An International, Phase 2, Open-Label, Efficacy and Safety Study of MDV9300 in Patients With an Incomplete Response Following Salvage Therapy or Autologous Stem Cell Transplantation for Relapsed or Refractory CD20+ Diffuse Large B-Cell Lymphoma

The purpose of this study is to evaluate the efficacy and safety of MDV9300 in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) that have achieved either stable disease or a partial remission following definitive salvage therapy.
Two cohorts of patients will be enrolled: a cohort treated with salvage chemotherapy but considered ineligible for autologous stem cell transplant (ASCT), and a cohort of patients who have received ASCT following salvage chemotherapy.

开始日期2016-12-01

申办/合作机构

MediVation, Inc.

NCT02530125

/ Terminated临床2期IIT

Phase II Study of Pidilizumab (MDV9300) in Patients With Diffuse Large B-Cell Lymphoma Following First Remission

The purpose of this study is to evaluate pidilizumab and its effect, bad and/or good, on the immune system in relation to its ability to fight cancer cells. Many cancers can be brought to a phase called complete remission (no cancer is found) but have a chance that they may come back. Researchers are working to improve therapy and to find new drugs that lower the chance of disease coming back. This study uses a drug called pidilizumab. The drug targets our immune system. It can change how our immune system finds cancer cells. The drug may kill any remaining cancer cells that we cannot see with computed tomography (CT) scans. The drug, pidilizumab, is being studied in other cancers.

开始日期2015-09-01

申办/合作机构

Northwestern University

[+2]

NCT02077959

/ Terminated临床1期IIT

Phase I/II Study of Lenalidomide in Combination With Anti-PD-1 Monoclonal Antibody CT-011 in Patients With Relapsed/Refractory Multiple Myeloma

This phase I/II trial studies the side effects and best dose of lenalidomide and pidilizumab and to see how well they work in treating patients with multiple myeloma that has come back (relapsed) or has not responded to treatment (refractory). Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as pidilizumab, can block cancer growth by blocking the ability of cancer to grow and spread. Giving lenalidomide with pidilizumab may work better in treating relapsed or refractory multiple myeloma.

开始日期2014-03-03

申办/合作机构

Ohio State University Comprehensive Cancer Center

[+1]

100 项与 Pidilizumab 相关的临床结果

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100 项与 Pidilizumab 相关的转化医学

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100 项与 Pidilizumab 相关的专利（医药）

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项与 Pidilizumab 相关的文献（医药）

2022-09-22·JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS

Computationally-obtained structural insights into the molecular interactions between Pidilizumab and binding partners DLL1 and PD-1

Article

作者: Martins da Silva, João Hermínio ; Sartori, Geraldo Rodrigues ; Albuquerque, Aline de Oliveira ; da Silva Junior, Haroldo Cid

Pidilizumab is a monoclonal antibody tested against several types of malignancies, such as lymphoma and metastatic melanoma, showing promising results. In 2016, the FDA put Pidilizumab's clinical studies on partial hold due to emerging evidence pointing to the antibody target uncertainty. Although initial studies indicated an interaction with the PD-1 checkpoint receptor, recent updates assert that Pidilizumab binds primarily to Notch ligand DLL1. However, a detailed description of which interactions coordinate antibody-antigen complex formation is lacking. Therefore, this study uses computational tools to identify molecular interactions between Pidilizumab and its reported targets PD-1 and DLL1. A docking methodology was validated and applied to determine the binding modes between modeled Pidilizumab scFvs and the two antigens. We used Molecular Dynamics (MD) simulations to verify the complexes' stability and submitted the resulting trajectory files to MM/PBSA and Principal Component Analysis. A set of different prediction tools determined scFv interface hot-spots. Whereas docking and MD simulations revealed that the antibody fragments do not interact straightforwardly with PD-1, ten scFv hot-spots, including Met93 and Leu112, mediated the interaction with the DLL1 C2 domain. The interaction triggered a conformational selection-like effect on DLL1, allowing new hydrogen bonds on the β3-β4 interface loop. The unprecedented structural data on Pidilizumab's interactions provided novel evidence that its legitimate target is the DLL1 protein and offered structural insight on how these molecules interact, shedding light on the pathways that could be affected by the use of this essential immunobiological. Communicated by Ramaswamy H. Sarma.

2017-06-01·Hematological oncology3区 · 医学

Immunotherapy in lymphoma

3区 · 医学

Review

作者: Caligaris‐Cappio, Federico ; Maloney, David G. ; Ansell, Stephen M.

A multitude of studies have investigated why the immune system fails to develop an effective response against cancer and how to mobilize a successful immune therapeutic attack against cancer cells. Lymphomas are tumours of the immune system that develop from the cells devoted to the body defence within permissive specialized and well-vascularized tissue microenvironments, such as bone marrow and secondary lymphoid organs. Malignant lymphoid cells entail a bidirectional dialogue with a host of nonmalignant immune cells of both innate and adaptive immunity. This cross-talk not only favours malignant cell growth, survival, and drug resistance but also prevents antitumour response through resistance to cytotoxicity, compromised cytotoxic cell activity, and altered tumour-identifying ligand expression or secretion.1 Improving the understanding of the mechanisms that underlie the deficiency of an adequate antitumour immune response is now allowing manipulation of the immune system for the purpose of lymphoma eradication. The first question to address is through which mechanisms malignant cells subvert normal cells of the immune system to protect themselves from attack. A number of different mechanisms have been ascertained. As an example, diffuse large B cell lymphoma (DLBCL) cells commonly fail to express cell-surface molecules necessary for the recognition of tumour cells by immune-effector cells. This may occur because of mutations and deletions that inactivate either the β2-Microglobulin gene, thus preventing the cell-surface expression of the HLA class-I (HLA-I) complex that is necessary for recognition by cytotoxic T lymphocytes (CTL) or the CD58 gene, which encodes a molecule involved in T and natural killer cell-mediated responses.2 Lymphoma cells divert the classical activation of the innate immune system and subvert the antitumour immune response exerted by T helper (Th) cells, CTL, and macrophages. The apposition of lymphoma cells with T cells within involved tissues induces a dysfunction of the T-cell immunological synapse, the complex molecular structure that represents the site where the T-cell receptor (TCR) is triggered by the peptide–HLA complex. This dysfunction has been described initially in B-cell chronic lymphocytic leukemia (CLL) and subsequently also in follicular lymphoma (FL) and DLBCL. It is due to inhibitory ligand-induced impairment of T-cell actin dynamics and prevents the lysis of tumour cells through CTL.3 Notably malignant lymphoid cells may also secrete cytokines such as IL-12 that induce T cell "exhaustion," a reversible condition that occurs when T cells are exposed to prolonged stimulation with antigen and leads to a profound inability of T cells to respond to activation signals. Moreover, lymphomatous tissues are enriched with immune cell subsets that suppress an efficient immunological response against the tumour such as FoxP3 regulatory T cells (Tregs). Tregs suppress the proliferation and activity of both CD4+CD25– and CD8+ T cells, and their enrichment is contributed to by lymphoma cells that allow the preferential conversion of T helper cells into Tregs by proteins such as TGF-β or CCL22. A number of studies have suggested a critical role for monocyte/macrophage cells in chronic lymphoid malignancies. Their accumulation is favoured by the inflammatory microenvironment within infiltrated tissues that attracts monocytes/macrophages and cooperates with IL-10 to promote the M2 polarization of tumour associate macrophages. M2-polarized tumour associate macrophages promote tumour growth by stimulating angiogenesis and inducing an immunosuppressive Th2 response.4 A major achievement has been the understanding that the homeostasis of antigen-specific lymphocytes requires multiple different signals. Lymphocyte activation is triggered by specific antigen recognition through the TCR and costimulatory signals. Coinhibitory signals delivered through specialized receptors that function as immune checkpoints maintain self-tolerance and promote the resolution of inflammation during immune responses thereby preventing the development of autoimmunity. The molecular family of checkpoint inhibitors classically represented by the B7–CD28–CTLA-4 family has been enriched by the identification of the programmed cell death 1 (PD-1)/programmed death–ligands 1 and 2 (PD-L1 and PD-L2) immune checkpoint inhibitory receptor and ligands. The functional and biochemical properties of PD-1 are not limited to but have been best studied in T cells where PD-1, induced upon activation through the TCR and cytokine receptors, is necessary for the termination of the immune response. Programmed death–ligand 1 is constitutively expressed at low levels on both professional and nonprofessional antigen presenting cells as well as on a wide variety of nonhematopoietic cell types and its expression is also induced by proinflammatory cytokines. A key mechanism by which cancer cells limit the host immune response is the upregulation of PD-1 ligands and their ligation to PD-1 on tumour-specific CD8+ T cells. In the tumour microenvironment inflammatory mediators, among which interferon-γ produced by tumour-infiltrating T cells that are capable of recognizing tumour antigens is the most potent, can induce expression of PD-L1 and PD-L2 not only on cancer cells but also on other cell types such as macrophages, dendritic, and stromal cells. The expression of PD-1 ligands on tumour cells can have a genetic basis as best exemplified by classical Hodgkin lymphoma where chromosome 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) alterations have been shown to increase the abundance of PD-1 ligands.5 JAK2-STAT signalling further increases PD-1 ligand expression. Notably, Epstein-Barr virus (EBV) infection can increase expression of PD-1 ligands in EBV+ HL. Levels of PD-L1 expression in cancer cells are also regulated by epigenetic mechanisms. Lymphoma cells protect themselves from attack by the immune system through several different mechanisms. These observations have paved the way to the development of new therapeutic avenues of cancer immunotherapy. The use of genetically modified chimeric antigen receptor (CAR)-T-cells that overcome the mutational landscape of cancers and the blockade of immune checkpoint receptors that inhibit the immune response convincingly show that the possibility to eradicate lymphoid malignancies with immunotherapeutic approaches is more realistic than ever before. Two immune checkpoints have been targeted in lymphoma and antibodies that block signaling via these receptors have resulted in therapeutic benefit for patients. CTLA-4 is commonly expressed on T-cells after activation and specifically functions to down regulate T-cell activity through a variety of mechanisms. These mechanisms include preventing costimulation by outcompeting CD28 for its ligand B7 and also by inducing T-cell cycle arrest. Blocking CTLA-4 prevents down regulation of T-cell function and promotes the persistence and activation of intratumoural T-cells. Similarly, PD-1 is a negative regulator of T-cell activity and limits T-cell activation when stimulated by 1 of its 2 ligands, PD-L1 and PD-L2. Activation of this receptor typically down regulates T-cell activity and PD-1 is commonly expressed on activated and immunologically exhausted T-cells. Persistent stimulation via PD-1 results in an ineffective immune response and blocking signaling through PD-1 using an anti–PD-1 antibody allows for reactivation of suppressed or exhausted T-cells. Targeting these 2 immune checkpoints is therefore a rational therapeutic approach. Initial clinical studies utilized an anti–CTLA-4 antibody ipilimumab in B-cell lymphoma with a goal of enhancing antitumour T-cell responses. In an initial phase II clinical trial, 18 patients were treated and 2 responses were seen—1 patient with DLBCL had a complete response and 1 patient with FL had a partial response.6 Correlative studies showed that T-cell proliferation in response to recall antigens increased in most patients confirming activation of the immune system. Subsequent clinical trials were done using ipilimumab in patients with relapsed hematological malignancies post allogeneic stem cell transplant. In these studies, responses were seen in lymphoma patients including 2 complete responses in patients with HL and a partial response in patients with mantle cell lymphoma (MCL). Ipilimumab has subsequently been combined with nivolumab, an anti–PD-1 antibody, and the combination has shown significant clinical responses in HL. While targeting CTLA-4 has resulted in modest clinical benefit, clinical trials testing PD-1 blockade have shown significant promise in patients with lymphoma, particularly HL. Initial trials used an anti–PD-1 antibody pidilizumab, and while there is some controversy as to whether pidilizumab specifically targets PD-1, the initial trial of pidilizumab postautologous stem cell transplant did show a significant impact of this agent on progression free survival.7 A subsequent clinical trial of pidilizumab in combination with rituximab in FL showed a high complete response rate of 52% in the 32 patients treated. Additional clinical trials of other anti–PD-1 antibodies have been performed. Studies using nivolumab that targets PD-1 showed dramatic responses in patients with HL. In the initial phase I trial of nivolumab, the 23 patients in the HL cohort had an overall response rate of 87%.5 The responses seen in this trial have been durable and with longer-term follow-up, a significant proportion of patients have remained in remission. A subsequent confirmatory phase II study of nivolumab in HL patients confirmed an overall response rate of 68%.8 These responses have remained durable and with a median follow-up of 14 months, the median duration of response has not yet been reached. The response rates in other lymphomas have been lower but responses have been seen in patients with FL, DLBCL, and T-cell non-Hodgkin lymphoma.9 In general, responses in these histologies have been in the 20% to 40% range and responses have not been as durable. Similar results have been seen with pembrolizumab, a further antibody targeting interactions between PD-1 and its ligands. Data with this agent in classical HL have confirmed high response rates and good tolerability. In an initial phase I clinical trial, the overall response rate for the 31 patients treated was 58% and these responses have also been durable with longer-term follow-up.10 A subsequent phase II trial of pembrolizumab, including patients who progressed after autologous stem cell transplant as well as patients ineligible for a transplant, confirmed a high response rate of 68% with the responses varying between 64% and 74% depending on the subset analyzed. Correlative studies from the Hodgkin cohort in both the pembrolizumab and nivolumab studies have confirmed high expression of PD-1 ligands on the malignant cells and the majority of the overexpression is due to amplification or copy number gain at chromosome 9p24.1. The significant clinical results of particularly pembrolizumab and nivolumab in HL and other lymphomas have led to a plethora of combination studies. An initial study combining ipilimumab and nivolumab, so as to have dual immune checkpoint blockade, resulted in a 74% response rate in a cohort of 31 HL patients. Of note, however, responses have been significantly lower even with dual checkpoint blockade in other lymphoma histologies. Similarly, combination studies of immune checkpoint therapy with antibody drug conjugates such as brentuximab vedotin have been conducted. Recent reports of the results of combining brentuximab vedotin with nivolumab showed an overall response rate of 90% in HL patients in first relapse and 100% in patients who had progressed posttransplant. Further studies using multiple combinations in various lymphoma histologies are currently in progress. Clearly, targeting immune checkpoints is a promising approach to optimizing the antitumour immune response in both Hodgkin and non-Hodgkin lymphoma. A further option to overcome tumour resistance is to adoptively transfer large numbers of expanded or genetically reprogramed T-cells specific for a tumour expressed antigen. Approaches include the use of tumour infiltrating lymphocytes, cells transfected with TCR specific for tumour antigens in the context of the patient's HLA, or chimeric antigen receptor gene-modified T cells (CAR-T). Chimeric antigen receptor gene-modified T cells specific for the B cell lineage antigens CD19, CD20, and CD22 have shown the greatest promise in patients with acute lymphoblastic leukemia, NHL, and CLL. For NHL, the most encouraging antitumour activity has been with second-generation CAR constructs that have used a murine scFv specific for CD19 and linked to either the 41BB or CD28 costimulatory domains and a CD3zeta signaling sequence. Typically, cells are collected from the patient via leukapheresis and then either separated into subsets (CD4 and CD8 cells) or bulk lymphocytes directly stimulated through CD3 and CD28 and transfected with either a lentiviral or retroviral construct containing the CAR gene. After a 7- to 14-day period of cell growth in vitro, the cells are given back to the patient at a variety of doses, usually 2 to 4 days after the patient has received a cycle of lymphodepleting chemotherapy. Lymphodepletion appears important to allow upregulation of homeostatic regulatory cytokines (IL-7 and IL-15) that improve the expansion and persistence of the adoptively transferred cells and may provide some degree of transient tumour control. In most studies, low-dose or high-dose cyclophosphamide alone or in combination with fludarabine has been used. The CAR-T cells are a living therapy that may replicate and exponentially expand upon interaction with normal or abnormal cells expressing the target antigen. This can lead to very rapid tumour regression, including tumour lysis syndrome as well as toxicity resulting from cytokine release syndrome (CRS). Cytokine release syndrome appears to be caused by the interaction of CAR-T cells and antigen expressing tumour cells as well as interaction with the patient's immune system and release of inflammatory mediators including IL-6, TNF-alpha, and gamma interferon and manifest as fever, hypotension, capillary leak, and coagulopathy. This may require ICU-level care. For grading, see Lee et al.11 In most studies, an unexplained neurotoxicity with delirium and somnolence or even seizures and/or stroke like phenomena can occur in a subset of patients. Fortunately, even if significant, these neurotoxicities are usually fully reversible. Moderate-to-severe CRS can be treated by anti–IL-6 protein or receptor antibodies (tocilizumab or siltuximab) often in combination with a short course of dexamethasone. Tumour responses are usually quite rapid and occur in the first 1 to 2 months. Hospitalization is often required for supportive care, but approximately 30% of patients in the Seattle series were treated entirely as outpatients. Kochenderfer at the NCI has reported the longest outcomes for patients with NHL.12 This approach uses a murine scFv and a CD28 costimulatory domain that is transfected into bulk-stimulated T cells using a retroviral vector. Using this approach, cells are produced rapidly (<7 days), but may be comprised of widely variable T cell subsets. In the initial report, they treated 15 patients (9 with DLBCL, 2 indolent NHL, and 4 CLL) with 8 CR and 4 PR. In patients with DLBCL, 4/7 evaluable patients had a CR and 3 were ongoing between 9 and 22 months. The CRS and neurotoxicity was the most significant toxicity and 1 patient without known CRS had sudden death at day 16 post–CAR-T cells. Patients had extensive prior therapy, and the achievement of CR's in this population represents a significant finding. In addition, this was feasible in patients who had relapsed following allogeneic transplantation, without any apparent increase in graft-vs-host disease or graft rejection. Kite pharmaceuticals is planning to commercialize this approach (KTE-C19) in relapsed/refractory DLBCL and reported early results from the pivotal ZUMA-1 at ASH 2016.13 In 62 patients with DLBCL (n = 58) or transformed FL or PBMCL (n = 11), the overall response rate was 79% with a 52% initial CR rate to a targeted dose of 2 × 106 cells/kg after low-dose Cy/Fu conditioning. At 3 months, the ORR was 44% with a CR rate of 39%. Data have not yet been released for 6- and 9-month follow-up, but this compares favorably to historical data for patients with relapsed/refractory DLBCL (8% CR from the SCHOLAR-1 study). Grade 3 or greater CRS was observed in 18% and neurotoxicity in 34% of patients. Two patients died of related side effects. The Seattle group has taken a different approach by creating a more uniform CAR-T cell product by selecting CD4 and CD8 T cell populations and administering a CAR-T cell product containing CD4:CD8 cells in a defined 1:1 ratio in 32 patients with NHL.14 In this phase I/II trial, we observed that the dose of CAR-T cells was important as well as the type/intensity of lymphodepletion. Patients treated with Cy alone had a high incidence of immunologic rejection of the modified T cells that limited the duration of response. The addition of fludarabine decreased this immune rejection and resulted in more robust CAR-T cell expansion, which required a 1 log reduction in the administered T cell dose to limit toxicity. By using a defined ratio of cells, we were able to identify dose response and dose toxicity relationships. The overall response rate was 63% with a 33% CR rate. However, using Cy/Flu lymphodepletion the ORR was 72% with a 50% CR and with a longer duration of remission. This was correlated with greater CAR-T cell expansion and persistence. We were able to observe complete remission of disease in the blood, bone marrow, nodal and extra nodal tissues, and CNS. Severe CRS was observed in 13% and severe neurotoxicity in 28%, and 2 patients died of toxicity (both treated above the eventual MTD). Importantly, measurement of serum biomarkers 1 day after CAR-T cell infusion was correlated with the development of severe CRS or neurotoxicity suggesting an avenue for early intervention. Juno Therapeutics has developed this approach further (JCAR-17) in an ongoing multicenter phase I/II trial that also reported encouraging results at ASH 2016 with 82% OR and 73% CR in the first 11 evaluable patients with DLBCL.15 Of interest, 1 patient with a parenchymal brain lesion also responded with a CR and without CRS or CNS toxicity. At this time, it is difficult to compare these very different CAR-T cell products, but both approaches appear to be generating response rates and CR rates that are vastly superior to the current standards of care in this difficult to treat patient population (relapsed refractory DLBCL). The duration of remissions and the causes of disease relapse will be important to the field. However, this is likely just the beginning of a new treatment era because combination therapy with CAR-T cells and checkpoint inhibitors are a logical extension and clinical trials are ongoing. Stephen Ansell: Research funding from Bristol Myers Squibb and Merck. Federico Caligaris-Cappio: No relevant conflict of interest to declare. David Maloney: Research funding from Juno Therapeutics.

2016-04-02·Expert opinion on emerging drugs2区 · 医学

Emerging antibodies for the treatment of multiple myeloma

2区 · 医学

Review

作者: Zagouri, Flora ; Terpos, Evangelos ; Kastritis, Efstathios ; Dimopoulos, Meletios A

INTRODUCTION:

Monoclonal antibodies mark the beginning of a new era in the context of multiple myeloma (MM) treatment. Numerous antibodies have been tested or are currently in development for patients with MM, in order to improve tolerability and quality of life.

AREAS COVERED:

This manuscript reviews emerging antibodies for the treatment of MM i.e. elotuzumab, daratumumab, MOR03087, isatuximab, bevacizumab, cetuximab, siltuximab, tocilizumab, elsilimomab, azintrel, rituximab, tositumomab, milatuzumab, lucatumumab, dacetuzumab, figitumumab, dalotuzumab, AVE1642, tabalumab, pembrolizumab, pidilizumab, nivolumab.

EXPERT OPINION:

Amongst these antibodies, elotuzumab which targets SLAMF-7 and daratumumab which targets CD38, have been recently approved by FDA for patients with relapsed/refractory MM. Both agents are well tolerated. Multiple clinical trials incorporating these monoclonal antibodies in MM treatment are currently ongoing. Of special interest are the anticipated results of phase III clinical trials with elotuzumab [NCT0189164; NCT01335399; NCT02495922] and daratumumab [NCT02252172; NCT02195479] in newly diagnosed MM patients. Moreover, of great interest are the awaited data on pembrolizumabin combination with pomalidomide and dexamethasone in refractory/relapsed MM patients [NCT02576977] and in combination with lenalidomide and dexamethasone in newly diagnosed MM patients. It seems that the incorporation of monoclonal antibodies will change the landscape of myeloma therapy in the near future.

项与 Pidilizumab 相关的新闻（医药）

2026-01-29

·肿瘤界

整合医学引领突破：嵌合抗原受体T细胞疗法在消化道肿瘤治疗中的研究进展与展望

点击蓝字关注我们苏壬春王育生山西医科大学第一医院肿瘤消化科，山西太原 030001 通信作者：王育生，Email：wangyusheng@sxmu.edu.cn 引用本文：苏壬春, 王育生. 整合医学引领突破：嵌合抗原受体T细胞疗法在消化道肿瘤治疗中的研究进展与展望[J]. 中国药物与临床, 2026, 26(1)：4-11. 专家简介王育生教授山西医科大学第一医院主任医师、肿瘤学博士、博士生导师、肿瘤消化科主任、药物临床试验(GCP)办公室副主任。中国临床肿瘤学会(CSCO)理事；国家肿瘤质控中心胃癌质控专家委员会委员；中国研究型医院学会肿瘤学专委会常委；北京癌症防治学会食管癌、结直肠癌专委会常委；CSCO胰腺癌、胃肠间质瘤、胆道肿瘤、临床研究专委会委员；中国抗癌协会(CACA)整合肿瘤肾脏病专委会、食管肿瘤整合康复专委会常委；CACA肿瘤肝脏病学专委会、多学科会诊(MDT)专委会、信息化管理专委会委员；中国医师协会肿瘤医师分会多原发/不明原发灶肿瘤学组组员；中国医药创新促进会抗肿瘤药物临床研究专委会委员；山西省医学会消化病学专委会消化肿瘤学组组长；山西省医师协会肝病医师分会肝癌学组组长；山西省老年医学学会肿瘤整合医学分会会长；山西省抗癌协会肿瘤异质性与个体化治疗委员会主任委员；山西省抗癌协会肿瘤临床试验专委会、食管癌专委会、肿瘤胃肠病学专委会、肿瘤整体评估专委会副主任委员；山西省医师协会肝病医师分会青委会副主任委员；山西省健康管理学会健康教育专委会副主任委员；山西省老年医学学会胃肠间质瘤分会、临床营养分会副会长；山西省生物工程学会转化医学专委会副主任委员。【摘要】整合医学推动消化道肿瘤治疗模式革新。我国胃癌等消化道肿瘤发病率与死亡率居高不下，嵌合抗原受体T细胞(chimeric antigen receptor T-cell，CAR-T)疗法为其带来新的希望，该疗法在血液肿瘤中疗效显著，但受实体瘤抗原异质性、免疫抑制微环境限制，临床应用存在瓶颈，需要融入多学科体系突破。消化道肿瘤CAR-T治疗已获关键进展，Claudin18.2是胃癌核心靶点，其中人表皮生长因子受体2(HER2)、癌胚抗原等靶点的CAR-T疗法亦在探索中。联合治疗是核心策略，CAR-T与白细胞介素(IL)-12、程序性死亡配体-1(PD-1)抑制剂联用可增强疗效，纳米技术助力精准递送。医工结合通过CRISPR-Cas9编辑重塑T细胞表型、构建抗转化生长因子β(TGF-β)CAR-T等优化功能，与手术、腹膜内给药联用可提升腹膜转移肿瘤疗效。目前CAR-T仍面临靶点阳性人群占比低、成本高、毒性及疗效不稳等问题，未来需建多学科团队，以“靶点精准定位-医工技术赋能-多疗法协同-临床转化落地”为路径，推动其从挽救治疗向一线联合治疗跨越，助力肿瘤治疗迈入精准化新阶段。【关键词】整合医学；消化道肿瘤；嵌合抗原受体；胃肠肿瘤基金项目：中央引导地方科技发展资金项目(YDZJSX2025D069) 整合医学 (holistic integrative medicine，HIM)将人体视为一个整体，将医学各领域最先进的知识和理论以及临床各专业最有效的实践有机地结合起来，是医学未来发展的必要方向[1-2]。随着HIM的概念和实践在肿瘤学界的广泛推广[3]，实体瘤治疗逐渐进入HIM时代，肿瘤HIM大会在多地举办[4]，中国抗癌协会肿瘤HIM多瘤种相关指南发布[5-6]。据流行病学统计，2022年，中国癌症新发病例482.47万例，死亡257.42万例[7]，中国总体恶性肿瘤死因前5位为肺癌、肝癌、胃癌、结直肠癌和食管癌，消化系统肿瘤占中国全部恶性肿瘤死亡病例的67.5%，防治紧迫[8]。嵌合抗原受体T细胞(chimeric antigen receptorT-cell，CAR-T)疗法在血液系统肿瘤中成功验证细胞免疫潜力[9]，但实体瘤的有效性受到包括抗原异质性和肿瘤微环境(tumor microenvironment，TME)的免疫抑制[2]。为提高CAR-T细胞在实体瘤中的疗效，增强T细胞持久性和细胞毒性[10]、重新编程TME或CAR-T细胞[11]、靶向多种抗原和利用创新的同种异体CAR-T细胞制造等策略具有重要意义[12]。实体瘤的复杂性要求其跳出单药治疗模式，将CAR-T疗法与免疫检查点抑制剂、分子靶向治疗及其他局部治疗方式相结合，能有效克服TME局限性[13]。CAR-T疗法融入多学科体系可以突破单药治疗效果局限的瓶颈[14]。本综述以肿瘤HIM为核心框架，提出“靶点精准定位-医工技术赋能-多疗法协同-临床转化落地”的四维整合创新路径，以CAR-T在胃癌、结直肠癌、食管癌等主要消化道肿瘤治疗中的应用为核心，系统解析CAR-T治疗现状、细胞医工改造策略、手术/免疫/靶向/局部治疗等多手段的协同机制及临床转化价值，明确HIM视角下CAR-T突破消化道肿瘤治疗瓶颈的学术思路与实践方向。 1 消化道肿瘤CAR-T治疗的HIM现状 1.1 核心靶点精准定位奠定整合治疗基础靶点选择是CAR-T融入肿瘤整合治疗的前提[15]，目前研究聚焦于特异性高、疗效佳的靶点，以胃癌为例，Claudin18.2靶点基因的突破最为显著。该抗原在胃癌发生时表位暴露，正常组织中表达极少，是理想靶点。在一项多中心、随机对照Ⅲ期临床研究(NCT0354397)中，Claudin18.2阳性、人表皮生长因子受体2(human epidermal growth factor receptor 2，HER2)阴性、局部晚期不可切除或转移性胃或胃食管交界腺癌患者中，与安慰剂+mFOLFOX6相比，用佐妥昔单抗靶向Claudin18.2可显著延长无进展生存期和总生存期，但存在不良反应较突出、适用人群受限、成本高与耐药相关问题[16]。研究显示，靶向Claudin18.2的CAR-T药物舒瑞基奥仑赛注射液(satri-cel，也称为CT041)Ⅱ期随机对照试验(NCT04581473)显示对二线治疗失败的晚期胃癌患者中位无进展生存期达3.25个月，优于标准治疗的1.77个月，且能降低63%的疾病进展风险，客观缓解率达22%，远超对照组的4%，安全性方面，CT041组细胞因子释放综合征(cytokine release syndrome,CRS)发生率为93.2%，但多为1~2级(88.1%)，3级CRS发生率仅5.1%，无4~5级CRS发生，神经毒性发生率为13.6%，均为1~2级，未出现治疗相关死亡[17]。此外，其他消化道肿瘤靶点的研究也在推进中，癌胚抗原(carcinoembryonic antigen,CEA)在结直肠癌中阳性率达70%~80%，Fan等[18]开发了一种逆转录病毒嵌合抗原受体(CAR)构建体，其中包含具有Bcl-xL基因的CEA靶向CAR，并测试了抗CEA CAR-T细胞免疫治疗结直肠癌。在体内体外，抗CEA CAR-T细胞的过继细胞转移显著增强了CAR-T细胞在肿瘤组织中积累的能力，一项“应用CEA CAR-T细胞疗法，治疗CEA阳性转移性结直肠癌”的Ⅰ期临床试验(NCT02349724)，在CEA阳性转移性结直肠癌患者中耐受性良好，且半数以上接受治疗的患者评估为稳定，2例稳定超过30周[19]。上皮细胞黏附分子(EpCAM)在干细胞和循环肿瘤细胞上表达，并与肿瘤复发转移密切相关，是包括消化道肿瘤等实体瘤的诊断标志物，在一项Ⅰ期临床研究(NCT02915445)中，纳入多例结直肠癌、胃癌EpCAM高表达患者，2例患者为部分缓解。3例患者显示>23个月的无进展生存期，其中1例患者在输注后200d经历了2年无进展生存期，可检测到CAR-T细胞，安全性仅1例患者(8.3%)发生可逆性3级白细胞减少[20]。黏蛋白1(mucin 1,MUC1)[21]等靶点也在探索中，MUC1在肿瘤中显著扩增，阻碍免疫细胞进入和与抗原结合。靶向HER2的CAR-T在体外实验中可清除阳性胃癌细胞系[22]，HER2蛋白在高比例的癌症病例中过表达，并影响癌症干细胞亚群的维持，其被用作HER2阳性胃癌患者的临床治疗靶点。研究结果表明，表达增加的中央记忆表型的扩增CAR-T细胞被HER2抗原的特异性识别以主要组织相容性复合物(major histocompatibility complex，MHC)非依赖性方式激活，并有效杀死了患者来源的HER2阳性胃癌细胞[23]。CAR-T细胞疗法具有良好的临床疗效，一项Ⅰ期临床试验(NCT01935843)评估HER2 CAR-T治疗晚期胆道癌和胰腺癌患者的安全性和有效性，纳入HER2阳性(>50%)的晚期胆道癌和胰腺癌，在经过白蛋白结合型紫杉醇联合环磷酰胺治疗后给予输注CART-HER2细胞，无进展生存时间是4.8个月(1.5~8.3个月)，安全性方面，包括1例3级急性发热综合征和1例转氨酶升高外、1例因胃窦转移导致的出血，提示HER2靶向CAR-T细胞治疗在抗肿瘤过程中有较好的有效性，同时可能存在一定风险[24]。 1.2 多疗法协同CAR-T破解消化道肿瘤治疗瓶颈消化道肿瘤的免疫抑制性肿瘤微环境、肿瘤异质性等问题，单靠CAR-T难以彻底解决，联合治疗成为HIM的核心思路[25]。一方面，CAR-T与免疫调节剂联合，如Chi等[26]将靶向CEA的CAR-T与重组人白细胞介素(IL)-12联合，分别对胰腺癌、胃癌、结直肠癌细胞，并对上述瘤种的移植瘤小鼠进行研究，证实IL-12显著提升了CAR-T细胞的活化、增殖能力和细胞毒性；一项单臂、开放标签、Ⅰ期临床试验(NCT03874897)，开展了与抗程序性死亡受体1(PD-1)抑制剂联合的相关探索，期望改善肿瘤微环境的免疫抑制状态，主要终点是安全性，没有报告剂量限制性毒性、免疫效应细胞相关神经毒性综合征，CRS均为1~2级；总缓解率(ORR)为40.0%(6/15)，疾病控制率(DCR)为86.7%(13/15)；具体而言，6例患者达到部分缓解(PR)，7例疾病稳定(SD)，2例疾病进展(PD)，未报告完全缓解(CR)[27]。另一方面，结合纳米技术等创新手段，有研究开发类似BiCD30/5-GF的纳米颗粒策略用于胃癌治疗，靶向表达成纤维细胞生长因子受体4(FGFR4)的肿瘤细胞，这类技术可辅助CAR-T精准递送药物，增强局部治疗效果，减少全身毒性[28]。 1.3 制约CAR-T整合治疗困境首先适合CAR-T治疗的靶点阳性人群占比不高，如Claudin18.2高表达且符合治疗阈值的胃癌患者仅35%~38%[29]，HER2阳性患者仅占晚期胃癌的12%左右[30]，多数患者暂无法受益于现有CAR-T疗法。其次技术与成本壁垒高，当前CAR-T多为自体细胞制备，流程复杂、耗时久，且通用型CAR-T仍在研发中，高昂的成本让很多患者难以承担[31]。此外，毒性反应管控难度大，CAR-T细胞治疗存在CRS、神经毒性和中靶脱瘤毒性三大毒性问题，治疗中虽satri-cel的CRS多为轻度[17]，但部分靶点的CAR-T仍可能出现中靶脱瘤毒性等问题，有研究揭示了淋巴细胞功能相关抗原-1(LFA-1)及迟现抗原-4(VLA-4)信号通路在CAR-T细胞治疗中引发的“中靶脱瘤毒性”的关键作用及其发生机制。通过同时敲除CAR-T细胞中的P选择素糖蛋白配体1(PSGL-1)、CD11a及CD49d，降低毒性并增强了CAR-T细胞的记忆性功能[32]。最后是疗效稳定性不足且耐药机制复杂，肿瘤异质性易导致抗原逃逸，部分患者治疗后可能出现靶标丢失，使CAR-T失效，而双靶点CAR-T细胞治疗，成为提高血液系统恶性肿瘤治疗效果的新策略[33]。同时，不同患者的免疫状态差异大，也会影响CAR-T细胞的存活和产生的抗肿瘤反应，这些都需要通过整合基因检测、免疫评估等手段精准筛选患者并调整方案[34]。 2 HIM下的细胞工程学优化 2.1 重塑T细胞功能表型在癌症中，CD8+T细胞持续暴露于抗原信号。这种过度和结构性的信号会导致T细胞功能的恶化，称为“耗竭”，有研究表明，核受体家族4A(NR4A)和胸腺细胞选择相关高迁移率族盒蛋白(TOX)转录因子与耗竭表型密切相关。然而，包括干细胞记忆T细胞在内的早期记忆T细胞的增加对于T细胞的持久性和有效的肿瘤杀伤至关重要，特别是CAR-T细胞疗法[35]。CRISPR-Cas9基因编辑为增强人类T细胞对抗癌症的天然能力提供了一个强大的工具，有一项Ⅰ期临床试验(NCT0339448)，通过对癌症患者的T细胞基因进行编辑，从而提高T细胞的抗肿瘤免疫力[36]。对临床使用的抗CD19 CAR-T细胞的分析表明，积极的治疗结果与线粒体质量增加有关，研究发现叉头框蛋白O1(FOXO1)的过表达促进了健康人或患者的CAR-T细胞中的干细胞样表型，这与体内线粒体适应性、持久性和治疗效果的改善有关。因此，从基因上强制实现有利的代谢表型具有很高的转化潜力，可以提高CAR-T细胞对消化道肿瘤的疗效[37]。 2.2 微环境调控型CAR-T 细胞因子IL-7在T细胞的发育和成熟中起着关键作用。它促进幼稚和中枢记忆T细胞亚群的产生并调节其稳态。IL-15介导CD8记忆T细胞的形成和稳态。已有报道IL-7和IL-15能够指导T细胞向记忆干细胞样表型发展，其分化程度较低，具有上级扩增和存活能力[38]，研究证明在IL-7/IL-15存在下扩增的CAR-T细胞显示出增强的增殖和上级的抗肿瘤活性。IL-7/IL-15选择性扩增了幼稚和中枢记忆T细胞，这有助于CAR-T细胞在荷瘤小鼠中的植入[39]。抑制性细胞因子转化生长因子β(TGF-β)的产生，限制了CAR-T细胞的持久性和功能[40]。有研究表明一种新的ICR修饰的CAR-T细胞策略，不仅可以阻断TGF-β信号，还可以增强抗肿瘤疗效。在患有高TGF-β实体瘤的小鼠中，信号反转CAR/TB15T细胞通过阻断TGF-β和重新利用IL-15刺激信号有效地治疗肿瘤，从而增强CAR-T细胞的持久性和功能[41]。肿瘤部位表达高水平的趋化因子C-X-C基序趋化因子(CXCL)13，而C-X-C基序趋化因子受体5(CXCR5)是CXCL13的唯一受体，主要在B细胞和辅助T细胞上表达(EGFR)CAR-T细胞来表达第二种受体CXCR5，以促进CAR-T细胞向表达CXCL13的非小细胞肺癌肿瘤迁移，并更有效地根除肿瘤[42]。 2.3 益生菌引导的CAR-T细胞益生菌引导的CAR-T细胞，肿瘤定植益生菌释放合成靶标，标记肿瘤组织进行CAR介导的原位裂解。设计共释放趋化因子的多功能益生菌，以增强CAR-T细胞的募集和治疗反应[43]。 2.4 纳米疫苗和纳米抗体一种设计用于将CAR抗原全身递送到淋巴隔室的纳米颗粒RNA疫苗可以刺激过继转移的CAR-T细胞。在驻留的抗原呈递细胞上呈递天然折叠的靶标可促进CAR-T细胞的同源和选择性扩增[44]。DeMunter等[45]设计了一种纳米类TCR抗体(TCR mimicantibody，TCR mAb)CAR-T治疗剂，其具有2个对HER2和CD20双特异性的串联TCR样纳米抗体以激活T细胞并杀死肿瘤细胞。 2.5 CAR自然杀伤细胞(CAR-NK)和CAR巨噬细胞(CAR-M) CAR-NK细胞可能是CAR-T细胞的有利替代品，因为它们不需要人类白细胞抗原系统(HLA)相容性，毒性有限。此外，CAR-NK细胞可能从多种来源大规模产生，这表明它们是有前景的现成产品。目前正在研究具有吞噬作用、肿瘤抗原呈递和广泛肿瘤浸润能力的CAR-M免疫疗法[12]。 3 HIM下的多模态联合治疗体系由于CAR-T细胞在肿瘤中的募集、浸润、激活和功能持久性方面的局限性，其在实体瘤中的疗效一直不佳。为了克服这些挑战，正在研究包括免疫检查点抑制剂、分子靶向治疗、局部治疗与CAR-T细胞治疗的组合策略[46]。上述疗法的既定功能特征为使用CAR-T细胞的组合方法提供了理论基础。化疗重塑肿瘤周围基质，减少免疫抑制细胞群，促进促炎环境，所有这些都可以增加CAR-T细胞的募集、浸润和积聚。放射治疗促进趋化因子梯度，这增强了CAR-T细胞的肿瘤浸润，并进一步增加了肿瘤相关抗原的表达，从而增加了CAR-T细胞的活化。免疫检查点抑制剂治疗可灭活T细胞耗竭途径，最显著的是PD1/程序性死亡配体-1(PD-L1)途径，从而改善CAR-T细胞的功能持久性并促进内源性免疫。 3.1 免疫检查点抑制剂 3.1.1 CAR-T联合免疫检查点抑制剂在过去10年间，针对PD-1和PD-L1的免疫检查点抑制剂的广泛研究使得该类药物数量迅速扩大[47]。CAR-T细胞疗法结合PD-1阻断剂已在血液恶性肿瘤的治疗中显示出协同效应。有研究证实，B细胞淋巴瘤在CAR-T细胞输注后使用帕博利珠单抗治疗是安全的，且耐受性良好。对CAR-T细胞治疗有应答与无应答患者在细胞生物学上存在潜在差异，这种差异影响了PD-1阻断的临床疗效[48]。一项CAR-T联合PD-1抑制剂的临床试验的Ⅰ期(NCT02414269)主要阐述了以间皮素为靶点的自体CAR-T细胞与帕博利珠单抗联用治疗恶性胸膜间皮瘤的临床疗效，中位生存期达到23.9个月，安全性耐受性良好，该研究中其他实体瘤中联合治疗方案应进一步评估[49]。此外，肿瘤细胞可以通过上调免疫检查点分子，如PD-L1和细胞毒性T细胞相关抗原4(CTLA-4)来增强CAR-T细胞的耐药性，并参与代谢竞争[11]。CAR-T细胞治疗实体瘤面临重大障碍，包括PD-1/PD-L1轴介导的T细胞抑制。CAR抗原亲和力可能是调节T细胞对PD-1/PD-L1轴敏感性的关键因素[50]。Ba等[51]研究结果表明，tmTNF-αCAR-T细胞具有强大的抗肿瘤作用，抗PD-L1/PD-1可以增强这种作用，因为tmTNF-α信号传导诱导三阴性乳腺癌(TNBC)中PD-L1的高表达，而在消化道肿瘤方面，一项单臂、开放标签、Ⅰ期临床试验(NCT03874897)、satri-cel联合PD-1抑制剂治疗标准化疗难治的消化道肿瘤，表现出良好的安全性和有效性[27]。 3.1.2 分泌免疫检查点抑制剂的CAR-T细胞检查点抑制剂和CAR-T细胞的协同治疗作用引起了装甲CAR-T细胞的发展，该装甲CAR-T细胞分泌免疫检查点抑制剂以克服实体瘤内的免疫抑制，它们具有限制CAR-T有效性的物理和免疫障碍[52]。T细胞可以被修饰以分泌抗体来抑制检查点(PD-1/PD-L1/CTLA-4)用于增强CAR-T疗法的强度、有效性和持久性，Suarez等[53]创建了可以分泌抗PD-L1抗体的CAR-T细胞，以实现延长癌细胞的消除，而不是使用PD-1阻断抗体。研究人员已经开发出具有抗PD-1自我分泌或PD-1沉默能力的CAR-T细胞，以阻断PD-1的负调控途径。PD-1阻断CAR-T细胞靶向表皮生长因子受体(EGFR)vⅢ表达细胞，显示出改善的抗PD-1抗体。在胶质母细胞瘤的小鼠模型中的肿瘤活性和延长的存活[54]。Fang等[55]计了具有自分泌抗PD-1 scFv模块的CAR-T细胞，以促进T细胞功能的调节：CAR-T只有在抗原接合后才有活性，以控制肿瘤部位抗PD-1抗体的分泌。这些研究人员将抗PD-1抗体基因上游的启动子构建体和CAR构建体共转染到T细胞中。这些抗PD-1CAR-T细胞具有较低的PD-1表达，较高的T细胞活化水平和更好的抗肿瘤活性，在体外和体内特异性针对间皮素(MSLN)和PD-L1阳性肿瘤细胞[55]。相反也有研究表明，CAR效应细胞会触发靶细胞上PD-L1的表达，在PD-L1-CAR的情况下，导致独特的自扩增现象。这种自我放大效应可能是PD-L1-CAR-T细胞对恶性和非恶性细胞的细胞毒性增强的原因，这意味着在将PD-L1-CER策略引入临床研究时要格外谨慎[56]。 3.2 与靶向药物的联合应用单克隆抗体和小分子抑制剂等靶向治疗提高了CAR-T细胞的浸润性和特异性。单克隆抗体靶向细胞表面特异性抗原，而小分子药物可以通过质膜转运，干扰与肿瘤生长、存活、血管生成和转移相关的酶活性和信号通路[57]。单克隆抗体既可以靶向肿瘤细胞上过表达的受体，如HER-2、EGFR、血管内皮生长因子受体(VEGFR)等，也可以靶向其配体以中和细胞表面的这些受体，如贝伐单抗用于血管内皮生长因子(VEGF)。大多数小分子靶向许多肿瘤中增殖和存活的信号转导机制；例如酪氨酸或丝氨酸/苏氨酸激酶和促分裂原活化蛋白激酶(MAPK)信号级联。激酶抑制剂可以靶向肿瘤中具有异常活化或失调的几种生长因子受体，例如EGFR、VEGFR、胰岛素样生长因子1受体(IGFR)，VEGF信号传导诱导抑制CD8+T细胞增殖并降低其细胞毒性活性[58]。此外，VEGF-A可诱导肿瘤浸润性CD8+T细胞上的PD-1表达，表明CAR-T细胞可能受益于VEGF-VEGFR通路阻断[59]。上述机制均说明CAR-T与靶向治疗联合的潜力，目前更多研究者将目光聚焦CAR-T治疗靶点，而联合治疗案例罕有报道，采用索拉非尼和磷脂酰肌醇蛋白聚糖3(GPC3) CAR-T(代号CT011)联合治疗肝细胞癌，取得了完全缓解的效果，表明GPC3 CAR-T有可能用于肝细胞癌早线治疗[60]。 3.3 CAR-T与局部治疗的协同增效 3.3.1 CAR-T治疗与手术将CAR-T治疗与手术相结合可能会减少肿瘤复发并对预后产生积极影响。CAR-T细胞的优势和局限性对于外科手术治疗都是至关重要的，也有越来越多的研究探索非手术治疗方式和CAR-T细胞的联合治疗模式，来改善手术和非手术干预的预后。伤口愈合，功能/美学恢复和围术期患者管理可以明显改善手术治疗疗效[61]。在这项研究中，含有人类CAR-T细胞的特殊凝胶应用于小鼠部分肿瘤切除后的手术伤口，几乎所有的病例中，CAR-T细胞显著地消除了残留的肿瘤细胞，使小鼠存活下来，免于肿瘤复发导致的死亡[62]。 3.3.2 CAR-T腹膜内给药肿瘤细胞减灭术和腹腔热灌注化疗(hyperthermicintroperitoneal chemotherapy，HIPEC)在治疗高肿瘤负荷的腹膜播散癌(peritoneal carcinomatosis，PC)方面效果较差，但缺乏能够提高生存率的治疗方法。目前的治疗，包括细胞减灭术联合HIPEC，中位总生存期为18~21个月[63-64]。Katz等[65]首次描述了使用CAR-T治疗PC，他们在动物模型中使用靶向CEA的CAR-T细胞治疗结直肠PC。作者观察到腹膜内给药优于全身给药。与全身给药相比，腹膜内输注与更高的肿瘤减少率和更持久的效果有关，因此表明可以防止复发和其他远处转移。此外，CAR-T细胞的腹膜内给药在皮下结节等远端部位显示出抗肿瘤活性，这不是CAR-T细胞直接作用的结果；相反，它是与放疗中发生的远位效应类似的效应结果。这种机制是由CAR-T细胞破坏后释放多种肿瘤抗原触发的，允许它们被树突状细胞识别，并产生针对CAR-T靶标以外的抗原的免疫应答[66]。 4 临床转化瓶颈与突破路径当前CAR-T整合治疗消化道肿瘤的临床转化面临三大核心障碍：靶点筛选的临床转化效率低：多数靶点仍处于基础研究阶段，从实验室到临床试验的转化周期长达3~5年，需建立“靶点-动物模型-临床试验”的快速转化平台；联合方案的临床试验设计复杂：多疗法联合涉及给药顺序、剂量调整、毒性叠加等问题，如CAR-T与PD-1抑制剂联合的最佳给药间隔尚未明确，需开展更多剂量递增和给药时序探索的Ⅰ期临床试验；成本控制困难：自体CAR-T的个性化制备流程导致成本居高不下，需推进通用型CAR-T的研发，同时优化细胞制备工艺，降低耗材成本。突破路径包括：建立多中心HIM研究联盟，实现临床样本、数据共享；提高临床试验效率；政策层面加大对创新CAR-T药物的扶持，推动医保准入，降低患者负担。 HIM为CAR-T疗法突破消化道肿瘤困境提供了方案。本综述提出的“靶点精准定位-医工技术赋能-多疗法协同-临床转化落地”四维整合创新路径，是对传统CAR-T研究视角的重要补充。从Claudan18.2等靶点定位，到CT041的临床获益，再到多手段协同探索，CAR-T已成为整合治疗核心，印证“多学科融合”是必然趋势。对胃癌、结直肠癌、食管癌等消化道肿瘤，CAR-T联合免疫、靶向、局部治疗等探索已显示出潜力。随着HIM深入，协同疗法克服CAR-T在消化道肿瘤治疗的固有瓶颈，实现CAR-T疗法的全方位突破，为患者带来更优选择，推动肿瘤治疗迈入新阶段用。参考文献向上滑动查看 [1] Fan DM. Holistic integrative medicine：toward a new era of medical advancement [J]. Front Med，2017，11 (1)：152-159. DOI：10.1007/s11684-017-0499-6. [2] Du B，Qin JL，Lin BX，et al. CAR-T therapy in solid tumors[J]. Cancer Cell， 2025， 43 (4)： 665-679. DOI：10.1016/j.ccell. 2025.03.019. [3] 中国整合医学发展战略研究院，樊代明. 整合医学宣言[J]. 空军军医大学学报，2024，45(7)：721-722. [4] 中国抗癌协会. 2025 CACA 华北整合肿瘤学大会在京成功召开[J]. 癌症康复，2025(3)：封3. [5] 中国抗癌协会胃癌专业委员会，梁寒，徐惠绵，等. 2024 版CACA 胃癌整合诊治指南(精简版)[J]. 中国肿瘤临床，2024，51(13)：650-657. [6] 中国抗癌协会腹膜肿瘤专业委员会. 中国肿瘤整合诊治指南：腹膜肿瘤(胃肠肿瘤部分)[J/CD]. 消化肿瘤杂志(电子版)，2023，15(2)：100-108. DOI10.3969/j.issn.1674-7402.2023. 02.002. [7] Bray F，Laversanne M，Sung H，et al. Global cancer statistics 2022：GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin，2024，74(3)：229-263. DOI：10.3322/caac.21834. [8] 张希，杨雷，刘硕，等. 2022 年全球恶性肿瘤统计报告解读[J].中华肿瘤杂志，2024，46 (7)：710-721. DOI：10.3760/cma.j.cn112152-20240416-00152. [9] Zhang XM，Zhu LL，Zhang H，et al. CAR-T cell therapy inhematological malignancies：current opportunities and challenges[J]. Front Immunol，2022，13 (1)：927153. DOI：10.3389/fimmu.2022.927153. [10] Liu Y，An LN，Huang RH，et al. Strategies to enhance CAR-T persistence [J]. Biomark Res，2022，10 (1)：86. DOI：10.1186/s40364-022-00434-9. [11] Lamplugh ZL， Wellhausen N， June CH， et al.Microenvironmental regulation of solid tumour resistance to CAR T cell therapy [J]. Nat Rev Immunol，2025，25 (10)：1. DOI：10.1038/s41577-025-01229-3. [12] Maalej KM，Merhi M，Inchakalody VP，et al. CAR-cell therapy in the era of solid tumor treatment： current challenges and emerging therapeutic advances[J]. Mol Cancer，2023，22(1)：20.DOI：10.1186/s12943-023-01723-z. [13] Nguyen A，Johanning G，Shi YH. Emerging novel combined CAR-T cell therapies [J]. Cancers，2022，14 (6)：1403. DOI：10.3390/cancers14061403. [14] Ren P，Zhang CY，Li WP，et al. CAR-T therapy in clinical practice：technical advances and current challenges[J]. Adv Biol，2022，6(8)：e2101262. DOI：10.1002/adbi.202101262. [15] Wei JS，Han X，Bo J，et al. Target selection for CAR-T therapy [J]. J Hematol Oncol，2019，12 (1)：62. DOI：10.1186/s13045-019-0758-x. [16] Shitara K， Lordick F， Bang YJ， et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive，HER2-negative， untreated，locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT)： a multicentre，randomised，double-blind，phase 3 trial[J]. Lancet，2023，401 (10389)：1655-1668. DOI：10.1016/S0140-6736 (23)00620-7. [17] Qi CS，Liu C，Peng Z，et al. Claudin-18 isoform 2-specific CAR T-cell therapy (satri-cel) versus treatment of physician’s choice for previously treated advanced gastric or gastro-oesophageal junction cancer (CT041-ST-01)： a randomised， open-label， phase 2 trial [J]. Lancet，2025，405 (10494)：2049-2060. DOI： 10.1016/S0140-6736(25)00860-8. [18] Fan J，Das JK，Xiong X，et al. Development of CAR-T cell persistence in adoptive immunotherapy of solid tumors [J]. Front Oncol， 2020， 10 (1)： 574860. https：//doi.org/10.3389/fonc. 2020.574860. [19] Zhang C，Wang Z，Yang Z，et al. Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers[J]. Mol Ther，2017，25 (5)：1248-1258. https：//doi.org/10.1016/j.ymthe.2017.03.010. [20] Li D，Guo XL，Yang K，et al. EpCAM-targeting CAR-T cell immunotherapy is safe and efficacious for epithelial tumors[J]. SciAdv，2023，9(48)：eadg9721. DOI：10.1126/sciadv.adg9721. [21] Jing X，Liang HP，Hao CH，et al. Overexpression of MUC1 predicts poor prognosis in patients with breast cancer [J]. Oncol Rep，2019，41(2)：801-810. DOI：10.3892/or.2018.6887. [22] Shao QZ， Deng JG，Wu HR， et al. HER2-positive gastric cancer：from targeted therapy to CAR-T cell therapy [J]. Front Immunol，2025，16：1560280. DOI：10.3389/fimmu.2025.1560280. [23] Song YJ，Tong C，Wang Y，et al. Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo [J]. Protein Cell，2018，9 (10)：867-878. DOI：10.1007/s13238-017-0384-8. [24] Feng KC，Liu Y，Guo YL，et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers [J]. Protein Cell，2018，9(10)：838-847. DOI：10.1007/s13238-017-0440-4. [25] Uslu U，Castelli S，June CH. CAR T cell combination therapies to treat cancer [J]. Cancer Cell，2024，42 (8)：1319-1325. DOI：10.1016/j.ccell.2024.07.002. [26] Chi XW，Yang PW，Zhang EH，et al. Significantly increased anti-tumor activity of carcinoembryonic antigen-specific chimeric antigen receptor T cells in combination with recombinant human IL-12[J]. Cancer Med，2019，8(10)：4753-4765. DOI：10.1002/cam4.2361. [27] Qi CS，Liu C，Gong JF，et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers：phase 1 trial final results [J]. Nat Med， 2024， 30 (8)： 2224-2234. DOI：10.1038/s41591-024-03037-z. [28] Xia BJ，Feng HL，Jiang XM，et al. Development of chimeric Nanobody-Granzyme B functionalized ferritin nanoparticles for precise tumor therapy[J]. Pharmacol Res，2025，213(3)：107628. DOI：10.1016/j.phrs.2025.107628. [29] Cao WJ， Xing HZ， Li YM， et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy [J]. Biomark Res， 2022， 10 (1)： 38. DOI：10.1186/s40364-022-00385-1. [30] Van Cutsen E，Bang YJ，FENG-YI F，et al. HER2 screening data from ToGA：targeting HER2 in gastric and gastroesophageal junction cancer[J]. Gastric Cancer，2015，18(3)：476-484. https：//doi.org/10.1007/s10120-014-0402-y. [31] Ai KX，Liu BW，Chen XM，et al. Optimizing CAR-T cell therapy for solid tumors： current challenges and potential strategies[J]. J Hematol Oncol，2024，17(1)：105. DOI：10.1186/s13045-024-01625-7. [32] Wang HY，Wu ZR，Cui D，et al. Triple knockdown of CD11a， CD49d，and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice[J]. Sci Transl Med， 2025，17(782)：eadl6432. DOI：10.1126/scitranslmed.adl6432. [33] Wang SY， Li X， Ning HM， et al. Dual-target CAR-T cell therapy： a new strategy to improve the therapeutic effect of hematological malignancies [J]. Crit Rev Oncol Hematol，2025， 214(10)：104824. DOI：10.1016/j.critrevonc.2025.104824. [34] Peng JJ，Wang LM，Li ZY，et al. Metabolic challenges and interventions in CAR T cell therapy [J]. Sci Immunol，2023，8 (82)：eabq3016. DOI：10.1126/sciimmunol.abq3016. [35] Ando M，Ito M，Srirat T，et al. Memory T cell，exhaustion，and tumor immunity [J]. Immunol Med，2020，43 (1)：1-9. DOI：10.1080/25785826.2019.1698261. [36] Stadtmauer EA， Fraietta JA， Davis MM， et al. CRISPRengineered T cells in patients with refractory cancer [J]. Science，2020，367(6481)：eaba7365. DOI：10.1126/science.aba7365. [37] Chan JD，Scheffler CM，Munoz I，et al. FOXO1 enhances CAR T cell stemness，metabolic fitness and efficacy[J]. Nature，2024，629(8010)：201-210. DOI：10.1038/s41586-024-07242-1. [38] Cieri N， Camisa B， Cocchiarella F， et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naïve precursors [J]. Blood，2013，121 (4)：573-584. DOI：10.1182/blood-2012-05-431718. [39] Zhou JX，Jin LY，Wang FP，et al. Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects[J]. Protein Cell，2019，10(10)：764-769. DOI：10.1007/s13238-019-0643-y. [40] Rubtsov YP，Rudensky AY. TGFbeta signalling in control of Tcell-mediated self-reactivity [J]. Nat Rev Immunol，2007，7(6)：443-453. DOI：10.1038/nri2095. [41] Zheng S，Che X，Zhang K，et al. Potentiating CAR-T cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal[J]. Mol Ther，2025，33(2)：688-702. DOI：10.1016/j.ymthe.2024.12.014. [42] Li GC，Guo JT，Zheng YF，et al. CXCR5 guides migration and tumor eradication of anti-EGFR chimeric antigen receptor T cells [J]. Mol Ther Oncolytics，2021，22(1)：507-517. DOI：10.1016/j.omto.2021.07.003. [43] Vincent RL，Gurbatri CR，Li FD，et al. Probiotic-guided CAR-T cells for solid tumor targeting [J]. Science，2023，382 (6667)： 211-218. DOI：10.1126/science.add7034. [44] Reinhard K，Rengstl B，Oehm P，et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors [J]. Science，2020，367 (6476)：446-453. DOI：10.1126/science.aay5967. [45] De Munter S，Ingels J，Goetgeluk G，et al. Nanobody based dual specific CARs [J]. Int J Mol Sci，2018，19 (2)：403. DOI：10.3390/ijms19020403. [46] Misawa K，Bhat H，Adusumilli PS，et al. Combinational CAR Tcell therapy for solid tumors：requisites，rationales，and trials[J]. Pharmacol Ther， 2025， 266 (2)： 108763. DOI：10.1016/j.pharmthera.2024.108763. [47] Beaver JA，Pazdur R. The wild west of checkpoint inhibitor development [J]. N Engl J Med，2022，386 (14)：1297-1301. DOI：10.1056/NEJMp2116863. [48] Chong EA，Alanio C，Svoboda J，et al. Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR Tcell therapy[J]. Blood，2022，139(7)：1026-1038. DOI：10.1182/ blood.2021012634. [49] Adusumilli PS，Zauderer MG，Rivière I，et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease，in combination with the anti-PD-1 agent pembrolizumab [J]. Cancer Discov，2021，11 (11)：2748-2763. DOI：10.1158/2159-8290.CD-21-0407. [50] Andreu-Saumell I，Rodriguez-Garcia A，Mühlgrabner V，et al. CAR affinity modulates the sensitivity of CAR-T cells to PD-1/ PD-L1-mediated inhibition[J]. Nat Commun，2024，15(1)：3552. DOI：10.1038/s41467-024-47799-z. [51] Ba HP，Dai ZG，Zhang ZY，et al. Antitumor effect of CAR-T cells targeting transmembrane tumor necrosis factor alpha combined with PD-1 MAb on breast cancers [J]. J Immunother Cancer，2023，11(1)：e003837. DOI：10.1136/jitc-2021-003837. [52] Rodriguez-Garcia A，Palazon A，Noguera-Ortega E，et al. CART cells hit the tumor microenvironment：strategies to overcome tumor escape [J]. Front Immunol，2020，11 (1)：1109. DOI：10.3389/fimmu.2020.01109. [53] Suarez ER，Chang DK，Sun JS，et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model[J]. Oncotarget， 2016，7(23)：34341-34355. DOI：10.18632/oncotarget.9114. [54] Song YJ，Liu QT，Zuo T，et al. Combined antitumor effects of anti-EGFR variant III CAR-T cell therapy and PD-1 checkpoint blockade on glioblastoma in mouse model [J]. Cell Immunol，2020，352(6)：104112. DOI：10.1016/j.cellimm.2020.104112. [55] Fang Y，Zhang YJ，Guo CX，et al. Safety and efficacy of an immune cell-specific chimeric promoter in regulating anti-PD-1 antibody expression in CAR T cells[J]. Mol Ther Meth Clin Dev，2020，19(1)：14-23. DOI：10.1016/j.omtm.2020.08.008. [56] Bajor M，Graczyk-Jarzynka A，Marhelava K，et al. PD-L1 CAR effector cells induce self-amplifying cytotoxic effects against target cells [J]. J Immunother Cancer，2022，10 (1)：e002500.DOI：10.1136/jitc-2021-002500. [57] Roskoski R. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes [J]. Pharmacol Res，2016，103 (1)：26-48. DOI：10.1016/j.phrs.2015.10.021. [58] Yoshida T， Zhang GL， Smith MA， et al. Tyrosine phosphoproteomics identifies both codrivers and cotargeting strategies for T790M-related EGFR-TKI resistance in non-small cell lung cancer[J]. Clin Cancer Res，2014，20(15)：4059-4074. DOI：10.1158/1078-0432.CCR-13-1559. [59] Voron T，Colussi O，Marcheteau E，et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+T cells in tumors[J]. J Exp Med， 2015， 212 (2)： 139-148. DOI：10.1084/jem.20140559. [60] Sun H，Xing C，Jiang S，et al. Long term complete response of advanced hepatocellular carcinoma to glypican-3 specific chimeric antigen receptor T-Cells plus sorafenib，a case report[J]. Front Immunol，2022，13 (1)：963031. https：//doi.org/10.3389/fimmu.2022.963031. [61] Knoedler L，Herfeld K，Schaefer DA，et al. CAR-T cell therapy and reconstructive oncologic surgery in peripheral solid tumors：a narrative review [J]. Cell Rep Med，2025，6 (8)：102240. DOI：10.1016/j.xcrm.2025.102240. [62] Uslu U， Da T， Assenmacher CA， et al. Chimeric antigen receptor T cells as adjuvant therapy for unresectable adenocarcinoma [J]. Sci Adv，2023，9 (2)：eade2526. DOI：10.1126/sciadv.ade2526. [63] Yang XJ，Huang CQ，Suo T，et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer：final results of a phase III randomized clinical trial [J]. Ann Surg Oncol， 2011， 18 (6)： 1575-1581. DOI：10.1245/s10434-011-1631-5. [64] Gill RS，Al-Adra DP，Nagendran J，et al. Treatment of gastric cancer with peritoneal carcinomatosis by cytoreductive surgery and HIPEC：a systematic review of survival， mortality， and morbidity [J]. J Surg Oncol，2011，104 (6)：692-698. DOI：10.1002/jso.22017. [65] Katz SC，Point GR，Cunetta M，et al. Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery [J]. Cancer Gene Ther，2016，23 (5)：142-148. DOI：10.1038/cgt.2016.14. [66] Benmebarek MR， Karches CH， Cadilha BL， et al. Killing mechanisms of chimeric antigen receptor (CAR) T cells [J]. Int J Mol Sci，2019，20(6)：1283. DOI：10.3390/ijms20061283. 声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。来源：《中国药物与临床》编辑：Lagertha 审核：素问

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2025-07-09

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抗癌月报（6月）|上市新药，CAR-T，癌症疫苗等新技术进展汇总

在生命与病魔的漫长拔河中，抗癌之路仿若暗夜行舟，每一次新突破都似远方亮起的航标。踏入6 月，抗癌领域再次迎来诸多令人瞩目的进展，宛如熠熠星辰照亮前行方向。新药的上市为患者开启全新希望之门，CAR - T 技术持续革新，在精准打击癌细胞的征程中迈出坚实步伐，癌症疫苗的研发也不断传来佳音，为人类抵御癌症构筑更坚固防线。抗癌新药月报（2025.6） MET扩增有救了！国研肺癌新药赛沃替尼震撼上市！ 6月30日，和黄医药宣布沃瑞沙（ORPATHYS，赛沃替尼/ savolitinib）和泰瑞沙（TAGRISSO，奥希替尼/ osimertinib）的联合疗法的新药上市申请获中国国家药品监督管理局（NMPA）批准，用于治疗表皮生长因子受体（EGFR）基因突变阳性经EGFR酪氨酸激酶抑制剂（TKI）治疗后进展的伴MET扩增的局部晚期或转移性非鳞状非小细胞肺癌患者。沃瑞沙是一款选择性MET抑制剂，用于治疗伴有MET外显子14 跳变的局部晚期或转移性非小细胞肺癌成人患者。临床研究结果显示：沃瑞沙和泰瑞沙的联合疗法降低患者的疾病进展风险达66%，中位PFS为8.2个月，而化疗组则为4.5个月。小细胞肺癌新药度伐利尤单抗获批上市 6月4日，阿斯利康宣布抗PD-L1单抗度伐利尤单抗已获中国国家药品监督管理局(NMPA)批准新适应症，作为单药用于在接受铂类药物为基础的放化疗后未出现疾病进展的局限期小细胞肺癌（LS-SCLC）成人患者的治疗。此次获批是基于ADRIATIC 3期临床试验的积极结果，数据显示：接受度伐利尤单抗治疗的患者显示出了显著的总生存获益，三年总生存率高达57%，度伐利尤单抗有望成为中国乃至全球的治疗新标准。宫颈癌一线治疗迎来重磅新方案 6月4日，中国国家药监局（NMPA）官网最新公示，康方生物研发的PD-1/CTLA-4双特异性抗体卡度尼利单抗注射液的一项新适应症上市申请已获得批准。根据康方生物早先新闻稿，该药本次获批的适应症为：卡度尼利单抗加含铂化疗联合/不联合贝伐珠单抗用于一线治疗持续、复发或转移性宫颈癌。 ROS1肺癌新药获FDA批准上市！ Taletrectinib 是一种强效的新一代ROS1靶向药，在未接受 TKI 治疗和接受克唑替尼治疗的ROS1+ NSCLC 患者中均表现出显著的疗效。在未接受 TKI 治疗和接受克唑替尼治疗的患者中均观察到高且持久的 ORR，无论采用哪种治疗方案，颅内 ORR 均较高，未接受 TKI 治疗和接受克唑替尼治疗的患者的 PFS 延长，并且对 G2032R 的活性也具有很高的临床意义，为ROS1 TKI 治疗领域增添了新的选择！2025 年 6 月 11 日，美国食品药品监督管理局批准激酶抑制剂塔雷替尼 (Ibtrozi，Nuvation Bio Inc.) 用于治疗局部晚期或转移性 ROS1 阳性非小细胞肺癌 (NSCLC) 的成年人。奥希耐药迎来新方案！Dato-DXd获批上市 2025 年 6 月 23 日，美国食品药品监督管理局加速批准 datopotamab deruxtecan-dlnk（Datroway，第一三共株式会社），用于治疗已接受过 EGFR 靶向治疗和铂类化疗的局部晚期或转移性表皮生长因子受体 (EGFR) 突变非小细胞肺癌 (NSCLC) 成人患者。研究结果显示：既往接受奥希替尼（Tagrisso；n = 96）治疗的患者客观缓解率（ORR）高达 44.8% ，其中 4.2% 的患者肿瘤靶病灶全部消失，达到完全缓解（ CR），疾病控制率（DCR ）为 85.4% 。中位无进展生存期（ PFS）和总生存期（ OS）分别为 5.7 个月和 14.7 个月。抗癌新药招募（2025.6）肺癌药品名称： SYS6010 作用靶点： EGFR 研发公司：石药药物介绍： SYS6010抗肿瘤1类新药SYS6010是一种EGFR抗体-偶联药物，其与肿瘤细胞表面的EGFR受体结合后，通过内吞作用进入到细胞内，在溶酶体内被蛋白酶降解，释放毒素小分子JS-1(新型拓扑异构酶I抑制剂)，JS-1和DNA形成稳定复合物，诱导DNA损伤，进而导致细胞凋亡，且发挥旁观效应非特异性杀伤周围肿瘤组织细胞。临床前研究发现SYS6010对EGFR高表达的人结直肠癌(DiFi)、人乳腺癌(MDA-MB-468)移植瘤模型具有抗肿瘤作用，对一代TKI吉非替尼耐药的非小细胞肺腺癌PC9-GR、L858R/T790M双突变的非小细胞肺癌NCI-H1975、三代TKI奥希替尼耐药且Ex19del/T790M/C797S三突变的非小细胞肺癌PC9-DTC等移植瘤模型也有显著的抗肿瘤作用，药效均显著优于基于MMAE或Dxd等成熟毒素的对照ADC药物。目前开展的I期临床试验中，该产品在非小细胞肺癌以及诸多瘤种患者中均显示出积极的抗肿瘤疗效。SYS6010已于2024年12月24日被CDE授予经EGFR-TKI和含铂化疗治疗失败的EGFR突变阳性晚期NSCLC突破性治疗。招募信息（部分）： 1.组织学确诊的局部晚期或转移性NSCLC患者，包括：基于AJCC分期第8版，ⅢB或ⅢC期且不适合进行手术切除或接受根治性放化疗患者，或IV期NSCLC患者。既往接受过针对局部晚期或转移性疾病的EGFR TKI治疗且治疗失败（必须包括三代已上市EGFR TKI）的EGFR突变型局部晚期或转移性NSCLC； 2.至少携带一种EGFR敏感突变（ex19del、L858R、G719X、S768I或L861Q，可合并其他EGFR突变）。药品名称： SYS6040 作用靶点：小细胞肺癌研发公司：石药药物介绍： SYS6040是一种靶向人DLL3的ADC。 SYS6040可与表达DLL3的肿瘤细胞特异性结合，通过受体介导的内吞作用进入细胞并释放毒性载荷，从而起到杀伤肿瘤细胞作用。适应症：经组织学或细胞学证实的晚期小细胞肺癌队列1:既往至少接受一线含铂化疗失败或不耐受的 SCLC参与者队列 2:既往经标准治疗失败或标准治疗方案不耐受或无标准治疗的其他神经内分泌肿瘤参与者队列3:既往经标准治疗失败或标准治疗方案不耐受或无标准治疗方案的 DLL3表达阳性的其他恶性实体瘤参与者。药品名称：谷美替尼作用靶点： MET 研发公司：海和药物适应症：MET过表达的局部晚期或转移性非小细胞肺癌药物介绍：谷美替尼（商品名：海益坦；英文通用名：Glumetinib；代号：SCC244）是一款口服强效、高选择性小分子MET抑制剂。临床前研究显示谷美替尼可强效和特异性靶向抑制MET激酶活性，并可以选择性抑制MET异常的非小细胞肺癌（NSCLC）肿瘤模型的生长。此外，临床研究结果显示，谷美替尼具有优良的药代动力学特性以及良好的安全性和耐受性，并且在具有MET改变的晚期NSCLC人群中显示了明确疗效。2023年3月8日，国家药监局（NMPA）官网最新公示，谷美替尼的上市申请已获得附条件批准，用于治疗MET外显子14跳变的局部晚期或转移性NSCLC患者。招募信息（部分）：　经由申办方指定的中心实验室确认肿瘤组织标本中MET过表达： ①3+，≥90%； ②3+，50%~89%； ③≥ 2+，≥50%且3+，<50%。胃癌试验药组LM302注射液药物介绍CLDN18.2ADCC单克隆抗体适合患者无法手术切除初治胃癌，需要CLDN18.2 表达阳性。HER-2 阴性的胃和胃食管结合部腺。试验药组TQB2103药物介绍Claudin 18.2ADC适合患者标准治疗后不耐受或进展，需要CLDN18.2 表达检测。HER-2 阴性的胃和胃食管结合部腺癌试验药组SYSA1801药物介绍Claudin 18.2ADC适合患者无法手术切除初治胃癌，需要CLDN18.2 表达检测。尿路上皮癌【项目名称】： SYS6002 联合 SG001 在晚期尿路上皮癌及其他晚期实体瘤患者中的安全性、耐受性、药代动力学特征和初步疗效的开放、多中心Ⅱ期临床试验。【入排信息（部分）】：对于一线尿路上皮癌需要满足：病理学确诊的、未接受过系统性抗肿瘤治疗的局部晚期或转移性尿路上皮癌患者，如果既往接受过新辅助或辅助治疗，则新辅助或辅助治疗结束至疾病进展（影像学证实）的时间间隔超过 12 个月可入组；对于后线尿路上皮癌需要满足：病理学确诊的、既往接受过含铂化疗治疗或不耐受或不适合接受含铂治疗的尿路上皮癌患者。其他热招新药【项目名称】评价Vx-001在晚期实体瘤/非小细胞肺癌患者中的安全性、免疫原性和临床抗肿瘤效果的剂量递增和扩展临床研究。【入排信息（部分）】： 1.经组织学和/或细胞学明确诊断为局部晚期或复发、转移性非小细胞肺癌患者，既往PD-1/PD-L1 治疗失败或不适合 PD-1/PD.L1治疗，且接受过完整含铂类化疗治疗(4~6 个疗程)后，无疾病进展； 2.18 周岁≤年龄≤75 周岁，性别不限； 3.患者 HLA 抗原检测必须含有 HLAA*0201型(多肽呈递的基序仅与该 HLA 分子匹配)TERT 表达阳性且肿瘤浸润淋巴细胞(CD3/CD8 TILS)表达为阴性4)根据实体瘤疗效评价标准(RECISTv1.1)，具有至少一个可测量病灶。【项目名称】实体瘤疫苗-ABO2011 【入排信息（部分）】 1、受试者必须为18岁及以上。 2、经病理组织学或细胞学证实的进展或转移的晚期实体瘤。 3、既往接受过系统性标准治疗后疾病进展或不可耐受毒性(不可耐受毒性定义:>IV级的血液学毒性;或>亚级的非血液学毒性:或>工级的心、肝、肾等主要脏器的损害)，且缺乏有效治疗方案的晚期实体瘤。抗癌新技术进展（2025.6）实现近10年无癌超长生存！“钻石”靶点GPC3为晚期肝癌创下生命奇迹！ CT011是肝细胞癌中同类首创的针对GPC3靶点的CAR T细胞疗法。2015年5月，国内知名的癌症中心启动了全球首个针对GPC3(Glypican-3)蛋白的CAR T细胞疗法治疗晚期肝细胞癌的临床研究，这项研究数据曾在2020年发表在国际重磅肿瘤学期刊《Clin Cancer Res》上。值得振奋的是，其中两位患者接受CAR-T治疗后，仅接受口服抗乙型肝炎病毒药物治疗，未接受其他癌症治疗。近日，两位幸运的患者接受了随访，截至目前已实现无癌超过9年，接近10年，完全回归正常生活！实现近10年无癌超长生存！“钻石”靶点GPC3为晚期肝癌创下生命奇迹！ 2名患者在最近一次随访（2025年4 月11日）时，仍处于无癌状态肠癌患者实现完全缓解！新型TIL疗法为胃肠道癌症患者带来生存新希望近日，一项刊登于国际顶级期刊《柳叶刀》的 Ⅰ 期临床研究（NCT04426669）带来震撼突破 —— 经 CRISPR-Cas9 基因编辑的肿瘤浸润淋巴细胞（TIL）疗法，通过敲除胞内免疫检查点基因 CISH，在转移性胃肠道癌患者中展现出显著抗肿瘤活性，尤其对传统免疫治疗耐药的患者实现完全缓解，为消化道肿瘤治疗开辟了全新路径。免疫治疗新边疆：新型TIL 疗法为胃肠道癌患者带来生存新希望第一个人体Ⅰ期研究入组的是18-70岁、一线治疗失败的转移性胃肠道组织上皮癌患者（包括疤痕、结直肠癌等），要求可手术肿瘤获得以制备TIL，且存在可测量病灶。2020年5月12日至2022年9月16日期间，共有22名参与者入组接受TIL治疗。结果显示：疾病控制率（DCR）第28天：50%（6/12）局势稳定（SD）第56天：33%（4/12）持续SD 值得警惕的是，1名幸运的微卫星不稳定性高（MSI-H）结直肠癌患者，在既往接受PD-1/CTLA-4联合治疗后，接受新型CISH敲除TIL治疗后，肿瘤靶病灶全部消失，实现完全缓解（CR），需持续超21个月，且未接受其他抗肿瘤治疗。全球首例！NK细胞疗法助胃癌患者无病生存近4年，点亮免疫治疗新希望自然杀伤（NK）细胞无需预先致敏即可诱导细胞毒性的独特特性，使其成为免疫治疗的理想选择。《Medicine》杂志曾报道一则经典案例：一位晚期胃印戒细胞癌（SRC）患者经NK细胞辅助治疗联合手术及化疗后，实现了长达46个月的无病生存。这一突破首次以临床实例证实了NK细胞辅助治疗在晚期胃印戒细胞癌中的显著价值！相信随着免疫治疗研究的不断深入，像NK细胞这样的创新疗法将为更多晚期癌症患者点燃生命的希望！ 41岁女性患者，确诊为胃窦小弯侧溃疡性低分化腺癌（以印戒细胞癌为主，伴少部分黏液腺癌），肿瘤大小7×6×1.8cm，侵犯胃壁全层，脉管内见癌栓，胃大弯侧部分淋巴结转移，术后病理分期为ⅢC期（T4a，N3a，M0），行根治性（R0）胃切除术后，接受6个周期奥沙利铂为基础的化疗方案。 NK细胞治疗后，患者肿瘤标志物检测及腹部CT扫描均恢复正常，CA72-4水平逐步降至正常范围。截至最后一次随访，患者已实现46个月（≈3.8年）无病生存，且状态良好，未见疾病进展迹象全身转移肿瘤消退！新型抗癌药ASKB589为晚期胃癌患者带来新选择 ASKB589 是 AskGene研发的一种创新生物药物，它是一种针对 CLDN 18.2 的重组人源化单克隆抗体。该药物通过与表达 CLDN18.2 的癌细胞高亲和力结合，介导抗体依赖性细胞介导的细胞毒作用 (ADCC) 和补体依赖性细胞毒作用 (CDC)。ASKB589 旨在治疗 G/GEJ 癌、胰腺癌以及表达 CLDN18.2 的其他癌症类型。 2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI）上公布了这款国研药物的鼓舞人心的最新数据。 ASKB589 联合化疗 (CAPOX) 和 PD-1 抑制剂作为局部晚期、复发和转移性胃 (G) 或胃食管连接部 (GEJ) 腺癌患者的一线治疗，疾病控制率高达 100% ！中位生存暴增5倍！《Science》揭示“粪菌移植+免疫”组合拳，打破PD-1耐药魔咒近期，国际顶刊《Science》发布的一项单臂临床试验（NCT03341143）带来颠覆性突破！研究团队大胆创新，将粪便微生物群移植（FMT）与抗PD-1疗法强强联合，直击转移性黑色素瘤患者的耐药困局。这场“菌群+免疫”的协同作战，不仅成功重塑肠道菌群生态，更强势改写肿瘤微环境的“免疫剧本”！15例患者中，6人重获临床获益，从而逆转了部分患者对抗PD-1药物的耐药性，为无数陷入治疗僵局的患者带来了新的希望与选择！想寻求癌症疫苗，TCR-T疗法及其他国内外新抗癌治疗帮助，且经济条件允许的情况下，可以先将病历提交至全球肿瘤医生网医学部进行初步评估，一旦审核通过，有机会获得”天价“疗法免费治疗的机会。过去十年，肿瘤的治疗已经取得了长足的进展，逆转了晚期患者的生存期，除了上面整理的内容，还有更多的新药正在研发中，更多的病友可以通过新药获得更长的生存期。让我们拭目以待，期待更多新药早日上市，造福大众！也期待2025，病友们能够打败癌症，活过一个又一个10年！本文为全球肿瘤医生网原创，未经授权严禁转载

上市批准免疫疗法细胞疗法临床3期临床结果

2025-06-09

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抗癌月报（5月）|上市新药，CAR-T，癌症疫苗等新技术进展汇总

在生命与病魔的漫长拔河中，抗癌之路仿若暗夜行舟，每一次新突破都似远方亮起的航标。踏入5 月，抗癌领域再次迎来诸多令人瞩目的进展，宛如熠熠星辰照亮前行方向。新药的上市为患者开启全新希望之门，CAR - T 技术持续革新，在精准打击癌细胞的征程中迈出坚实步伐，癌症疫苗的研发也不断传来佳音，为人类抵御癌症构筑更坚固防线。抗癌新药月报（2025.5）疾病控制率高达86.3%！国研肺癌KRAS新药--戈来雷塞震撼上市 2025年5月22日，针对KRAS突变有效，革命性国研抗癌药-- 枸橼酸戈来雷塞片（glecirasib，JAB-21822）获得中国国家药品监督管理局药品审评中心（NMPA）批准正式上市，用于单药治疗至少接受过一种系统性治疗的 KRAS G12C突变型晚期非小细胞肺癌（NSCLC）成人患者。同时，这款药物也有了自己的响当当的大名-- 艾瑞凯！原文链接：刚刚！国研肺癌KRAS新药--艾瑞凯震撼上市！疾病控制率高达86.3%！恒瑞PD-1“万金油”-卡瑞利珠单抗新适应症在华获批，宫颈癌缓解率达98% 2025年5月21日，国家药监局（NMPA）官网传来重磅喜讯——恒瑞医药研发的“卡瑞利珠单抗”新适应证正式在中国获批！与“苹果酸法米替尼”联合，用于既往接受含铂化疗失败的复发或转移性宫颈癌的治疗！这也是该药在中国获批的第十个适应症！这一突破性进展，标志着国内妇科肿瘤免疫联合治疗领域再攀高峰！两款药物强强联手，以“免疫治疗+抗血管生成”双重机制精准打击肿瘤，有望打破复发转移困境，为晚期宫颈癌患者点燃生命新曙光！刚刚！恒瑞PD-1“万金油”-卡瑞利珠单抗新适应症在华获批，宫颈癌缓解率达98% 百济神州HER2双抗「泽尼达妥单抗」在中国获批上市！ 5月29日），中国国家药监局（NMPA）官网最新公示，百济神州申报的1类新药注射用泽尼达妥单抗上市申请已经获得批准，适用于既往接受过全身治疗的HER2高表达（IHC3+）的不可切除局部晚期或转移性胆道癌患者。泽尼达妥单抗（ ZW25 ）是一种双特异性抗体，可诱导抗肿瘤活性，并且对HER2阳性经过各种治疗失败的患者具有良好的耐受性。里程碑！全球首款c-Met靶向ADC药物Teliso-V震撼获批！非小细胞肺癌中位总生存长达14.5个月 2025年5月14日，抗癌新药研发迎来历史性突破！ Telisotuzumab vedotin（Teliso-V）获得了美国食品药品监督管理局（FDA）的加速批准，用于既往接受过全身治疗的局部晚期或转移性、高c-Met蛋白过表达（OE）的非鳞状非小细胞肺癌（NSCLC）成人患者的治疗。作为目前全球唯一获批针对该适应症的创新疗法，Teliso-V以“精准靶向+c-Met过表达”的双重优势，正式开启该领域“专属治疗”新时代！这一突破不仅填补了临床空白，更意味着无数曾面临治疗困境的患者，终于等来了从“无药可治”到“精准破局”的全新生存希望！里程碑！全球首款c-Met靶向ADC药物Teliso-V震撼获批！非小细胞肺癌中位总生存长达14.5个月「卡度尼利」新适应症获批，一线治疗晚期宫颈癌！ 6月4日），中国国家药监局（NMPA）官网最新公示，康方生物研发的 PD-1/CTLA-4双特异性抗体卡度尼利单抗注射液的一项新适应症上市申请已获得批准。根据康方生物早先新闻稿，该药本次获批的适应症为：卡度尼利单抗加含铂化疗联合/不联合贝伐珠单抗用于一线治疗持续、复发或转移性宫颈癌。抗癌新药招募（2025.5）肺癌药品名称： SYS6010 作用靶点： EGFR 研发公司：石药药物介绍： SYS6010抗肿瘤1类新药SYS6010是一种EGFR抗体-偶联药物，其与肿瘤细胞表面的EGFR受体结合后，通过内吞作用进入到细胞内，在溶酶体内被蛋白酶降解，释放毒素小分子JS-1(新型拓扑异构酶I抑制剂)，JS-1和DNA形成稳定复合物，诱导DNA损伤，进而导致细胞凋亡，且发挥旁观效应非特异性杀伤周围肿瘤组织细胞。临床前研究发现SYS6010对EGFR高表达的人结直肠癌(DiFi)、人乳腺癌(MDA-MB-468)移植瘤模型具有抗肿瘤作用，对一代TKI吉非替尼耐药的非小细胞肺腺癌PC9-GR、L858R/T790M双突变的非小细胞肺癌NCI-H1975、三代TKI奥希替尼耐药且Ex19del/T790M/C797S三突变的非小细胞肺癌PC9-DTC等移植瘤模型也有显著的抗肿瘤作用，药效均显著优于基于MMAE或Dxd等成熟毒素的对照ADC药物。目前开展的I期临床试验中，该产品在非小细胞肺癌以及诸多瘤种患者中均显示出积极的抗肿瘤疗效。SYS6010已于2024年12月24日被CDE授予经EGFR-TKI和含铂化疗治疗失败的EGFR突变阳性晚期NSCLC突破性治疗。招募信息（部分）： 1.组织学确诊的局部晚期或转移性NSCLC患者，包括：基于AJCC分期第8版，ⅢB或ⅢC期且不适合进行手术切除或接受根治性放化疗患者，或IV期NSCLC患者。既往接受过针对局部晚期或转移性疾病的EGFR TKI治疗且治疗失败（必须包括三代已上市EGFR TKI）的EGFR突变型局部晚期或转移性NSCLC； 2.至少携带一种EGFR敏感突变（ex19del、L858R、G719X、S768I或L861Q，可合并其他EGFR突变）。药品名称： SYS6040 作用靶点：小细胞肺癌研发公司：石药药物介绍： SYS6040是一种靶向人DLL3的ADC。 SYS6040可与表达DLL3的肿瘤细胞特异性结合，通过受体介导的内吞作用进入细胞并释放毒性载荷，从而起到杀伤肿瘤细胞作用。适应症：经组织学或细胞学证实的晚期小细胞肺癌队列1:既往至少接受一线含铂化疗失败或不耐受的 SCLC参与者队列 2:既往经标准治疗失败或标准治疗方案不耐受或无标准治疗的其他神经内分泌肿瘤参与者队列3:既往经标准治疗失败或标准治疗方案不耐受或无标准治疗方案的 DLL3表达阳性的其他恶性实体瘤参与者。药品名称：谷美替尼作用靶点： MET 研发公司：海和药物适应症：MET过表达的局部晚期或转移性非小细胞肺癌药物介绍：谷美替尼（商品名：海益坦；英文通用名：Glumetinib；代号：SCC244）是一款口服强效、高选择性小分子MET抑制剂。临床前研究显示谷美替尼可强效和特异性靶向抑制MET激酶活性，并可以选择性抑制MET异常的非小细胞肺癌（NSCLC）肿瘤模型的生长。此外，临床研究结果显示，谷美替尼具有优良的药代动力学特性以及良好的安全性和耐受性，并且在具有MET改变的晚期NSCLC人群中显示了明确疗效。2023年3月8日，国家药监局（NMPA）官网最新公示，谷美替尼的上市申请已获得附条件批准，用于治疗MET外显子14跳变的局部晚期或转移性NSCLC患者。招募信息（部分）：　经由申办方指定的中心实验室确认肿瘤组织标本中MET过表达： ①3+，≥90%； ②3+，50%~89%； ③≥ 2+，≥50%且3+，<50%。胃癌试验药组LM302注射液药物介绍CLDN18.2ADCC单克隆抗体适合患者无法手术切除初治胃癌，需要CLDN18.2 表达阳性。HER-2 阴性的胃和胃食管结合部腺。试验药组TQB2103药物介绍Claudin 18.2ADC适合患者标准治疗后不耐受或进展，需要CLDN18.2 表达检测。HER-2 阴性的胃和胃食管结合部腺癌试验药组SYSA1801药物介绍Claudin 18.2ADC适合患者无法手术切除初治胃癌，需要CLDN18.2 表达检测。尿路上皮癌【项目名称】： SYS6002 联合 SG001 在晚期尿路上皮癌及其他晚期实体瘤患者中的安全性、耐受性、药代动力学特征和初步疗效的开放、多中心Ⅱ期临床试验。【入排信息（部分）】：对于一线尿路上皮癌需要满足：病理学确诊的、未接受过系统性抗肿瘤治疗的局部晚期或转移性尿路上皮癌患者，如果既往接受过新辅助或辅助治疗，则新辅助或辅助治疗结束至疾病进展（影像学证实）的时间间隔超过 12 个月可入组；对于后线尿路上皮癌需要满足：病理学确诊的、既往接受过含铂化疗治疗或不耐受或不适合接受含铂治疗的尿路上皮癌患者。其他热招新药【项目名称】评价Vx-001在晚期实体瘤/非小细胞肺癌患者中的安全性、免疫原性和临床抗肿瘤效果的剂量递增和扩展临床研究。【入排信息（部分）】： 1.经组织学和/或细胞学明确诊断为局部晚期或复发、转移性非小细胞肺癌患者，既往PD-1/PD-L1 治疗失败或不适合 PD-1/PD.L1治疗，且接受过完整含铂类化疗治疗(4~6 个疗程)后，无疾病进展； 2.18 周岁≤年龄≤75 周岁，性别不限； 3.患者 HLA 抗原检测必须含有 HLAA*0201型(多肽呈递的基序仅与该 HLA 分子匹配)TERT 表达阳性且肿瘤浸润淋巴细胞(CD3/CD8 TILS)表达为阴性4)根据实体瘤疗效评价标准(RECISTv1.1)，具有至少一个可测量病灶。【项目名称】实体瘤疫苗-ABO2011 【入排信息（部分）】 1、受试者必须为18岁及以上。 2、经病理组织学或细胞学证实的进展或转移的晚期实体瘤。 3、既往接受过系统性标准治疗后疾病进展或不可耐受毒性(不可耐受毒性定义:>IV级的血液学毒性;或>亚级的非血液学毒性:或>工级的心、肝、肾等主要脏器的损害)，且缺乏有效治疗方案的晚期实体瘤。抗癌新技术进展（2025.5）实现近10年无癌超长生存！“钻石”靶点GPC3为晚期肝癌创下生命奇迹！ CT011是肝细胞癌中同类首创的针对GPC3靶点的CAR T细胞疗法。2015年5月，国内知名的癌症中心启动了全球首个针对GPC3(Glypican-3)蛋白的CAR T细胞疗法治疗晚期肝细胞癌的临床研究，这项研究数据曾在2020年发表在国际重磅肿瘤学期刊《Clin Cancer Res》上。值得振奋的是，其中两位患者接受CAR-T治疗后，仅接受口服抗乙型肝炎病毒药物治疗，未接受其他癌症治疗。近日，两位幸运的患者接受了随访，截至目前已实现无癌超过9年，接近10年，完全回归正常生活！实现近10年无癌超长生存！“钻石”靶点GPC3为晚期肝癌创下生命奇迹！ 2名患者在最近一次随访（2025年4 月11日）时，仍处于无癌状态肠癌患者实现完全缓解！新型TIL疗法为胃肠道癌症患者带来生存新希望近日，一项刊登于国际顶级期刊《柳叶刀》的 Ⅰ 期临床研究（NCT04426669）带来震撼突破 —— 经 CRISPR-Cas9 基因编辑的肿瘤浸润淋巴细胞（TIL）疗法，通过敲除胞内免疫检查点基因 CISH，在转移性胃肠道癌患者中展现出显著抗肿瘤活性，尤其对传统免疫治疗耐药的患者实现完全缓解，为消化道肿瘤治疗开辟了全新路径。免疫治疗新边疆：新型TIL 疗法为胃肠道癌患者带来生存新希望第一个人体Ⅰ期研究入组的是18-70岁、一线治疗失败的转移性胃肠道组织上皮癌患者（包括疤痕、结直肠癌等），要求可手术肿瘤获得以制备TIL，且存在可测量病灶。2020年5月12日至2022年9月16日期间，共有22名参与者入组接受TIL治疗。结果显示：疾病控制率（DCR）第28天：50%（6/12）局势稳定（SD）第56天：33%（4/12）持续SD 值得警惕的是，1名幸运的微卫星不稳定性高（MSI-H）结直肠癌患者，在既往接受PD-1/CTLA-4联合治疗后，接受新型CISH敲除TIL治疗后，肿瘤靶病灶全部消失，实现完全缓解（CR），需持续超21个月，且未接受其他抗肿瘤治疗。全球首例！NK细胞疗法助胃癌患者无病生存近4年，点亮免疫治疗新希望自然杀伤（NK）细胞无需预先致敏即可诱导细胞毒性的独特特性，使其成为免疫治疗的理想选择。《Medicine》杂志曾报道一则经典案例：一位晚期胃印戒细胞癌（SRC）患者经NK细胞辅助治疗联合手术及化疗后，实现了长达46个月的无病生存。这一突破首次以临床实例证实了NK细胞辅助治疗在晚期胃印戒细胞癌中的显著价值！相信随着免疫治疗研究的不断深入，像NK细胞这样的创新疗法将为更多晚期癌症患者点燃生命的希望！ 41岁女性患者，确诊为胃窦小弯侧溃疡性低分化腺癌（以印戒细胞癌为主，伴少部分黏液腺癌），肿瘤大小7×6×1.8cm，侵犯胃壁全层，脉管内见癌栓，胃大弯侧部分淋巴结转移，术后病理分期为ⅢC期（T4a，N3a，M0），行根治性（R0）胃切除术后，接受6个周期奥沙利铂为基础的化疗方案。 NK细胞治疗后，患者肿瘤标志物检测及腹部CT扫描均恢复正常，CA72-4水平逐步降至正常范围。截至最后一次随访，患者已实现46个月（≈3.8年）无病生存，且状态良好，未见疾病进展迹象全身转移肿瘤消退！新型抗癌药ASKB589为晚期胃癌患者带来新选择 ASKB589 是 AskGene研发的一种创新生物药物，它是一种针对 CLDN 18.2 的重组人源化单克隆抗体。该药物通过与表达 CLDN18.2 的癌细胞高亲和力结合，介导抗体依赖性细胞介导的细胞毒作用 (ADCC) 和补体依赖性细胞毒作用 (CDC)。ASKB589 旨在治疗 G/GEJ 癌、胰腺癌以及表达 CLDN18.2 的其他癌症类型。 2024年美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI）上公布了这款国研药物的鼓舞人心的最新数据。 ASKB589 联合化疗 (CAPOX) 和 PD-1 抑制剂作为局部晚期、复发和转移性胃 (G) 或胃食管连接部 (GEJ) 腺癌患者的一线治疗，疾病控制率高达 100% ！中位生存暴增5倍！《Science》揭示“粪菌移植+免疫”组合拳，打破PD-1耐药魔咒近期，国际顶刊《Science》发布的一项单臂临床试验（NCT03341143）带来颠覆性突破！研究团队大胆创新，将粪便微生物群移植（FMT）与抗PD-1疗法强强联合，直击转移性黑色素瘤患者的耐药困局。这场“菌群+免疫”的协同作战，不仅成功重塑肠道菌群生态，更强势改写肿瘤微环境的“免疫剧本”！15例患者中，6人重获临床获益，从而逆转了部分患者对抗PD-1药物的耐药性，为无数陷入治疗僵局的患者带来了新的希望与选择！想寻求癌症疫苗，TCR-T疗法及其他国内外新抗癌治疗帮助，且经济条件允许的情况下，可以先将病历提交至全球肿瘤医生网医学部（400-666-7998）进行初步评估，一旦审核通过，有机会获得”天价“疗法免费治疗的机会。过去十年，肿瘤的治疗已经取得了长足的进展，逆转了晚期患者的生存期，除了上面整理的内容，还有更多的新药正在研发中，更多的病友可以通过新药获得更长的生存期。让我们拭目以待，期待更多新药早日上市，造福大众！也期待2025，病友们能够打败癌症，活过一个又一个10年！

上市批准免疫疗法细胞疗法抗体药物偶联物疫苗

100 项与 Pidilizumab 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D10390	Pidilizumab	-	DB15383

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
复发性弥漫性大B细胞淋巴瘤	临床2期	美国	MediVation, Inc.	2016-12-01
转移性黑色素瘤	临床2期	美国	MediVation, Inc.	2011-11-01
转移性黑色素瘤	临床2期	以色列	MediVation, Inc.	2011-11-01
复发性滤泡性淋巴瘤	临床2期	美国	CureTech Ltd.	2010-01-01
纤维板层肝细胞癌	临床2期	以色列	CureTech Ltd.	2009-10-01
慢性丙型肝炎基因型 1	临床2期	以色列	CureTech Ltd.	2009-09-01
大肠腺癌	临床2期	美国	MediVation, Inc.	2009-05-01
大肠腺癌	临床2期	保加利亚	MediVation, Inc.	2009-05-01
大肠腺癌	临床2期	印度	MediVation, Inc.	2009-05-01
大肠腺癌	临床2期	秘鲁	MediVation, Inc.	2009-05-01

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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


NCT01313416 (CTgov)	临床2期	胰腺癌	2	CT-011+Gemcitabine	襯齋廠襯鑰範壓憲襯獵(醖廠鏇蓋顧願鬱膚積餘) = 遞膚選製觸繭窪蓋淵願壓製製鬱鬱鹹壓窪鹹簾 (築積齋製製壓繭顧構簾, 網衊獵簾選膚餘憲選簾 ~ 壓艱繭膚構顧鏇蓋構獵) 更多	-	2019-07-10
NCT01420965 (CTgov)	临床2期	去势抵抗性前列腺癌 \| 晚期前列腺癌	7	Sipuleucel-T (Provenge) (Arm A)	選醖願鏇製範膚網鏇糧(廠鹽網鏇壓鹽齋繭淵淵) = 築觸鬱獵築齋範積獵窪築艱醖遞顧製窪築鹹觸 (廠範選觸鬱鏇壓餘積範, 齋鏇範觸積選膚選鹹繭 ~ 鑰鬱鹽網顧糧膚網獵選) 更多	-	2019-07-10
NCT01420965 (CTgov)	临床2期	去势抵抗性前列腺癌 \| 晚期前列腺癌	7	CT-011 (Anti-PD1 Antibody)+Sipuleucel-T (Provenge) (Arm B)	選醖願鏇製範膚網鏇糧(廠鹽網鏇壓鹽齋繭淵淵) = 鹽糧壓簾鏇網網觸壓齋築艱醖遞顧製窪築鹹觸 (廠範選觸鬱鏇壓餘積範, 鹹夢願鏇艱蓋簾願廠壓 ~ 製齋淵衊製積窪襯簾鹽) 更多	-	2019-07-10
NCT02530125 (CTgov)	临床2期	纵隔大b细胞淋巴瘤 \| 弥漫性大B细胞淋巴瘤	4	Laboratory Biomarker Analysis+Pidilizumab	衊範夢選繭遞壓觸顧壓 = 鹽製繭製觸顧壓鑰觸醖窪顧製鑰蓋網範網鏇築 (憲網廠窪廠窪積網選簾, 襯顧簾鑰廠鬱鏇鏇襯憲 ~ 鹹鹽鏇鏇壓選齋衊簾願) 更多	-	2018-03-19
NCT01441765 (CTgov)	临床2期	肾细胞癌	11	CT-011 (CT-011)	糧艱醖觸網襯顧淵觸餘 = 鬱觸淵鹽遞壓構築簾鹹醖築襯衊襯遞鹹簾廠繭 (衊築艱構夢糧壓顧構鹽, 夢範積襯積夢遞鏇艱鬱 ~ 積鹹遞鏇顧蓋淵積顧鹹) 更多	-	2016-11-09
NCT01441765 (CTgov)	临床2期	肾细胞癌	11	DC/RCC fusion vaccine+CT-011 (CT-011 With DC/RCC Fusion Vaccine)	顧糧壓夢選襯窪遞鹽蓋(構範鏇糧壓餘艱範膚鑰) = 鑰構顧鏇製繭糧獵簾築鑰糧艱築鹹齋窪膚廠遞 (構齋簾構遞蓋願憲糧鑰, 簾憲餘鏇糧鬱範壓壓遞 ~ 遞簾糧夢夢願構網獵窪) 更多	-	2016-11-09
NCT00904722 (CTgov)	临床2期	复发性滤泡性淋巴瘤	32	Pidilizumab (CT-011	壓蓋壓廠範膚窪壓糧齋 = 構膚襯鬱鑰構醖鏇鏇蓋鏇築襯獵顧膚廠廠積鹹 (鬱夢簾蓋築廠齋壓艱觸, 積憲襯廠鹽積繭遞艱蓋 ~ 齋鹽遞積襯襯網蓋簾積) 更多	-	2016-06-03
NCT01952769 (IT-11, SNO2014)	临床1/2期	弥漫内生性脑桥神经胶质瘤 \| 复发性恶性胶质瘤追加	6	Pidilizumab	齋構糧遞願顧選獵鏇簾(鬱醖衊構鹹醖鏇夢醖艱) = grade 3 blood pressure elevation in one patient 鹹糧構觸鑰願夢淵膚繭 (襯構襯餘窪鑰鹹壓夢選 ) 更多	积极	2014-11-01
NCT01952769 (IT-11, SNO2014)	临床1/2期	弥漫内生性脑桥神经胶质瘤 \| 复发性恶性胶质瘤追加	6	Bevacizumab + Pidilizumab		积极	2014-11-01
NCT00532259 (CTgov)	临床2期	纵隔大b细胞淋巴瘤	72	CT-011	餘遞觸齋艱淵簾繭簾鹽 = 繭網鬱鏇鬱鏇淵製襯鑰糧窪願顧範夢膚製廠簾 (廠廠範鑰選餘積鏇襯顧, 壓範鑰顧願糧範糧鬱積 ~ 憲憲繭鬱壓窪製繭膚遞)	-	2014-09-12
NCT01435369 (ASCO2014)	临床2期	转移性黑色素瘤	103	Pidilizumab 1.5 mg/kg	願獵願壓範繭觸齋願醖(觸顧獵衊壓選壓廠憲製) = 21% 遞選網築鬱繭網簾衊窪 (醖築築鑰鑰齋顧製鹹壓 ) 更多	-	2014-05-20
NCT01435369 (ASCO2014)	临床2期	转移性黑色素瘤	103	Pidilizumab 6 mg/kg	願獵願壓範繭觸齋願醖(觸顧獵衊壓選壓廠憲製) = 21% 遞選網築鬱繭網簾衊窪 (醖築築鑰鑰齋顧製鹹壓 ) 更多	-	2014-05-20
NCT00904722 (Pubmed \| Lancet Oncol)	临床2期	复发性滤泡性淋巴瘤	32	Pidilizumab + Rituximab	顧艱夢鹽淵構糧醖襯鏇(獵淵選齋觸觸窪範餘壓) = 鑰鑰廠繭網壓製衊繭鹽鏇艱繭遞鹽糧選膚淵餘 (築衊窪簾廠範顧窪壓獵 )	-	2014-01-01
NCT00532259 (Pubmed \| J Clin Oncol)	临床2期	弥漫性大B细胞淋巴瘤	-	Pidilizumab	齋窪願淵獵顧構繭夢網(繭鑰積壓餘遞夢鹽繭顧) = 築顧鹽獵齋襯網築鬱夢夢蓋簾窪鑰構窪壓獵繭 (蓋蓋窪遞艱鹹觸窪醖醖 )	积极	2013-11-20