酮 [ 106 ]。为确定抗雄激素醋酸氯地孕酮在治疗 A 期前列腺癌方面的成功，对 111 名接受醋酸氯地孕酮治疗的患者进行了一项研究。A1 期和 A2 期患者与抗雄激素治疗相关的进展率在非治疗接受组中较低，结论是醋酸氯地孕酮抗雄激素治疗抑制了进展 [ 107 ]]. Chlormadinone 还用于治疗良性前列腺增生，它降低睾酮水平、前列腺特异性抗原 (PSA) 水平和前列腺体积，在良性前列腺增生中减缓前列腺癌的进展 [ 108 ]。2.5.7. 阿比特龙 阿比特龙是针对肾上腺和肿瘤雄激素生成的第二代疗法。它与 CYP17A 的羟化酶和裂解酶活性、AR 通路和 3β-羟基类固醇脱氢酶活性的不可逆抑制有关，用于治疗已经转移到身体其他部位的前列腺癌 [ 109 ]。阿比特龙也被证明是其他微粒体药物代谢酶的有效抑制剂，包括 CYP1A2 和 CYP2D6 [ 109 ]。阿比特龙的临床数据显示出显着的效果，但也有报道称其反应不一，同时 PSA 水平升高。阿比特龙与高 CYP17A 上游盐皮质激素相关，伴随的副作用包括水肿、高血压、疲劳和低钾血症 [110 ]。 免疫疗法或生物疗法基于刺激或抑制免疫系统。该疗法使用旨在与患者的免疫系统协同工作以对抗癌细胞的疫苗。Sipuleucel-T (Provenge) 是此类疫苗之一，专为对激素治疗产生耐药性的晚期和转移性前列腺癌细胞而设计。它是通过收集白细胞并用前列腺酸性磷酸酶激活它们而从免疫细胞发展而来的 [ 109 ]。然后，这与一种蛋白质有关，这种蛋白质可以在注入血液之前触发免疫系统 [ 99 ]]. Sipuleucel-T（Provenge，Dendreon）是一种基于自体树突细胞的免疫疗法，通过协助患者的免疫系统抵抗癌细胞来治疗无症状患者。它在一个月内分三剂静脉内给药。与其他化学疗法相比，其较小的副作用使其更受欢迎。它的副作用包括发烧、恶心、发冷和肌肉疼痛 [ 111 ]。2.5.8. 化疗 化疗使用抗癌药物来杀死或抑制癌细胞的生长。经过数十年的学习和理解遗传学、诊断和治疗，前列腺癌的治疗取得了进展。最常见的前列腺癌化疗药物是多西紫杉醇 (Taxotere) [ 112 ]。多西紫杉醇 多西紫杉醇被认为是去势抵抗性前列腺癌细胞的一线标准疗法。它是一种抗微管剂，附着于 β-微管蛋白以抑制微管解聚，从而抑制有丝分裂细胞分裂并启动细胞凋亡 [ 113 ]。CYP3A 是激活多西紫杉醇的主要要求。多西紫杉醇耐药性的发展与复发有关。多西紫杉醇耐药性归因于编码 P-糖蛋白的多药耐药性 (MDR) 1 基因的上调增加 [ 114 ]。卡巴他赛 Cabazitaxel 是一种新型抗肿瘤半合成药物，来源于各种紫杉树 (Taxus) 的针叶。它通常以 Jevtana 的名义出售。卡巴他赛是第二代疗法，旨在抑制多西他赛耐药性 [ 99 ]。由于其额外的甲基，它对 P 糖蛋白的亲和力较低。它在肝组织中通过 CYP3A4/5 和 CYP2C8 (10–20%) 代谢。低血压、支气管痉挛、肾功能衰竭、神经毒性疲劳、脱发和全身性皮疹/红斑是与其使用相关的常见副作用。也有与卡巴他赛治疗相关的腹泻死亡报告，导致电解质失衡和脱水 [ 114 ]。恩杂鲁胺 恩杂鲁胺是第二代AR抑制剂，2012年被认定为前列腺癌的化疗药物之一。该药物主要作用于雄激素通路，具有（1）竞争性抑制雄激素与雄激素受体的结合，（ 2) 抑制核转位和辅因子募集，以及 (3) 抑制激活的雄激素受体的结合。恩杂鲁胺靶向雄激素，如睾酮和二氢睾酮。其治疗机制包括： 竞争性抑制雄激素与雄激素受体的结合； 抑制核易位和辅因子募集； 抑制 DNA 与激活的雄激素受体的结合。 恩杂鲁胺的副作用包括疲劳、乏力、腹泻和呕吐 [ 115 ]。2.6. 联合治疗 联合疗法已被证明是前列腺癌治疗的有效策略。联合疗法是一种用于治疗去势抵抗性前列腺癌和其他形式的前列腺癌的策略。迄今为止还没有治疗去势抵抗性前列腺癌 (CRPC) 的药物，目前批准的治疗方案无论是单独使用还是联合治疗，都有助于将患者的寿命延长几个月 [ 116 ]]. 目前用于治疗前列腺癌的治疗方案无法治愈，并且疾病会在一段时间内发展为去势抵抗表型。结合目前使用的前列腺癌治疗方案，可以成功延长患者的寿命并抑制肿瘤。在所有可用于转移性前列腺癌的治疗策略中，与前列腺癌的其他治疗策略相比，雄激素剥夺疗法 (ADT) 具有更多潜在的联合治疗，并且批准和目前正在进行的 ADT 治疗临床试验包括 ADT 与放射疗法，这通常治疗高危患者以延缓或预防疾病进展为 CRPC；(ii) ADT 和化疗，在几项临床研究中表明，它可以提高患者的存活率，但会导致不良副作用，有时甚至会导致死亡；(iii) 免疫疗法和 ADT，据报道可使患者生存期延长 8.5 个月 [117 ]。正在进行临床试验以分析 ADT 和 PSA 靶向痘病毒疫苗 PROSTVAC-IF 对生存的影响；在 ADT 下结合放射疗法和免疫疗法；在 ADT 下联合化疗和免疫治疗；以及 ADT [ 118 ] 下的多西紫杉醇组合。有许多针对前列腺癌联合治疗的已完成和正在进行的临床研究/试验。部分临床试验列于表 5和表 6.2.7. 药物再利用 药物再利用，也称为药物重新定位、重新配置或重新分配任务，是一种确定已批准药物新用途的方法 [ 119 ]。药物再利用相对于从头药物开发（开发新药）的优势在于，再利用候选药物已经在动物模型和临床试验中进行了广泛的研究，测试了药物的安全性、优化，并且在大多数情况下还进行了制剂开发，因为以及药代动力学和药效学特性。这种优势通常会加快药物新用途的研发，并降低后期功效测试临床试验的失败率 [ 120 ]]. 这些以前测试过的药物可以迅速进入 II 期和 III 期人体临床研究，这意味着相关的药物开发成本可能会大大降低。研究人员对这种现象表现出极大的兴趣，因为药物再利用缓解了目前临床研究中寻找新的癌症疗法所面临的一些挑战的困境，例如药物短缺。开发一种新药可能需要 10-17 年的时间，而开发新药则需要 3-12 年。技术进步在扫描大型数据库和检测不同疾病的关键分子相似性以识别可重新利用的药物方面发挥着重要作用。雄激素剥夺疗法 (ADT) 用于治疗晚期前列腺癌患者。二甲双胍是一种常用于治疗II型糖尿病的药物，重新用于治疗前列腺癌。它可用于使前列腺癌对目前使用的标准前列腺癌疗法敏感并提高治疗效果。据报道，二甲双胍能够增加ADT治疗前列腺癌的有效性[121]. 在这里，我们讨论了 PCa 药物再利用研究的三个主要类别，按不同的发现和验证类别分类，例如要研究的药物的知识和能力。例如，奥美洛昔芬是一种选择性雌激素受体调节剂，以其在多种癌症（如乳腺癌和卵巢癌）中的抗癌特性而闻名，但据报道，奥美洛昔芬通过显着介导前列腺癌中致癌 β-连环蛋白信号传导和 EMT 进展的抑制作用抑制 β-连环蛋白/TCF-4 转录活性、N-钙粘蛋白、MMP，并触发 pGSK3β 表达。另一类是已经过化验测试并根据其活性进行分类的药物。例如，伊曲康唑，122 ]。表 7显示在前列腺癌临床试验研究中重新定位候选药物的不同方法。 目前正在体外和体内研究用于治疗前列腺癌的其他抗癌药物包括萘哌地尔，一种α受体阻滞剂；氯硝柳胺，一种抗蠕虫剂；奥美昔芬，一种雌激素受体调节剂；奈非那韦，一种抗逆转录病毒药物；格列吡嗪，一种抗糖尿病药；clofoctol，一种抗菌剂；和三氯生，一种抗菌剂 [ 32 ]。前列腺癌的药物再利用提供了解决当前治疗挑战的机会。应使用计算基因组学和蛋白质组学工具实施该策略，以协助和指导研究人员做出有关患者治疗的决策 [ 122 ]。2.8. 治疗挑战 尽管有多种治疗选择，但 mCRPC 仍然是一种无法治愈的疾病。随着时间的推移，该疾病继续对不同的常规治疗方案产生耐药性 [ 123 ]。这导致了对促进疾病进展的生长、转移、肿瘤发生、肿瘤微环境和肿瘤环境相互作用的持续研究。2.8.1. 耐药性 据报道，在已达到晚期的前列腺癌中存在去势抵抗。去势抵抗允许通过放大雄激素受体合成肿瘤内激素来进行雄激素信号传导，同时破坏雄激素受体的共表达因子和共激活因子 [ 124 ]。对恩杂鲁胺和醋酸阿比特龙的耐药性，以及转移性前列腺癌的基因突变，都归因于患者体内活性雄激素受体 (AR) 的过度表达。前列腺癌通常由雄激素引起；因此，大多数治疗的目标是阻断雄激素。这有利于抗癌药物耐药的患者。 突变也被证明有助于癌细胞的耐药性，从而绕过靶向通路。AR 信号通路、MAPK/ERK 通路、内皮素 A 受体 (EAR) 和 Akt/PI3K 通路等内在通路的改变以及雄激素受体表达的加剧已被证明有助于 ADT 耐药 [ 46 ]。2.8.2. ABC 转运体 这些转运蛋白在质膜中表达，在那里它们充当外排泵，并且是众所周知的多药耐药性触发因素。它们将药物和异生素运输进出细胞 [ 125 ]。多药耐药蛋白 (MRP) 转运蛋白 MRP2、MRP3、MRP4 和 MDR-1 蛋白（P-糖蛋白）已在前列腺癌中得到报道 [ 110 ]]. 这些转运蛋白的表达加剧与药物流出增加有关，从而导致多药耐药性。据报道，在这些转运蛋白中，MRP2 对天然产物制剂表现出最高的抗性，MRP3 对依托泊苷表现出最低的抗性，MRP4 和 MRP5 负责对核苷类似物和转运环核苷酸的抗性。MRP4 还会影响对喜树碱、环磷酰胺、拓扑替康、甲氨蝶呤和核苷类似物等化疗药物的耐药性 [ 126 ]。2.8.3. 细胞色素P450 细胞色素 P450 是众所周知的含血红素单加氧酶的多基因超家族，它既是组成型的又是诱导型的。它们催化各种异生素和内分泌干扰物的代谢 [ 127 ]。据报道，该家族包括 CYP2C19、CYP4B1、CYP3A5、CYP2D6、CYP1A2 和 CYP1B1，存在于人类前列腺细胞中 [ 128 ]。CYP4B1 的主要功能是通过 N-羟基化代谢和激活芳胺，这是一种导致膀胱肿瘤的活性 [ 129 ]。CYP1B1 的表达加剧与前列腺癌耐药性的进展有关。这通常通过氟他胺的 2-羟基化实现 [ 130]. CYP17A 加速了人类雄激素生物合成途径中的连续羟化酶和裂解酶步骤的过程，因此，使其成为前列腺癌治疗的关键治疗标志物 [ 131 ]。2.8.4. 雄激素受体突变 由于雄激素敏感性紊乱，雄激素受体发生突变。雄激素受体 (AR) 信号在前列腺的发育、活动和体内平衡中起着重要作用。它通过附着在特定基因上的雄激素反应元件以及允许雄激素受体的核转位来调节基因转录过程 [ 132 ]。AR信号通路中的基因变化（图 2)在摄护腺癌被报告了。AR 突变首先在雄激素反应性细胞系 LNCap 中报道。这些突变与 AR 靶向治疗引起的 AR 耐药性的发展有关 [ 133 ]。这导致使用雄激素剥夺疗法 (ADT) 和抗激素疗法治疗晚期前列腺癌。大多数 AR 突变导致单个氨基酸替换，这些替换主要存在于 AR 雄激素结合域中。在大约 30% 的转移性 CRPC 患者中发现的突变 T877A 是最常见的 [ 134 ]]. 其他突变导致 AR 与共调节因子的结合增强，从而导致相对于 H874Y 和 W435L 突变更高的 AR 转录活性。这些突变与 AR 靶向治疗引起的 AR 耐药性的发展有关 [ 124 ]。图 3说明了雄激素受体基因的转录活性 [ 135 ]。 图 2 AR 信号在前列腺癌和发展中的功能：( A ) 通过间质层和上皮层之间的相互信号在健康的前列腺中维持前列腺稳态；( B ) 正常前列腺细胞通过未知机制转化为癌症起始细胞，出现前列腺上皮内瘤变和早期癌症病变的组织学证据，基底层细胞表达更高水平的 AR 以响应这一事件；( C ) 前列腺腺癌中发生细胞和分子改变，导致具有 AR 转录途径的管腔细胞；( D) CRPC 中的前列腺癌细胞通过其他机制（包括 AR 及其剪接变体的上调、肿瘤内雄激素合成、与其他信号通路的交叉通信以及 AR 辅助因子表达的增加/改变）维持 AR 活性，因为雄激素来自血流变得有限 [ 134 ]。 图 3 雄激素受体基因编码一个 110 kD 的蛋白质，由 919 个氨基酸组成，分为雄激素结合结构域 (ABD)、保守的 DNA 结合结构域 (DBD) 和 N 末端反式激活结构域，该结构域具有两个多态性三核苷酸重复片段。这些由可变数量的聚甘氨酸重复序列和聚谷氨酰胺组成的重复片段高度影响雄激素受体的转录活性。基因转录物总共由八个外显子组成：外显子 1 编码 N 末端结构域，外显子 2-3 编码 DBD，外显子 4-8 编码 ABD [ 135 ]。 2.8.5. 肿瘤微环境 根据最近的研究，肿瘤微环境在前列腺癌的发展和进展到晚期阶段起着至关重要的作用。根据实验研究，环境与恶性肿瘤细胞具有相辅相成的关系，正常组织微环境的早期变化可以促进癌变，而肿瘤细胞可以促进微环境中更多的促癌修饰[ 136 ]。肿瘤微环境包括一个广泛相互关联的生态位，包括细胞外基质和特殊细胞，如神经细胞、血管、免疫细胞和间充质/基质干细胞，所有这些细胞都会分泌趋化因子、细胞因子和基质降解酶等因子。它们通过旁分泌和自分泌机制与癌细胞相互作用[137、138 ]。_ 根据肿瘤分期特异性组织学研究，高级别 PC 与增强的基质免疫细胞浸润与多种细胞类型有关 [ 139 ]。直接感染、尿液反流、高脂肪饮食和雌激素等慢性压力会长期影响前列腺发炎的能力 [ 140 ]。在持续的炎症中，基质室经历了几种免疫细胞的流入，包括 CD3+ T 细胞、巨噬细胞和肥大细胞 [ 141 ]]. 炎症细胞产生高水平的细胞因子和趋化因子、原发性肿瘤坏死因子、核因子 kappa B，仅举几例。血管生成、细胞增殖和炎症的调节涉及这些蛋白质等。它们控制 PC 向恶性表型的转变 [ 136 ]。 由于前列腺上皮细胞与肿瘤微环境之间的相互作用，周围的基质因子会经历复杂的修饰，这些变化控制着疾病的严重程度、传播能力及其对传统治疗的敏感性[ 142、143 ]。2.9. 雌激素受体 (ER) 在前列腺癌病因和进展中的作用 前列腺癌通常被认为是激素依赖性的，因为类固醇激素指导其发生和发展。早期的报告强调了类固醇水平在 PCa 病因学中的重要性 [ 144 , 145 ]。雌激素在雄性激素的分泌中起着不可或缺的作用，在前列腺组织的生长、分化和体内平衡中也起着重要作用。雌激素也有助于前列腺癌的发展 [ 146]. 在 Ellem 和 Risbridger 使用芳香化酶敲除 (KO) 小鼠的报告中，敲除小鼠不能将雄激素代谢为雌激素，并且观察到高水平的睾酮导致前列腺肿大（前列腺增生）的发展。同时，雌激素水平升高和睾酮水平降低导致炎症事件和病变 [ 147 ]。流行病学研究还提出，血清雌二醇水平和血清雌二醇/睾酮 (E/T) 比率会影响 PC 的发生及其进展 [ 148 ]。雌激素的活动是由两种受体进行的，它们是雌激素受体α（ERα）或β（ERβ）；ERα 和 Erβ 在前列腺组织中表达 [ 125]. ERα 局限于前列腺间质，对上皮细胞有间接作用，而 ERβ 被发现在上皮结构域内表达并调节上皮增殖和分化 [ 149 ]。人类中存在不少于五种 ERβ 同系物（ERβ1、-2、-3、-4 和 -5）[ 145 ]。ERβ1 发挥功能性作用，而其他亚型控制其活性。因此，ERβ 的作用可能取决于 ERβ1 和 ERβ 亚型的表达比率。众所周知，ERα 会引起雌激素诱导的不良反应，而 ERβ 会指导雌激素在 PCa 中的保护和抗细胞凋亡作用 [ 149]. 一方面，已发现雌二醇受体 α 的表达与 PCa 患者的高 Gleason 评分和低生存率显着相关 [ 150 ]；另一方面，在检查的 PCa 样本中发现 ERβ 表达减少或丢失 [ 151 ]。此外，ERβ2 和 ERβ5 的共同表达已被证明构成了 PCa 患者生化复发、手术后扩散/转移和根治性前列腺切除术后扩散期的标志物。基于上述，随着PCa的进展，ERβ1的表达减少，ERβ2和ERβ5的表达增加。这种表达模式与 PCa 的扩散和转移相对应 [ 152]. 一方面，在 PCa 中，ERα 具有致癌作用并指导雌激素的有害作用，包括增殖、炎症和前列腺癌发生。另一方面，Erβ 可能在配体对 ERβ 的 PCa 操纵中引发抗肿瘤活性（肿瘤抑制因子）。新型候选药物可能对 PCa 的治疗策略有用，特别是在疾病的早期阶段 [ 145 ]。2.10. 探索替代疗法的实验工作前列腺癌中的传统医学 前列腺癌治疗中的医学 传统医学在发展中国家的医疗保健中发挥着重要作用，这些国家在治疗各种疾病方面也有着悠久的历史。药用植物在癌症治疗中的应用受到了广泛关注，最近，研究正在进行中，美国国家癌症研究所 (NCI) 在传统医学治疗癌症的研究中发挥着关键作用 [ 153 ]。传统医学被癌症患者大量使用，以最大限度地减少副作用，或者完全用作单一疗法而不是常规疗法。这是因为植物易于获取、有效且负担得起。植物来源的化合物和植物提取物因其抗炎、抗氧化和抗菌特性而被广泛使用 [ 154 ]]. 当今治疗中使用的各种抗癌剂均来自植物，例如，紫杉醇和紫杉醇来自短叶紫杉，多西紫杉醇 (Taxotere) 来自红豆杉，长春新碱和长春花碱来自长春花[ 155 ]。 有相当多的证据支持使用植物性饮食来预防急性疾病。植物性食物的消费提供了必要的营养补充剂和植物化学物质，有助于生长和防止各种急性疾病的发生 [ 156 ]。它们还可以防止与癌症等慢性疾病相关的氧化应激。酚类化合物具有保护作用，包括抗菌、抗炎和抗癌作用 [ 157 ]。含有有机硫化合物的植物具有化学保护活性。类胡萝卜素和多酚具有抗炎和抗氧化活性 [ 158 ]。因此，药用植物通常用于治疗癌症 [ 159]. 几种类黄酮在治疗前列腺癌方面显示出抗癌活性。类黄酮是多酚类化合物，其特征是苯环与连接在碳 2 和碳 3（C2 和 C3）碳位置上的六元苯环缩合。在类黄酮中，黄酮醇可以通过碳 3 碳位置上的独特羟基来识别，已经在许多临床前和临床研究中报道了它们在前列腺癌细胞系中的抗癌活性。黄酮醇、杨梅素、非瑟酮和山柰酚普遍存在于多种水果和蔬菜中，在不同的细胞中表现出抗炎、抗病毒、抗肿瘤、抗菌和抗氧化等活性 [ 160 ]。 已经分析了几种特定植物作为癌症治疗的抗癌剂的活性。植物抗癌活性与提取物中存在的植物化学成分有关。表 8总结了用于癌症治疗的各种药用植物 [ 161 ]。 遗传学、生物技术、肿瘤生物学和免疫学的发展促进了基因治疗的新进展。基因疗法是一种包括插入或删除 DNA 序列或碱基对以纠正特定蛋白质中的遗传缺陷或靶向特定分子途径的疗法。目前正在开发一些用于基因治疗的基因编辑技术。基因疗法通常涉及将 DNA 核苷酸封装到病毒和非病毒载体中，将基因传递到特定位点，然后将基因插入人类基因组以编辑 DNA 序列并调节细胞过程 [ 162 ]]. 基因治疗的主要思想是将外源性核苷酸递送至各种组织细胞中的特定 DNA 部分。众所周知，病毒可以有效地将其基因组转移到宿主体内以感染宿主。病毒载体可以通过将其直接注射到目标组织中进行静脉内给药。还研究了非病毒载体如纳米颗粒和聚合物在治疗前列腺癌的基因疗法中的用途。这些非病毒载体通常通过静电相互作用压缩 DNA，这也可以保护遗传物质不被降解。基因疗法也探索细胞凋亡的用途。细胞无法进行细胞凋亡会导致不受控制的细胞分裂，进而导致癌症的发展 [ 163 ]]. 细胞凋亡的抑制通常由于癌细胞中的基因突变而发生。前列腺癌的基因治疗通过在编码细胞凋亡诱导剂、介体或执行者的缺陷细胞中引入编码细胞凋亡介体或诱导剂的基因来靶向细胞凋亡途径。细胞凋亡诱导基因，如半胱天冬酶，诱导癌细胞死亡[ 164]. 基因治疗面临着许多挑战，例如提高 DNA 向细胞的转移效率，以及干扰基因表达的免疫反应。然而，尽管困难重重，但基因治疗无疑将成为未来用于治疗前列腺癌的下一个新兴医疗技术。一些使用基因疗法研究前列腺癌治疗的临床试验研究包括各种转基因，例如 p53 和单纯疱疹病毒基因 [ 165 ]]. 最近使用的前列腺癌基因治疗程序包括纠正异常基因表达，利用程序性细胞死亡机制和生物途径，专门针对重要的细胞功能，启动突变或细胞溶解自杀基因，加强免疫系统抗癌反应，以及将治疗与放射疗法或疗法结合起来。化疗 [ 166]. 前列腺癌基因治疗的动物研究利用了基因治疗递送系统的前列腺内给药。已发现这种给药途径更有效，因为大部分剂量直接输送到前列腺。这种靶向递送允许给药剂量达到前列腺癌转移。乳铁蛋白和转铁蛋白是多功能蛋白，可以与通常在前列腺癌细胞上过度表达的铁结合蛋白结合 [ 167 ]]. 这些蛋白质负责调节游离铁水平。高铁水平具有负面副作用，例如增加细菌感染的风险，以及产生自由基和促进氧化态亚铁离子 (Fe2+) 向三价铁离子 (Fe3+) 的转化。各种动物研究已经使用转铁蛋白和乳铁蛋白主动靶向前列腺癌细胞。前列腺干细胞抗原 (PSCA) 是一种细胞表面抗原，在雄激素依赖性和雄激素非依赖性前列腺癌细胞中表达；因此，它可以用作前列腺癌的标志物。人表皮生长因子受体 2 (HER2) 是另一种配体，由于突变导致肿瘤细胞过度表达，可用作靶向治疗前列腺癌的标志物 [ 168 ]]. 对前列腺癌诱导的异种移植小鼠模型进行的一项研究表明，通过特异性靶向肿瘤起始细胞来抑制 HER2 和表皮生长因子受体 (EGFR)，可以显着提高化疗治疗去势抵抗性前列腺癌的疗效，并激活 STAT3 ，并且可以防止转移 EGF 诱导的 STAT3 磷酸化，这是导致前列腺癌转移的原因[ 169，170]. 各种基因打靶系统已经对使用编码 IL12 的 DAB-Lf 树状复合物进行免疫反应治疗进行了实验，这表明 PC3 和 DU145 前列腺肿瘤的肿瘤显着减少。MiRNA (miR)-205、miR-455-3p、miR-23b、miR-221、miR-222、miR-30c、miR-224 和 miR-505 在前列腺癌患者中下调，并且已知与前列腺癌相关前列腺癌细胞中的肿瘤抑制因子，影响增殖、侵袭和有氧糖酵解。MiR-663a 和 miR-1225-5p 与前列腺癌的发展有关，显示出用作候选标记物的潜力。miR-663a 和 miR-1225-5p 在刺激前列腺癌生长和肿瘤进展中的具体功能尚不清楚 [ 171 , 172 , 173 ]。2.12. CRISPR Cas9 成簇的规则间隔短回文重复序列 (CRISPR)/CRISPR 相关蛋白 9 (Cas9) 是一种在古细菌和细菌中发现的天然防御机制。由于其简单性和有效性 [ 145 ] ，该系统目前正在被广泛研究。靶向特定基因治疗载体的前列腺内接种的能力是基于免疫治疗和细胞毒性基因治疗方法的优势。由于 DNA 序列的变化会导致导致癌症的突变，科学家们一直对通过操纵 DNA 来纠正此类变化的新方法感兴趣 [ 174 ]]. 成簇的规则间隔短回文重复 (CRISPR)/CRISPR 相关蛋白 9 (Cas9) 系统使用单向导 RNA (sgRNA) 通过 Watson–Crick 碱基配对识别和结合某些 DNA 序列 [ 175]. CRISPR 和 CRISPR-Cas9（CRISPR-associated 9）系统已被广泛研究，并改变了生物系统的研究。CRISPR 允许通过启动双链断裂精确改变、插入或删除目标 DNA 序列中的 DNA 核苷酸。引导 RNA 与 Cas9 结合，将其引导至互补的 DNA 靶序列，在该序列中插入双链断裂以修复或编辑 DNA 核苷酸。CRISPR 还可用于从癌细胞和致癌病毒的 RNA 中检测 DNA。CRISPR/Cas9 在基于脂质的纳米颗粒载体中的递送更安全有效 [ 176]. 脂质体载体具有广泛的优势和修饰，可以直接控制脂质体表面的物理化学性质，并且可以适应靶向配体的缀合。最初开发了脂质纳米颗粒 (LNP) 的抗体靶向递送系统，并针对小干扰 RNA (siRNA) 的靶向治疗进行了标准化。最近，LNP 被用于概念验证研究，以使用 CRISPR/Cas9 靶向小鼠体内的播散性卵巢癌 [ 177]. Ye 等人于 2017 年开展的一项研究分析了 GPRC6A 在体外和动物研究中前列腺癌进展中的功能。该研究表明 GPRG6A 在人类前列腺癌细胞系中表达，并且还显示出改善 mTOR 信号传导的多态性。成簇规律间隔的短回文重复 (CRISPR) 和 CRISPR 相关蛋白 9 核酸酶 (Cas9) (CRISPR/Cas9) 用于中断 PC-3 细胞系中的 GPRC6A 基因。结果表明，使用 CRISPR/Cas9 编辑 GPRC6A 基因可在体外停止细胞增殖和迁移，并且骨钙素还可以激活 ERK、AKT 和 mTOR 信号通路。在动物研究中发现 GPRC6A 基因主要通过评估在具有表达 GPRC6A 基因或 CRISPR/Cas9 介导的基因缺失的细胞的人前列腺癌异种移植模型中对骨钙素的反应来介导前列腺癌的进展。该研究的结果支持使用 CRISPR 作为潜在的治疗靶点 [178 ]。转移性 PCa 模型中的第一个基因组规模 CRISPRi 筛选表明驱动蛋白家族成员 4A (KIF4A) 和 WD 重复结构域 62 (WDR62) 启动侵袭性 PCa。前列腺特异性细胞系中的 CRISPR 筛选也提供了前列腺癌的新靶标，这也表明评估其他癌细胞结果的重要性，这可能会导致发现用于前列腺癌治疗的生物标志物 [ 179 ]。2.13. 纳米技术 纳米技术是结合了药理学、生物医学科学和纳米技术的综合领域。纳米粒子具有允许药效的特性，可以很容易地穿透肿瘤，防止药物降解，并且可以被修饰以靶向特定组织 [ 170 ]。纳米粒子如脂质体、聚合物、金属纳米材料和多孔硅纳米粒子已被广泛研究用于前列腺癌的治疗和预后。主动靶向纳米粒子的表面经过修饰，附着有抗体、亲和体、肽或寡糖。这些靶向配体靶向癌细胞上的受体细胞，例如前列腺癌细胞上的前列腺特异性膜抗原 (PSMA) 受体 [ 180 ]]. 由于当前使用的治疗面临的挑战，人们对开发用于前列腺癌治疗的纳米颗粒很感兴趣。在纽约西奈山对 16 名患者进行的一项研究使用金二氧化硅纳米粒子治疗局部前列腺癌。金二氧化硅纳米粒子吸收波长可以穿透生物组织的红外光。金纳米粒子具有等离子体共振，可以大大减少与治疗相关的副作用。通过激光消融为患者静脉注射金纳米颗粒。在治疗 48 和 72 小时后，使用磁共振成像分析肿瘤的生长情况。结果显示肿瘤大小减小且无副作用。虽然只有少数研究进入临床试验阶段，155 ]。与癌症治疗中的脂质体药物递送相关的临床前和临床改进结果表明，脂质体封装预示着前列腺癌治疗的积极前景。纳米载体已被证明可用于联合治疗，因为它们能够克服化疗药物的药代动力学差异 [ 173 ]]. 将纳米技术与其他治疗策略相结合，可以有效地增强和提高药物的疗效。在前列腺癌中，纳米技术用于诊断和治疗。纳米粒子不仅是有效的递送系统，而且还提高了难溶性药物的溶解度，多功能纳米粒子对泌尿系统癌症、膀胱癌、肾癌和前列腺癌显示出足够的特异性。在 Zhang 等人进行的一项研究中，多西紫杉醇和多柔比星在纳米颗粒中的包封增加了在前列腺癌细胞中观察到的细胞毒性 [ 180 ]]. 另一项旨在评估纳米载体对多柔比星 (DOX) 和多西紫杉醇 (DOC) 的协同递送协同作用的研究表明，纳米颗粒中的抗癌药物 DOX 和 DOC 协同作用，促进了 Dox 和 Doc 在异种移植小鼠中的疗效模型，作用于雄激素依赖性和雄激素非依赖性前列腺癌细胞系 [ 181]. 一项由 42 名接受醋酸阿比特龙和/或恩杂鲁胺治疗的进展性 mCRPC 患者组成的多中心 II 期开放标签临床试验研究了靶向前列腺特异性膜抗原 (PSMA) 的含多西紫杉醇的纳米颗粒 (BIND-014) 的安全性和有效性在转移性去势抵抗性前列腺癌中。通过前列腺特异性膜抗原 (PSMA) 缀合的纳米颗粒靶向递送多西他赛被发现在临床上有效，可显着减少循环肿瘤细胞 [ 182 ]]. 一种在接种磁性纳米颗粒后加热肿瘤的现代方法已在前列腺癌临床试验中得到广泛研究。在单独使用磁性纳米粒子热疗或与永久性种子近距离放射治疗相结合的研究中，使用交变磁场施加器的第一个原型评估了可行性和耐受性。结果报告称，磁性纳米粒子热疗已被证明是高温疗法，对热消融温度有效，并且可以在 4–5 kA/m 的低磁场强度下在前列腺中实现[ 183、184 ]。2.14. 下一代测序 最近，下一代测序 (NGS) 技术的发展已被证明是记录独特基因改变的重大进步，这些改变提高了我们对癌细胞生物学的理解 [ 185 ]。精准医疗，也称为个性化医疗，致力于制定个性化的治疗计划，并摒弃“一刀切”的治疗方法 [ 186 ]。NGS 支持个性化治疗的发展，这不仅增加了我们对癌症的了解，还为肿瘤学家提供了一个强大的工具来了解每位患者的疾病及其独特的遗传特征和全基因组突变状态[ 187、188 ]]. NGS 可以通过单核苷酸分辨率识别肿瘤特异性改变 [ 189 ]。NGS 技术是全基因组、全外显子组、RNA、还原代表性亚硫酸氢盐和染色质免疫沉淀测序。NGS 的三个关键阶段是文库制备和扩增、测序和数据分析 [ 190]. 尽管长期以来一直使用 Sanger 测序和 PCR 方法来检查肿瘤生物标志物，但 NGS 的发展使得在一次测试中筛选更多基因成为可能。随后开发了预测性生物标志物，以帮助选择合适的患者群体进行临床研究。此外，NGS 使研究人员能够识别最普遍的已知变异以及发生在不到 1% 患者身上的不常见突变的长尾，并且可以提供有关治疗敏感性的有用数据 [ 187 ]。 NGS 在 PC 基因组学中的应用显着推进了对癌症中发生的所有 DNA 改变的系统分类 [ 188 ]。RNA 测序的使用极大地帮助了 PC 中新型长链非编码 RNA 和新型基因融合的鉴定和生产。这导致发现了已经确定的新的复发性改变，即 TMPRSS2-ERG 易位、SPOP 和 CHD1 突变以及染色体复杂性，并且之前已经确立的途径也得到了验证（例如，雄激素受体过度表达和突变；PTEN、RB1 和 TP53 丢失/突变）[ 189、190 ]。由于 NGS [ 191 ]，DNA 测序现在更加灵敏和可扩展]. 由于其高度多样化的性质，PC 在诊断和预后方面继续提出重大挑战 [ 192 ]。为了更准确地确定癌症的侵袭性，应将临床病理学和放射学数据与从 NGS 调查中收集的知识相结合[ 193、194 ]。尽管对 NGS 的益处寄予厚望，但应考虑该方法的许多局限性 [ 194 ]。首先，有有效的论据反对 NGS 取代已建立并得到充分支持的组织病理学诊断。尽管 NGS 通常可用于识别和分型各种癌症实体，但始终应首先进行准确的病理检查 [ 195]. 其次，来自肿瘤活检的 NGS 只能提供整个肿瘤的有限时间和地理分辨率，因为它只能评估特定时间点一小群肿瘤细胞中的 DNA 和 RNA 变化 [ 196 ]。这个问题可以从多个角度来解决，包括通过新技术提高空间分辨率、单细胞测序、循环游离核酸或肿瘤细胞的系列分析，或者通过功能研究务实地关注特定目标的可操作性 [ 197]. 第三，NGS 产生的支持临床决策的“大数据”的分析和临床解释所需的软件工具的创建仍然落后于目前用于其计算、管理和存储的硬件基础设施 [ 198 ]。此外，需要大量的生物信息学工作来直接比较在各种 NGS 平台上获得的数据以及通过各种生物信息学管道和算法评估的数据。因此，NGS 和精准肿瘤学的成功在很大程度上取决于各方之间的有效沟通和建设性团队合作 [ 199 ]。3.结论 前列腺癌是全球男性死亡的主要原因之一，仅次于肺部疾病。与前列腺癌发展风险增加相关的常见突变基因、蛋白质和通路可用作该疾病的生物标志物，它提供有关癌症分期和病因的信息。生物标志物还可以给出癌症所需治疗类型的规格。迫切需要针对前列腺癌的有效且有针对性的特异性治疗。目前可用于前列腺癌的治疗仅对少数患者有益，并且存在许多最终影响大多数患者生活质量的副作用。化疗、放疗和激素治疗具有不良副作用，包括耐药性，这仍然是抗癌治疗的障碍。许多药用植物、基因疗法、纳米技术目前在研究中的应用已被证明可以减少副作用并恢复耐药肿瘤细胞的化学敏感性。药用植物组分和化合物、封装在目标特异性纳米载体中的可控释放遗传物质以及基于细胞通路的靶向疗法似乎是前列腺癌治疗的有前途的替代方案。