This study aims to evaluate safety and effect of combining an oncolytic adenovirus (delolimogene mupadenorepvec; LOAd703) with atezolizumab in patients with melanoma. LOAd703 will be administered intratumorally for up to 12 injections while atezolizumab will be administered intravenously for the duration of the active study visits (up to 57 weeks). The patients are then monitored for survival for maximum study participation of 48 months. The treatments will be given every 3 weeks. The patients will then be monitored for toxicity, PK, ADA, immune responses, virus shedding, tumor response by RECIST 1.1 and survival.

开始日期2020-01-28

申办/合作机构

Lokon Pharma AB

[+1]

NCT03555149

/ Terminated临床1/2期

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC)

A phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with metastatic colorectal cancer (mCRC) that became refractory to first- and second-line standard therapies. Eligible patients will be assigned to one of several treatment arms.

开始日期2018-09-27

申办/合作机构-

NCT03225989

/ Completed临床1/2期

Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer

This Phase I/II trial evaluates LOAd703 in patients with cancer (pancreatic, biliary, colorectal or ovarian) together with their standard of care chemotherapy or using gemcitabine immune-conditioning. LOAd703 is administered by intratumoral image-guided injections. Maximum 50 patients can be enrolled.
LOAd703 is an immunostimulatory gene therapy using an selection replication competent adenovirus as a gene vehicle. The virus is derived from serotype 5 adenovirus with the fiber from serotype 35. It expresses the transgenes trimerized membrane-bound isoleucine zipper (TMZ) TMZ-CD40L and 41BBL under control of a cytomegalovirus (CMV) promoter.

开始日期2018-03-01

申办/合作机构

Lokon Pharma AB

[+1]

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项与 Delolimogene mupadenorepvec 相关的文献（医药）

2024-04-01·The Lancet. Oncology

LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study

Article

作者: Musher, Benjamin L ; Leen, Ann M ; Sandin, Linda C ; Patel, Kalpesh ; Ullenhag, Gustav J ; Jing, James ; Othman, Mohamed ; Jawaid, Salmaan ; Hilsenbeck, Susan G ; Wu, Mengfen ; Loskog, Angelica S I ; Rowinsky, Eric K ; Wenthe, Jessica ; Eriksson, Emma ; Grilley, Bambi ; Brisco, Amanda ; Smaglo, Brandon G ; Abidi, Wasif ; Brenner, Malcolm K ; Leja-Jarblad, Justyna

BACKGROUND:

Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma.

METHODS:

LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m² plus gemcitabine 1000 mg/m² (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 μL of LOAd703 at 5 × 10¹⁰ (dose 1), 1 × 10¹¹ (dose 2), or 5 × 10¹¹ (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants.

FINDINGS:

Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8⁺ effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response.

INTERPRETATION:

Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing.

FUNDING:

Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council.

2021-10-01·Cancer immunology, immunotherapy : CII2区 · 医学

Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy

2区 · 医学

Article

作者: Eriksson, Emma ; Wikström, Kristina I ; Enblad, Gunilla ; Lövgren, Tanja ; Wenthe, Jessica ; Labani-Motlagh, Alireza ; Loskog, Angelica ; Naseri, Sedigheh

Abstract:

Pretreatment of B-cell lymphoma patients with immunostimulatory gene therapy using armed oncolytic viruses may prime tumor lesions for subsequent chimeric antigen receptor (CAR) T-cell therapy, thereby enhancing CAR T-cell functionality and possibly increasing response rates in patients. LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus (serotype 5/35) that encodes for the transgenes CD40L and 4-1BBL, which activate both antigen-presenting cells and T cells. Many adenoviruses failed to demonstrate efficacy in B-cell malignancies, but LOAd703 infect cells via CD46, which enables B cell infection. Herein, we investigated the therapeutic potential of LOAd703 in human B-cell lymphoma models, alone or in combination with CAR T-cell therapy. LOAd703 could infect and replicate in B-cell lymphoma cell lines (BC-3, Karpas422, Daudi, DG-75, U-698) and induced an overall enhanced immunogenic profile with upregulation of co-stimulatory molecules CD80, CD86, CD70, MHC molecules, death receptor Fas and adhesion molecule ICAM-1. Further, CAR T-cell functionality was boosted by stimulation with lymphoma cells infected with LOAd703. This was demonstrated by an augmented release of IFN-γ and granzyme B, increased expression of the degranulation marker CD107a, fewer PD-1 + TIM-3+ CAR T cells in vitro and enhanced lymphoma cell killing both in in vitro and in vivo xenograft models. In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.

2020-12-01·Cancer gene therapy2区 · 医学

Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40

2区 · 医学

Article

作者: Wenthe, Jessica ; Hellström, Ann-Charlotte ; Wiklund, Helena Jernberg ; Loskog, Angelica ; Eriksson, Emma ; Naseri, Sedigheh

Abstract:

Multiple myeloma (MM) is a plasma cell malignancy that is characterized by immune dysregulation. MM is commonly treated with immunomodulating agents, but still remains incurable. Herein, we proposed and evaluated immunostimulatory Lokon oncolytic adenoviruses (LOAd) for MM treatment. LOAd viruses are serotype 5/35 chimera, which enables infection of hematopoietic cells. Oncolysis is restricted to cells with a dysregulated retinoblastoma protein pathway, which is frequently observed in MM. Further, LOAd viruses are armed with human immunostimulatory transgenes: trimerized membrane-bound CD40L (LOAd700, LOAd703) and 4-1BBL (LOAd703). LOAd viruses were assessed in a panel of MM cell lines (ANBL-6, L363, LP-1, OPM-2, RPMI-8226, and U266-84). All cells were sensitive to infection, leading to viral replication and cell killing as analyzed by quantitative PCR and viability assay. Transgene expression was verified post infection with flow cytometry. Cell phenotypes were further altered with a downregulation of markers connected to MM progression (ICAM-1, CD70, CXCL10, CCL2, and sIL-2Rα) and an upregulation of the death receptor Fas. In a co-culture of immune and MM cells, LOAd viruses promoted activation of cytotoxic T cells as seen by higher CD69, CD107a, and IFNγ expression. This was most prominent with LOAd703. In conclusion, LOAd viruses are of interest for MM therapy.

项与 Delolimogene mupadenorepvec 相关的新闻（医药）

2025-05-19

·PRNewswire

Intra-tumoral Cancer Therapies Market to Show Tremendous Growth at a CAGR of 31.3% During the Study Period (2020-2034) | DelveInsight

As per DelveInsight's estimates, among the 7MM, the US captured the highest market of intra-tumoral cancer therapies of nearly USD 74 million in 2024, which is expected to increase due to the launch of emerging therapies such as CAN-2409, RP1 (vusolimogene oderparepvec), SP-002 (ASN-002), Bizaxofusp (MDNA55), and others. LAS VEGAS, May 19, 2025 /PRNewswire/ -- DelveInsight's Intra-tumoral Cancer Therapies Market report includes a comprehensive understanding of current treatment practices, emerging intra-tumoral cancer therapies, market share of individual therapies, and current and forecasted intra-tumoral cancer therapies market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Key Takeaways from the Intra-tumoral Cancer Therapies Market Report Currently, only three Intra-tumoral Cancer Therapies are approved; namely, IMLYGIC (Talimogene laherparepvec/T-VEC; Amgen), approved in the US and Europe in 2015, DELYTACT (teserpaturev/G47Δ; Daiichi Sankyo) approved in Japan in 2021, and HENSIFY in Europe in 2019. As per DelveInsight's analysis, the total market size of intra-tumoral cancer therapies in the 7MM was USD 109 million in 2024 and is projected to grow during the forecast period (2025-2034). In 2024, the total cases of selected indication (based on current landscape and pipeline activity) were 8.9 million in the 7MM, which is anticipated to increase by 2034. Leading intra-tumoral cancer therapies companies, such as Janssen, Stamford Pharmaceuticals, Ascend Biopharmaceuticals, Replimune, Highlight Therapeutics, Cytovation ASA, Intensity Therapeutics, Ascendis Pharma, Treovir, Matica Biotechnology, QBiotics, NanOlogy, Lokon Pharma AB, EpicentRx, Medicenna Therapeutics, Philogen S.p.A., Candel Therapeutics, Lytix Biopharma, Verrica Pharmaceuticals, CEI-SCI, and others, and others, are developing novel intra-tumoral cancer therapies that are expected to enter the intra-tumoral cancer therapies market in the coming years. Some of the key intra-tumoral cancer therapies in the pipeline include INT230-6, Vusolimogene oderparepvec (RP1), Nidlegy (Daromun), G207, Ilixadencel (INTUVAX), Tigilanol tiglate, SP-002 (ASN-002), BO-112, Bizaxofusp (MDNA55), and others. In March 2025, NANOBIOTIX announced topline data from the completed dose-escalation portion of a Phase I study, conducted under the sponsorship of The University of Texas MD Anderson Cancer Center, evaluating JNJ-1900 (NBTXR3) activated by radiation therapy as a second-line or later (2L+) treatment for patients with locally advanced NSCLC eligible for re-irradiation. In March 2025, NANOBIOTIX announced an amendment to its global licensing agreement with Janssen Pharmaceutica NV. The amendment removes NANOBIOTIX's funding obligation for NANORAY- 312 and releases Johnson & Johnson from select future potential milestone payments while safeguarding NANOBIOTIX's path to sustainable cash flow through significant potential milestone payments. In March 2025, Candel Therapeutics and IDEA Pharma announced a strategic commercial partnership. Under this agreement, IDEA will provide strategic commercial input throughout the development and commercialization process for Candel's lead asset, CAN-2409. In January 2025, Lokon Pharma AB announced that the Food and Drug Administration (FDA) had granted Fast Track Designation (FTD) for the company's product candidate LOAd703 for the treatment of pancreatic cancer. In January 2025, Intensity Therapeutics announced that the Data Monitoring Committee (DMC) recommended the continuation of its Phase III sarcoma trial (INT230-6, INVINCIBLE-3) without modification based on data reviewed from July 2024 to December 2024. Some factors, such as the precedence of failure of emerging therapies, insufficient knowledge about Intra-tumoral Cancer Therapies , and several other drawbacks, might hinder the Intra-tumoral Cancer Therapies market growth. Discover which therapies are expected to grab the intra-tumoral cancer therapies market share @ Intra-tumoral Cancer Therapies Market Report Intra-tumoral Cancer Therapies Market Dynamics The intra-tumoral cancer therapies market dynamics are expected to change in the coming years. Various classes of intra-tumoral immunotherapies, including radioenhancer nanoparticles, recombinant fusion proteins, oncolytic therapy, gene therapy, synthetic dsRNA complexes, and others, are currently in preclinical and clinical development. These therapies increase drug concentration and availability within the tumor microenvironment while limiting systemic exposure and reducing the likelihood of immune-related side effects in other parts of the body. Intra-tumoral therapeutic strategies offer a powerful approach to in situ vaccine development, utilizing immune-stimulating agents to trigger local and systemic anti-tumor immune responses. Additionally, the ability of intra-tumoral immunotherapy combinations to elicit both T-cell and B-cell antitumor responses presents a potential strategy to overcome immune escape mechanisms, such as the loss of HLA-I expression on tumor cells, which are often associated with immune checkpoint therapy monoclonal antibody monotherapies. Furthermore, potential therapies are being investigated, and it is safe to predict that the treatment space will significantly impact the intra-tumoral cancer therapies market during the forecast period. Moreover, the anticipated introduction of emerging therapies with improved efficacy and a further improvement in the diagnosis rate are expected to drive the growth of the intra-tumoral cancer therapies market in the 7MM. However, several factors may impede the growth of the intra-tumoral cancer therapies market. The lack of standardized guidelines for intra-tumoral immunotherapy delivery results in variations in lesion selection, injection frequency, and needle technique, which directly affect treatment outcomes and safety. Patients are required to visit clinics for each dosing session, and the administration necessitates both trained radiologists and logistics support alongside skilled physicians. While research into intra-tumoral therapies has grown in recent years, several therapies, such as tilsotolimod/Ipilimumab, sotigalimab (APX005M), and vidutolimod (CMP-001), have failed clinical trials, impacting the market. Additionally, tumors with high intra-tumoral heterogeneity may lead to poorer clinical outcomes for patients. Intra-tumoral Cancer Therapies Therapeutics Market Although significant progress has been made in cancer treatment through methods like surgery, chemotherapy, radiation, immunotherapy, and targeted therapies, many of these treatments still face limitations such as systemic toxicity, inadequate tumor penetration, and poor targeting. These issues contribute to high mortality rates, underscoring the need for more precise and localized treatment options. Recently, cancer treatment strategies have increasingly focused on alternative delivery methods, including intra-tumoral administration. This approach is being actively researched, with several therapeutic candidates—such as immune receptor agonists, viral therapies, fusion proteins, monoclonal antibodies, and gene therapies—currently undergoing preclinical and clinical trials. Intra-tumoral immunotherapy, which involves directly delivering agents into or near the tumor site, is emerging as a promising approach. This strategy aims to boost localized immune responses while reducing systemic side effects. The first oncolytic virus, IMLYGIC (T-Vec; Amgen), was approved by the US FDA for treating unresectable melanoma lesions after surgery, following a Phase III trial. The European Commission approved the treatment of advanced melanoma in 2015. In 2019, Nanobiotix's HENSIFY (NBTXR3), a hafnium oxide nanoparticle therapy combined with radiation, received European approval for soft tissue sarcoma, with plans for data releases through 2025-2026 across multiple cancers. For STS the drug is approved in Europe but not yet launched. In Japan, DELYTACT (G47∆; Daiichi Sankyo) was granted conditional approval for malignant glioma, marking the first oncolytic virus for brain cancer, and is still under evaluation for its clinical benefits. IMLYGIC from Amgen is the first and only FDA-approved viral therapy that is injected directly into melanoma tumors. Despite the initial hype for this exciting intra-tumoral mode of cancer gene therapy, IMLYGIC's debut did not translate into much commercial success in the melanoma market. Limitations of the intra-tumoral administration, no statistically significant benefit in overall survival (OS), and the intense competition from immune checkpoint inhibitors (ICIs) due to their efficacy and manageable side effects are some of the main factors for ithe nsignificant revenues of this novel therapy. Learn more about the FDA-approved intra-tumoral cancer therapies @ Intra-tumoral Cancer Therapies Treatment Key Emerging Intra-tumoral Cancer Therapies and Companies The emerging pipeline of intra-tumoral cancer therapies is robust, including drugs from key players such as Candel Therapeutics (CAN-2409), Lytix Biopharma/Verrica Pharmaceuticals (LTX-315 [VP-315]), CEI-SCI (MULTIKINE), Philogen (Daromun [NIDLEGY; a combo of L19IL2 + L19TNF]), Replimune (RP2 and RP1 [vusolimogene oderparepvec]), Highlight Therapeutics (BO-112), Cytovation ASA (CY-101), Intensity Therapeutics (INT230-6), Ascendis Pharma (TransCon IL-2 β⁄γ), Treovir/Matica Biotechnology (G207), QBiotics (Tigilanol tiglate), NanOlogy (NanoPac), EpicentRx (AdAPT-001), Medicenna Therapeutics (Bizaxofusp [MDNA55]), and others. RP1 (vusolimogene oderparepvec), Replimune's lead product candidate, is based on a proprietary strain of Herpes Simplex Virus (HSV) engineered with a fusogenic protein (GALV-GP R-) and GM-CSF to enhance tumor killing potency, immunogenicity, and activation of a systemic antitumor immune response. In November 2024, Replimune announced that the FDA granted Breakthrough Therapy Designation (BTD) to RP1 in combination with nivolumab for the treatment of advanced melanoma in adult patients who have previously received an anti-PD1 regimen. Nidlegy is a biopharmaceutical product, proprietary to Philogen, designed for the treatment of skin cancer. It consists of two active ingredients, L19IL2 and L19TNF, which are manufactured independently and which are mixed prior to intralesional administration. In July 2024, Philogen and Sun Pharmaceutical announced that the European Medicines Agency (EMA) validated the submission of the Marketing Authorization Application (MAA) for Nidlegy. CAN-2409 (Candel Therapeutics) is an investigational, off-the-shelf, replication-defective adenovirus designed to deliver the HSV thymidine kinase (HSV-tk) gene to a patient's specific tumor and induce an individualized, systemic immune response against the tumor. In March 2025, according to the company's corporate highlights, the preparations for Biologics License Application (BLA) for CAN-2409 in prostate cancer are underway, with submission expected in Q4 2026. The anticipated launch of these emerging therapies are poised to transform the intra-tumoral cancer therapies market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the intra-tumoral cancer therapies market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. To know more about intra-tumoral cancer therapies clinical trials, visit @ Intra-tumoral Cancer Therapies Intra-tumoral Cancer Therapies Overview Cancer is a highly diverse disease, with its signs, symptoms, and treatments varying across different types, making it crucial to create targeted therapies for individual patients. Current treatment options for cancer include immunotherapy, radiotherapy, chemotherapy, targeted drug therapies, and more. While these approaches have improved OS and patient outcomes, they still have limitations and are not effective for everyone. Researchers are therefore working to develop new treatments that can overcome these challenges, with intra-tumoral cancer therapies emerging as a promising strategy. Intra-tumoral immunotherapy represents an innovative approach, where sophisticated antibodies are directly injected into tumors instead of being administered intravenously. This method focuses on delivering immunostimulatory agents straight into primary or metastatic tumor sites to initiate or enhance an antitumor immune response. Normally, the immune system detects and eliminates early tumors, but in immunosuppressive tumor environments, malignant cells can proliferate undetected. Regulatory T cells (Tregs), drawn to the tumor by chemokines, suppress Antigen-Presenting Cells (APCs) that would otherwise trigger an immune attack on tumor antigens. Moreover, tumor cells often release anti-inflammatory and regulatory cytokines like TGF-β and IL-10, which promote tumor growth and inhibit dendritic cell (DC) activation. To counteract this immunosuppressive environment, immunostimulants can be introduced. These agents work by attracting immune cells to the tumor or by activating the immune system to recognize and destroy cancer cells. Immunostimulants activate immune cells in the presence of tumor antigens, allowing them to travel to lymph nodes, where they stimulate tumor antigen-specific T cells through cross-presentation. These activated T cells can then return to the tumor or spread to distant tumors, leading to the targeted destruction of cancer cells. Intra-tumoral Cancer Therapies Epidemiology Segmentation In 2024, the total indication-wise treated cases of Intra-tumoral Cancer Therapies were 3.3 million in the 7MM, which is anticipated to increase by 2034. The intra-tumoral cancer therapies market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Cases of Selected Indications Indication-wise Target Patient Pool of Intra-tumoral Cancer Therapies Indication-wise Treated Cases of Intra-tumoral Cancer Therapies Scope of the Intra-tumoral Cancer Therapies Market Report Intra-tumoral Cancer Therapies Therapeutic Assessment: Intra-tumoral current marketed and emerging therapies Intra-tumoral Cancer Therapies Market Dynamics: Conjoint Analysis of Emerging Intra-tumoral Cancer Therapies Competitive Intelligence Analysis: SWOT analysis and Market entry strategies Unmet Needs, KOL's views, Analyst's views, Intra-tumoral Cancer Therapies Market Access and Reimbursement Discover more about intra-tumoral cancer therapies in development @ Intra-tumoral Cancer Therapies Clinical Trials Table of Contents Related Reports Oncolytic Virus Market Oncolytic Virus Market Size, Target Population, Competitive Landscape & Market Forecast – 2034 report deliver an in-depth understanding of oncolytic virus, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key oncolytic virus companies, including Targovax, Genelux, Imugene, EpicentRx, Replimune, Genelux Corporation, Candel Therapeutics, DNAtrix, SillaJen, Treovir, Lokon Pharma AB, Istari Oncology, CG Oncology, Amgen, Daiichio Sankyo, among others. 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About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法临床3期上市批准快速通道引进/卖出

2025-03-03

·行舟Drug

新型抗肿瘤药物的神经毒性研究进展

点击上方的行舟Drug ▲ 添加关注近年来，肿瘤诊疗技术快速发展，靶向治疗、免疫治疗、代谢治疗、基因治疗等肿瘤治疗产品不断获批上市。抗肿瘤新疗法为患者提供了更加个体化的治疗方案，具有更好的临床疗效，但嵌合抗原受体-T细胞（CAR-T）药物、抗体偶联药物（ADC）等多种抗肿瘤新药被报道具有神经系统不良反应，可导致中枢和周围神经系统损伤，神经毒性作为抗肿瘤药物主要的剂量限制性副作用，依然是抗肿瘤新药研究及临床转化的一大障碍。传统化疗药物主要诱发周围神经病变，其神经毒性不但与其原有细胞毒性有关，也涉及轴突损伤、神经炎症、氧化应激等多个过程[1]。细胞治疗药物、基因治疗药物、抗体类治疗药物等新型抗肿瘤药物除了可能导致周围神经病变外，还可能引起其他类型的神经系统问题。一些新型抗肿瘤疗法通过激活机体免疫发挥治疗作用，部分被激活的免疫细胞和细胞因子能够更好地穿过血脑屏障，增加中枢神经毒性风险；癌症治疗也可能通过多种机制引起继发性中枢神经系统损伤，如药物治疗引起的免疫抑制可导致脑膜炎、多瘤病毒重激活[2]。此外，传统化疗药物与新型抗肿瘤药物的治疗措施也有所不同。本文就抗肿瘤药物神经毒性评估及新型抗肿瘤药物神经毒性临床表现、毒性机制、治疗措施的研究进展进行总结分析，为临床新型抗肿瘤药物的安全使用提供参考。 1 抗肿瘤药物神经毒性评估的一般原则 1.1 临床评估神经毒性是抗肿瘤药物常见的不良反应之一，及早识别治疗相关的神经毒性，可及时改善神经系统症状，避免永久性神经损伤和非必要的治疗终止。抗肿瘤药物的神经毒性评估是一种排除性诊断[2]，确定神经毒性是否由癌症治疗引起，首先要了解药物治疗和毒性作用之间是否存在时间关系，排除与癌症转移以及其他神经系统疾病相关的神经症状，核磁共振成像和腰椎穿刺脑脊液检查有助于排除其他原因来评估可能与治疗相关的神经毒性。以传统化疗药物为例，确定患者是否患有化疗诱发的周围神经病变（CIPN），就必须对所使用的药物、累积剂量以及神经病变症状的临床特征和时间过程进行分析，患者通常在治疗2个月左右开始出现CIPN，大多数CIPN具剂量相关性，但也存在药物特异性，如紫杉醇和奥沙利铂具急性神经毒性，顺铂停药后会出现神经病变的恶化[3]。结合化疗药物的应用背景和临床症状，CIPN可以被明确诊断，但应注意与其他因素导致的周围神经病变相区别，目前CIPN的临床评估常用EORTC-QLQ-CIPN20评分量表和NCI-CTCAE分级量表，对于合并疼痛、抑郁情绪等症状的患者，建议进行多维度评估[4]。 1.2 临床前评估临床前药物神经毒性评估主要通过体外模型和体内模型实现，对药物或候选化合物进行潜在的神经毒物的早期、高通量筛选，研究药物对神经系统的作用及作用机制。目前常见的体外模型包括神经细胞系（SH-SY5Y、PC12、CG4等）、原代神经细胞、神经干细胞、再聚集脑细胞、类脑器官和器官芯片，体内模型包括哺乳动物（以啮齿类动物为主）和非哺乳动物（线虫、斑马鱼、果蝇等）[5]。目前关于神经毒性临床前评价的标准较少，经济合作与发展组织（Organization for Economic Cooperation and Development，OECD）和美国环境保护署（U.S.Environmental Protection Agency，EPA）对啮齿类动物的神经毒性评价作了详细的规定，概述了神经毒性研究中需要评估的主要终点，包括5个方面，即结构或神经病理学、神经生理学、神经化学、神经行为和神经发育[6-7]。 2 细胞治疗药物神经毒性 2.1 免疫细胞治疗药物过继细胞疗法是近年来肿瘤治疗的研究热点，包括CAR-T疗法、T细胞受体-T细胞（TCR-T）疗法和肿瘤浸润淋巴细胞（TIL）疗法等。细胞因子释放综合征（CRS）、免疫效应细胞相关神经毒性综合征（ICANS）和脱靶效应是其常见的不良反应[8]。 ICANS通常在CRS之后发生，可表现出多种神经系统症状，初期症状为震颤、书写障碍、表达性失语、失用、注意力障碍等，其中表达性失语为特征性症状，随着病程发展，患者可能会出现癫痫发作，极少数患者出现弥漫性脑水肿[9]。据统计，接受CAR-T治疗的患者中有20%～60%会出现ICANS，其中12%～30%的患者表现出严重症状（≥3级）[10]。年龄较大、骨髓系统疾病、神经系统疾病、CRS、肿瘤负荷大、给药剂量过大等因素会增加ICANS的发生[11]。 ICANS的发生机制尚未完全阐明，可能与脑血管内皮活化、血脑屏障受损、CAR-T细胞和细胞因子进入中枢神经系统有关。Santomasso等[12]在发生严重ICANS的患者体内观察到血管生成素（Ang）Ⅱ/Ang Ⅰ值较高，提示ICANS与脑血管内皮活化密切相关。Ang Ⅱ/Ang Ⅰ值增大可导致内皮通透性增加，多种免疫细胞和细胞因子进入血脑屏障，加剧炎症反应，引起神经炎症，并进一步破坏血脑屏障完整性。Juliane等[13]研究发现，在CAR-T治疗诱导神经毒性的过程中，星形胶质细胞受损，脑脊液中白细胞、蛋白质、γ干扰素（IFN-γ）、白细胞介素（IL）-6、IL-10和颗粒酶B（GzB）水平增加，CAR-T治疗可能通过全身性炎症引起星形胶质细胞损伤，进而对大脑产生不利影响。1项包括21名接受CD19 CAR-T治疗的B细胞急性淋巴细胞白血病患者的Ⅰ期临床研究报告称，与未出现神经毒性的患者相比，出现神经毒性的患者脑脊液CD19 CAR-T细胞浓度更高，可能是患者出现神经毒性的原因之一[14]。 2.2 神经干细胞（NSCs）治疗药物 NSCs是存在于中枢神经系统中的一类具分化潜能的细胞，具有肿瘤趋向性及良好的组织穿透能力，经基因工程改造后可作为药物递送系统将多种活性成分递送至病灶部位，既可以用于治疗原发性中枢神经系统恶性肿瘤，也可用于外周系统肿瘤发生的颅内转移的治疗[15]。现有临床前和临床研究数据表明，基于工程化NSCs的药物递送系统未见显著性神经毒性，临床试验中患者出现的神经系统不良反应主要与给药过程产生的损伤及所负载药物的神经毒性有关。 1项关于NSC-CRAd-S-pk7（一种由NSCs递送的工程化溶瘤腺病毒）治疗恶性胶质瘤的临床研究显示，NSCs作为一种药物递送系统用于肿瘤治疗是安全有效的，但接受药物治疗的患者依然出现了神经系统不良反应，包括硬膜下积液及注射失误引起的病毒性脑膜炎[16]。CD-NSCs是一种改造后的NSCs细胞系，可稳定表达胞嘧啶脱氨酶（CD），将原药5-氟胞嘧啶转化为5-氟尿嘧啶，在CD-NSCs重复给药的临床试验中，部分接受治疗的恶性胶质瘤患者出现药物相关的2/3级毒性反应，其中包括脑脓肿和疲劳[17]。值得注意的是，NSCs治疗产品的给药过程常涉及到开颅手术，应注意预防因手术感染引起的神经系统病变。 3 基因治疗药物神经毒性随着RNA干扰、CRISPR技术及mRNA核苷酸碱基修饰等新理论和新技术的出现，基因治疗技术体系不断拓展，除早期的基因替代治疗外，目前还涵盖了基因编辑治疗、经基因修饰的细胞治疗、RNA治疗和溶瘤病毒治疗等[18]。基因治疗对肿瘤的针对性和杀伤性更强，不良反应较小，但仍无法避免神经毒性，对患者的药物耐受和预后有一定影响。近年来，多个肿瘤基因治疗新药获批用于癌症治疗。ARO-HIF2是一种siRNA药物，可用于治疗转移性透明细胞肾细胞癌，在临床研究中，23.1%的受试者出现了与ARO-HIF2相关的神经毒性症状，包括周围神经病、慢性炎症性脱髓鞘多发性神经病和格林-巴利综合征，严重程度较高（≥3级）[19]。Delytact是经改造后的第3代重组1型单纯疱疹病毒（HSV-1）产品，不良反应以发热、恶心、呕吐为主，尽管患者在接受治疗过程中会出现一些神经毒性症状，但严重程度和发生率较低，通常表现为癫痫发作、脑水肿、运动及感觉神经病变、头痛等[20]。基因疗法引发神经毒性的机制尚未完全明确，可能涉及以下几个方面：（1）载体相关毒性。基因治疗通常依赖病毒载体（如溶瘤病毒、腺相关病毒、逆转录病毒）将治疗基因递送到目标细胞，某些病毒载体可能对神经系统具有直接毒性，或者触发免疫反应导致神经炎症，从而影响神经功能。例如，腺相关病毒可引起神经炎症和神经元缺失，并可能扩展到脊髓背侧柱，导致患者出现神经痛等症状[21]。HSV-1是常见的溶瘤病毒载体，野生型HSV-1具有显著的神经毒性副作用，可引起病毒性脑炎，降低患者生存率[22]。（2）脱靶效应相关毒性。某些基因疗法使用的载体可能会将治疗基因递送到非目标组织，导致治疗基因在神经系统中意外表达，可能会导致细胞功能障碍或死亡，引起神经毒性。ARO-HIF2的临床研究数据显示，基质细胞中ARO-HIF2水平较高，表明除肿瘤细胞外的其他细胞也会吸收ARO-HIF2，其神经毒性可能是脱靶效应导致[19]。（3）免疫相关毒性。基因治疗可能激活免疫系统，导致炎症反应，影响神经系统。Benjamin等[23]评估了LOAd703（一种基于溶瘤病毒的免疫刺激基因治疗）联合化疗治疗晚期胰腺导管恶性腺瘤的安全性和可行性，在16名接受治疗后T细胞检测的患者中，94%出现CD8+效应记忆细胞和腺病毒特异性T细胞的比例增加。 4 抗体类药物神经毒性神经毒性是抗肿瘤抗体药物常见的不良反应之一，不同类抗体药物神经毒性的发生率、严重程度和临床症状不同，减量或停药后通常有所缓解，对于本身有神经系统疾病或神经系统损伤的患者来说，神经毒性的发生率和严重程度更高[24]。 4.1 单克隆抗体单克隆抗体仅针对一种特定抗原表位，具有特异性高、亲和力强、血清半衰期长等优点，在肿瘤治疗领域应用广泛，目前已有多个药物获批上市。研究表明，单克隆抗体药物（尤其是靶向肿瘤坏死因子及其受体的单克隆抗体）可引起多发性硬化、视神经炎、外周脱髓鞘神经病等神经系统疾病[25]。1项针对帕博利珠单抗的II期临床研究显示，接受治疗的患者出现了一些神经毒性症状，关节痛、疲惫、无力等发生率大于10%，其中疲惫是最常见的3～4级治疗相关不良反应[26]。研究表明，CD20抗体（利妥昔单抗、替伊莫单抗、奥法木单抗等）引起的神经系统不良反应包括头痛、神经系统病变、脑病、痴呆、中枢神经系统出血、卒中等，与其他药物联用会增加神经毒性风险；CD30抗体（本妥昔单抗）引起的神经系统不良反应包括神经病变、头痛和肌痛/肌病，偶见脑病，3～4级神经病变的发生率为11%，其他严重的神经毒性较少见；CD52抗体（阿仑单抗）神经系统不良反应发生率较低，主要为外周神经病变、脊髓炎、视神经炎、格林-巴利综合征、运动障碍等[24]。单克隆抗体类药物的神经毒性机制有待进一步研究，不同类抗体的神经毒性机制存在差异。某些单克隆抗体可能会与神经细胞的受体或蛋白质直接相互作用，导致神经细胞功能障碍或凋亡。例如，接受本妥昔单抗治疗后，约半数以上患者会出现神经病变，这可能与该抗体与微管蛋白酶结合有关[27]。此外，单克隆抗体的使用可能会引起免疫系统激活，诱导针对神经组织的自身免疫反应，例如CTL4单抗可诱导垂体自身抗体的产生，从而导致垂体功能减退，此外，它还能激活补体依赖的细胞毒性作用（CDC）和抗体依赖细胞介导的细胞毒性作用（ADCC）[28]。 4.2 双特异性抗体（BsAb） BsAb可同时结合2种抗原或同一种抗原的2个不同表位，具备更加优势的生物学效应。目前有许多BsAb药物正在临床试验阶段，BsAb药物的开发由于剂量限制性神经毒性而面临重大挑战[29]。倍利妥是抗CD3和CD19的双特异性T细胞抗体（BiTE），Kantarjian等[30]使用倍利妥治疗晚期急性淋巴细胞白血病，研究数据显示，9.4%的患者出现神经系统不良反应，3级或3级以上神经系统不良事件的发生率与化疗相似，因神经系统不良反应中断治疗的患者比例为4%。1项关于AMG 420（一种抗B细胞成熟抗原的BiTE）的临床研究结果显示，与倍利妥相比，AMG 420的神经毒性发生率相对较低，而且没有中枢神经系统毒性，停药后可缓解，但在每天800 μg的剂量下，神经毒性仍为AMG 420的剂量限制性毒性之一，患者出现严重的3级多发性神经病[31]。特立妥单抗也是一种BiTE，其临床研究报告显示，14.5%的患者出现神经系统不良反应，包括头痛、癫痫发作、ICANs等，研究人员指出，神经毒性是特立妥单抗常见的不良反应，但临床症状通常严重程度较低且可逆[32]。BiTE的神经毒性作用机制尚未完全阐明，T细胞介导的B细胞激活和细胞因子释放破坏了血脑屏障可能是影响因素之一[33]。 4.3 免疫检查点抑制剂（ICIs） ICIs可通过增强内源性免疫反应破坏肿瘤细胞，发挥肿瘤治疗作用。据报道，在接受ICIs治疗的各年龄组患者中，神经系统免疫相关不良事件（n-irAE）的发生率为8%，大多数n-irAE症状轻微，但严重的n-irAE可致残或致死[34]。ICIs引起的n-irAEs可影响中枢和外周神经系统，主要表现为脑膜炎、脑炎、血管炎、脱髓鞘性神经病、多发性神经病、肌炎、神经肌接头紊乱[35]。 ICIs的神经毒性机制尚未完全阐明，目前已提出几种潜在机制。首先，ICIs可阻断调节性T细胞（Tregs），导致Tregs减少，效应细胞增殖并激活，打破机体免疫平衡[36]，其引起的神经毒性症状在自身患有免疫系统疾病的患者中尤为明显[37]。其次，基于对肿瘤细胞和正常细胞共有抗原的交叉反应也可能是诱导神经毒性的机制之一。ICIs可通过针对神经细胞和肿瘤细胞共有抗原的交叉反应性诱导免疫反应，促进免疫介导的副肿瘤神经系统综合征（PNS）[38]。此外，研究者们也提出了其他可能的机制，包括表位扩散、既往感染、微生物组改变以及对表达免疫检查点的细胞系的直接细胞毒性[39]。 4.4 ADC ADC是通过连接子将细胞毒类药物与单克隆抗体进行连接的新型靶向药物。ADC的神经毒性呈剂量相关性，与化疗药物（如顺铂、长春新碱、紫杉醇等）相似，常引起周围神经病变，严重程度多为1～2级，主要临床表现为感觉、运动和自主神经功能异常，包括四肢麻木、刺痛、触觉异常、自发性灼烧样/放射性/电击样疼痛、痛觉异常、肢体远端无力、精细运动受损等[40]。8种最常见的ADC相关神经系统不良反应为周围神经病变、脑出血、周围感觉神经病、多发性神经病、脑病、进行性多灶性白质脑病、味觉障碍和吉兰-巴雷综合症[41]。在靶向CDH6的ADC治疗晚期实体瘤的I期临床研究中，一名患者癫痫发作，另一名患者出现失语症和脑病[42]。在接受MLN2704（一种前列腺特异性膜抗体ADC）治疗的63名前列腺癌的患者中，71%的患者出现周围神经病变[43]。 ADC诱发神经毒性的作用机制与小分子药物的细胞毒性作用密切相关。研究表明，与ADC相关的神经毒性是由细胞毒性有效载荷引起的，与“非肿瘤细胞的靶抗原特异性摄入（靶向相关性）”“非肿瘤细胞的脱靶作用（脱靶相关性）”和“非肿瘤细胞的非靶抗原摄入”3个方面有关[41-44]。一方面，ADC靶向的抗原通常在正常组织细胞中也有表达，导致细胞毒性药物被正常细胞摄取并引起靶向相关性不良反应；另一方面，由于ADC连接子的不稳定性或其他因素，细胞毒药物提前释放，引起脱靶相关性不良反应；此外，某些非肿瘤细胞表面存在与ADC药物抗体Fc段结合的受体，介导药物进入非肿瘤细胞，引起不良反应[40]。 5 抗肿瘤药物神经毒性治疗措施抗肿瘤药物所引起的神经病变通常呈现剂量依赖性，一旦出现神经系统症状，应当及时减少剂量或停药，同时给予相应药物缓解症状。多数神经症状可在停药后减弱或消失，如果药物浓度较高、治疗时间过长，也可能引起不可逆性病变[45]。对于传统铂类化疗药，应用钠通道阻滞药物卡马西平、加巴喷丁等药物能够降低患者神经毒性症状的发生率，应用维生素B1、维生素C等可以改善患者中毒症状[46]。针对新型抗肿瘤药物引起的特殊类型神经系统毒性，需要采用更为个性化的管理方法，比如使用免疫抑制剂治疗由ICIs引发的自身免疫反应。Xiao等[47]提出，临床上可通过优化给药方式和剂量、优化CAR结构来降低CAR-T毒性，减少不良反应的发生。此外，出现ICANS症状的患者可根据严重程度采用不同药物治疗：1级ICANS患者可通过氟哌啶醇或劳拉西泮改善症状；2级ICANS患者，尤其是IL-6抗体治疗无效的患者，可使用地塞米松或甲基强的松龙；3级及以上ICANS患者应转入重症监护室；并发CRS的患者可使用托西珠单抗和IL-6抗体[48]。单克隆抗体药物出现神经毒性症状后应当及时减少药物剂量或停药，同时给予药物治疗，如果毒性为轻度至中度，可口服皮质类固醇；如果毒性较严重，可iv皮质类固醇[49]。对于特立妥单抗引起的不同神经毒性症状，可给予托西珠单抗、地塞米松、左乙拉西坦和加巴喷丁等药物治疗[32]。n-irAEs引起的神经毒性疾病的治疗方法为停用ICIs并使用皮质类固醇，在皮质类固醇耐药的情况下，可考虑iv免疫球蛋白、血浆置换以及使用利妥昔单抗、阿替利珠单抗等药物[35]。使用ADC治疗肿瘤的过程中出现神经毒性症状时，可通过神经毒性问卷评估患者严重程度，根据分级确定个性化护理方案，1～2级通常无需调整剂量，3级及以上需要降低剂量、延长用药间隔或终止治疗，必要时可使用B族维生素、叶酸、烟酰胺、度洛西汀等神经营养药物[40]。 6 结语与展望随着肿瘤学和相关学科的深入研究，多种抗肿瘤新疗法不断出现，纳米制剂、鞘内注射药物等新疗法的潜在神经毒性风险成为研究热点。为了全面应对这一挑战，研究者们从多个角度进行深入研究，包括神经毒性机制、加强监管和评估、调整治疗措施等。不同种类药物引起的神经毒性症状和机制也不同，常见机制包括载体或有效荷载相关毒性、免疫激活介导的自身免疫性反应和炎症反应、脱靶效应及血脑屏障受损等。在临床前新药安全性评价阶段，可采用体内外实验研究各类新型抗肿瘤候选药物的潜在神经毒性及作用机制，进而帮助识别和量化潜在的神经毒性风险，评估候选药物的安全性，为制定初期临床试验的试验方案、给药剂量、患者监测计划以及风险缓解策略提供参考。对临床上接受抗肿瘤药物治疗的患者，在提高疗效的同时要避免药物治疗造成的不可逆性神经损伤[3]。对于出现神经毒性的患者，要及时停药或减少给药剂量，并给予相应药物治疗，以避免更为严重的神经系统损伤。总之，近年来新型抗肿瘤药物研发快、创新品种多，已发现或潜在的神经毒性不良反应成为影响药物获批的重要因素之一，因此，需要研发企业、监管部门对其展开全面且深入的研究和监测。文章信息源于药物评价研究，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug 每日更新欢迎订阅+ 医药大数据|行业动态|政策解读

免疫疗法抗体药物偶联物细胞疗法上市批准基因疗法

2025-02-21

·ioncology

年度盘点丨李恩孝教授：继往开来——2024年胰腺癌领域重磅研究进展

点击蓝字关注我们年度盘点微专辑扫描二维码可查看更多内容编者按春风十里，春景初盛。回首2024年，胰腺癌领域的研究百花齐放，成果斐然。新年伊始，《肿瘤瞭望消化时讯》特邀西安交通大学第一附属医院李恩孝教授为我们梳理过去一年胰腺癌领域的诊疗进展，并展望未来的发展方向。李恩孝教授西安交通大学第一附属医院肿瘤内科学科带头人主任医师，教授，医学博士，博士研究生导师陕西省抗癌协会肿瘤生物治疗专业委员会主委 CSCO理事 CSCO胆道肿瘤专委会副主委、胰腺癌专业委员会委员、 GP-NET专委会常委、中西医结合专委会常委国家卫健委能力建设和继续教育肿瘤学专委会委员中国康复医学会肿瘤康复专委会常委中国老年医学学会肿瘤学分会副会长 CACA肿瘤分子靶向治疗专业委员会，NET专业委员会常委中国研究型医院协会精准医学与肿瘤MDT专业委员会副主委中国医疗保健国际交流促进会消化肿瘤综合诊疗学分会, NET专委会副主委《现代肿瘤医学》《中国肿瘤临床与康复》编委胰腺癌具有高致死率、起病隐匿、进展迅速和预后极差的特点。目前，胰腺癌的5年生存率仅为7%~10%。据GLOBOCAN 2022年的统计数据显示，我国胰腺癌的发病率排名第十，死亡病例为11万，死亡率位居肿瘤相关死亡原因第六位[1]。尽管胰腺癌的基础转化研究和临床研究面临严峻挑战，但多项研究为这一“癌王”的治疗带来了新的希望。指南领航，优化精准治疗策略 2024年美国国家综合癌症网络（NCCN）胰腺癌指南2025.V1版重磅发布[2]，重点更新了精准治疗策略、一线治疗方案及局晚期/转移性疾病的治疗推荐。指南特别强调了使用二代测序（NGS）检测临床上可操作的和/或新出现的突变，以加强靶向治疗的应用。其中包括基因融合（ALK、NRG1、NTRK、ROS1，FGFR2和RET）、基因突变（BRAF、BRCA、KRAS和PALB2）、基因扩增（HER2）、微卫星不稳定性（MSI）、错配修复缺陷（dMMR）及肿瘤突变负荷（TMB）。通过全面的基因组分析，可为患者提供更精准的个体化治疗方案，预测治疗效果并评估预后。多点开花，基于化疗排兵布阵新辅助治疗新辅助治疗在胰腺癌治疗中的地位日益凸显。如何制定有效的治疗方案，以实现肿瘤降期、提高R0切除率、建立药敏平台并改善患者预后，一直是临床探索的重点。 2024 ASCO GI大会公布的Ⅱ期NEO-Nal-IRI研究结果显示[3]，NALIRIFOX方案（伊立替康脂质体+奥沙利铂+5-氟尿嘧啶/亚叶酸钙）用于可切除及临界可切除胰腺癌患者新辅助治疗的客观缓解率（ORR）为45%，疾病控制率（DCR）为73%，R0切除率为90%，且安全性可控。这一结果为胰腺癌的新辅助治疗奠定了良好的基础。一线治疗一线治疗是胰腺癌患者长期生存的关键。2023 ASCO GI大会公布的Ⅲ期NAPOLI-3研究结果显示[4]，NALIRIFOX（伊立替康脂质体+奥沙利铂+5-氟尿嘧啶/亚叶酸钙）对比Gem+NabP（白蛋白紫杉醇+吉西他滨）在无进展生存期（PFS）和总生存期（OS）方面均显示出显著获益。2024 ASCO大会进一步公布了随访29.5个月后的数据[5]，NALIRIFOX组的OS获益持续优于Gem+NabP组，两组12个月和18个月的OS率分别为45.6% vs. 39.6%和26.6% vs. 20.0%（图1）。此外，在临床试验中，NALIRIFOX组腹泻不良发生率较低，且患者耐受性良好。图1. OS获益结果一线治疗中老年胰腺癌患者约占三分之一，但其治疗方案一直缺乏高质量的循证医学证据。2024 ASCO大会公布的Ⅱ期GIANT研究评估了吉西他滨+白蛋白紫杉醇（AG）+5-FU对比亚叶酸钙联合脂质体伊立替康（nal-IRI+5-FU/LV）一线治疗老年转移性胰腺肿瘤的疗效。结果显示[6]，两组患者的OS和PFS获益均无显著差异，且安全性相当。这一研究为老年胰腺癌患者的一线治疗提供了重要参考。二线治疗一线治疗失败后，胰腺癌患者的二线治疗选择有限。目前，多项基于伊立替康脂质体的二线治疗方案正在探索中。 2024 ESMO大会公布的一项Ⅱ期研究显示[7]，伊立替康脂质体联合替吉奥（S-1）用于一线含吉西他滨化疗失败的患者，中位OS为10.3个月，中位PFS为5.7个月，ORR为20.4%，DCR为79.6%，且安全性可控，表现显著的临床获益，同时S-1作为一种口服氟尿嘧啶类药物，可以替代静脉滴注，减轻患者的住院负担和不便。 2024 ESMO大会公布的另一项Ⅰ/Ⅱ期研究进一步比较了伊立替康脂质体联合S-1与联合5-FU/LV二线治疗吉西他滨化疗后的晚期胰腺癌患者的疗效。结果显示[8]，S-1组对比5-FU/LV组在OS方面具有获益趋势，且不良反应发生率更低。因此，当前伊立替康脂质体联合氟尿嘧啶/亚叶酸方案仍是最佳选择，其他联合方案仍需进一步探索。曙光初现，靶向治疗迎来“破局” 目前，胰腺癌最主要的四个驱动基因突变包括KRAS、TP53、SMAD4和CDKN2A已被证实在众多胰腺癌患者中存在突变。长期以来，KRAS一直被认为是不可成药靶点。但近年来越来越多的靶向药物及方案在胰腺癌临床研究显示出希望。 KRAS 2024 ASCO GI大会公布了KRAS G12C抑制剂glecirasib在胰腺癌和其他实体肿瘤患者中的初步活性和安全性结果。数据显示[9]，在28例胰腺癌患者中，ORR为46.4%，DCR为96.4%，中位DOR为4.1个月，中位PFS为5.5个月。安全性方面，患者耐受性良好，不良事件可控，未出现因治疗相关不良事件导致的死亡或治疗终止。针对KRAS G12D突变的药物研究也取得了初步成果。2023 ESMO大会公布了KRAS G12D抑制剂HRS-4642的Ⅰ期临床研究数据，其中1例胰腺癌患者获益显著[10]。此外，后续，Ⅰ/Ⅰb期RMC-9805-001研究结果显示[11]，新型口服KRAS G12D选择性共价抑制剂RMC-9805在KRAS G12D突变胰腺癌患者的后线治疗中ORR为30%，DCR为80%（图2）。尽管这些结果来自早期临床研究，但未来对其后续研究结果充满期待。图2. RMC-9805-001研究结果 RAS 同样，针对泛RAS抑制剂的研究也显示出潜力。Ⅰb期临床研究数据显示[12]，泛RAS抑制剂RMC-6236单药二线治疗KRAS G12X或任何RAS突变胰腺癌患者中位PFS分别为8.5个月和7.6个月，中位OS均为14.5个月，且安全性良好。目前，RMC-6236的Ⅲ期研究正在筹备中，未来值得期待。 HER2 HER2靶向ADC药物在胰腺癌领域的研究也备受关注。2024 ASCO大会公布的Ⅱ期DESTINY-PanTumor02研究显示[13]，胰腺癌患者的ORR为4.0%，中位PFS为3.2个月，这表明T-DXd在HER2表达的胰腺癌患者中显示出一定的抗肿瘤活性，但因纳入人群有限，特别是在IHC 3+组中，所以其疗效仍需进一步验证。 CLDN18.2 CLDN18.2是潜在的胰腺癌治疗靶点。2024 ASCO大会公布了一项Ⅰ期临床研究中抗CLDN18.2/CD3双特异性抗体IBI389在晚期胰腺癌患者中的安全性和有效性初步结果[14]。数据显示，在27例胰腺癌患者中，ORR为29.6%，DCR为70.4%，且安全性可控。这一结果为CLDN18.2靶点在胰腺癌中的应用提供了新的方向。此外，另一款针对CLDN18.2靶点的ADC药物ATG-022也正在临床研究中[15]，目前尚未有后续数据公布。创新引领，解锁免疫治疗新策略 2024年The Lancet Oncology首次公布Ⅰ/Ⅱa期LOKON001研究第1组的结果显示[16]，溶瘤腺病毒LOAd703+白蛋白结合型紫杉醇+吉西他滨用于既往治疗或未接受过治疗的不可切除或转移性胰腺癌患者，ORR为44%。不良反应多为1~2级，整体安全性良好。这一研究为溶瘤病毒联合化疗的临床应用提供了初步证据。 2024年Nature Medicine发表的一项Ⅰ期研究评估了新型淋巴结靶向性mKRAS特异性两亲疫苗ELI-002 2P在胰腺癌和结直肠癌患者中的安全性、耐受性、推荐的Ⅱ期剂量（RP2D）以及初步的抗肿瘤活性[17]。数据显示，中位无复发生存期（RFS）为16.3个月（图3），中位OS为16.3个月（图4）。研究结果证明了ELI-002 2P疫苗在治疗KRAS突变型肿瘤中的安全性和免疫原性，且可有效缓解结直肠癌和胰腺癌患者的肿瘤复发，增加患者生存率。这些结果为KRAS突变肿瘤的免疫治疗提供了新的策略，并为未来的Ⅱ期研究奠定了基础。图3. RFS获益结果图4. OS获益结果攻坚克难，齐心探索结硕果胰腺癌术后复发率高达70%以上，如何早期发现复发并采取干预措施是临床上的重大挑战。对此李恩孝教授所在团队通过基于循环肿瘤DNA（ctDNA）的微小残留病灶（MRD）检测对胰腺癌患者展开了前瞻性研究，通过ctDNA动态监测用于患者术前和术后的风险分层和指导疾病监测及辅助治疗决策。同时，李恩孝教授所在团队针对局部晚期胰腺癌患者开展了一项Ⅱ期临床研究，旨在探索索凡替尼联合AG方案用于此类患者转化治疗的疗效和安全性。目前，初步研究结果已在2024美国胰腺大会和欧洲胰腺大会等国际会议上以壁报形式发表。数据显示，截至2024年12月共纳入25例患者，其中24例可评估患者的ORR为45%，DCR为87.5%，83%患者实现了肿瘤退缩。在完成术前治疗的20例患者中65%达到切除标准，40%实现了R0切除，安全性总体可控。目前，PFS和OS等长期指标仍在随访中，研究结果值得期待。任重道远，未来曙光在前胰腺癌的治疗仍然面临诸多挑战，但近年来在靶向治疗、免疫治疗和细胞治疗等领域的研究进展为我们带来了新的希望。未来可从以下几个方面进一步突破：第一，通过基础研究深入探索包括NTRK、ROS1、SMAD4、BRCA、BRAF、KRAS等关键驱动基因的可成药性是关键。第二，探索联合治疗策略是提升疗效的重要方向。需进一步优化基于细胞毒性药物的联合治疗方案，如索凡替尼联合AG方案在转化治疗中已显示出潜力。第三，免疫治疗仍然是未来研究的重要方向。其中溶瘤病毒和癌症疫苗等新策略可为克服“免疫荒漠”胰腺癌提供新的思路。胰腺癌的治疗之路任重道远，期待未来更多研究成果的涌现，为患者带来新的希望。参考文献（上下滑动可查看） [1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. [2] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Pancreatic Adenocarcinoma, Version 1.2025, November 20, 2024. [3] Thomas J. Georgel, et al. ASCO GI 2024. Poster 655. [4] Wainberg ZA, et al. Lancet. 2023;402(10409):1272-81. [5] 2024 ASCO. Abstract 4136. [6] 2024 ASCO. Abstract 4003. [7] Hiroshi Imaoka, et al. 2024 ESMO 1521P. [8] Anne M. Gehrels, et al. 2024 ESMO LBA63 [9] 2024 ASCO GI.Abstract：604. [10] 2023 ESMO. Abstract LBA33. [11] Revolution Medicines Presents Initial Data from RMC-9805 Monotherapy Study in Patients with Advanced Pancreatic Ductal Adenocarcinoma. Retrieved October 25, 2024 from https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-initial-data-rmc-9805-monotherapy. [12]https://www.globenewswire.com/en/news-release/2024/10/23/2967583/0/en/Revolution-Medicines-Presents-Updated-Data-from-RMC-6236-Monotherapy-Study-in-Patients-with-Advanced-Pancreatic-Ductal-Adenocarcinoma.html. [13] Meric-Bernstam F, et al.J Clin Oncol. 2024;42(1):47-58. [14] Musher, Benjamin L et al. The Lancet Oncology. 2024; 25(4):488 - 500. [15] Pant S, et al. Nat Med. 2024;30(2):531-542. [16] 2024 ASCO. Abstract 4011. [17] 2024 ASCO. Abstract 2526. （来源：肿瘤瞭望消化时讯）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

ASCO会议CSCO会议临床结果

100 项与 Delolimogene mupadenorepvec 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
局部晚期黑色素瘤	临床2期	美国	Lokon Pharma AB	2020-01-28
局部晚期黑色素瘤	临床2期	瑞典	Lokon Pharma AB	2020-01-28
转移性黑色素瘤	临床2期	美国	Lokon Pharma AB	2020-01-28
转移性黑色素瘤	临床2期	瑞典	Lokon Pharma AB	2020-01-28
结直肠癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01
卵巢上皮癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01
胰腺腺癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01
铂耐药性卵巢癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01
铂敏感性卵巢癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01
不能切除的胆道癌	临床2期	瑞典	Lokon Pharma AB	2018-03-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04123470 (LOKON003, ESMO2024) 人工标引	临床1/2期	黑色素瘤	24	LOAd703ectoratezolizumab (LOAd703 (1x10^11 VP))	簾鹽醖夢獵構選窪衊顧(網鹹鏇範鏇選願鏇築簾) = Most common adverse events with suspected relationship to LOAd703 were pyrexia (n=14 patients), vomiting (n=5), and chills (n=5). 鏇選夢醖糧製簾積夢鹽 (網築網鹽鹹簾觸範襯齋 ) 更多	积极	2024-09-13
NCT04123470 (LOKON003, ESMO2024) 人工标引	临床1/2期	黑色素瘤	24	LOAd703ectoratezolizumab (LOAd703 (5x10^11 VP))		积极	2024-09-13
NCT03225989 (ESMO2024) 人工标引	临床1/2期	晚期恶性实体瘤	41	LOAd703 with standard of care chemotherapy	糧醖簾膚觸糧願艱製繭(網製顧糧齋鹽網選築範) = associated with LOAd703 and related procedures were overall transient and of grade 1-2. The most frequent adverse events were pyrexia (76%), chills (39%), and fatigue (34%). However, three patients developed nephrotoxicity possibly related to LOAd703. 繭艱獵鹹範鹹簾積觸網 (艱鹽築獵糧襯鹹顧廠範 )	积极	2024-09-13
NCT02705196 (LOKON001, Pubmed)	临床1/2期	不能切除性胰腺癌	22	LOAd703	鹽蓋鹽憲襯膚範襯網醖(衊構蓋繭襯淵鬱繭鑰鏇) = 齋壓鑰窪鏇窪鹹膚淵蓋憲構遞簾膚構獵獵醖膚 (願壓淵鹽憲襯醖壓襯廠 ) 更多	积极	2024-04-01
NCT03225989 (LOKON002, AACR2023) 人工标引	临床1/2期	晚期恶性实体瘤	28	LOAd703	夢鹽餘餘鹽齋餘積艱憲(壓鏇醖窪艱艱範鏇艱範) = 鑰醖顧積鏇獵積顧簾鹽鏇獵憲廠網簾觸鬱齋鏇 (鹹網獵壓製醖簾鏇膚艱 ) 更多	积极	2023-04-14
NCT02705196 (ASCO2022) 人工标引	临床1/2期	胰腺癌	22	LOAd703+nab-paclitaxel+gemcitabine	糧遞壓壓襯獵鑰糧築構(鏇鑰鹽窪獵鹹鏇製襯膚) = 鏇鹽觸夢艱簾遞膚糧鬱獵夢艱夢願鬱夢鬱願醖 (壓餘願窪積衊淵繭蓋鑰 ) 更多	积极	2022-06-02