A Phase 1 Study to Evaluate Chimeric Antigen Receptor (CAR) T cells Targeting TAG72 in Patients with Recurrent Epithelial Ovarian Cancer

评估复发性上皮性卵巢癌患者靶向 TAG72 的嵌合抗原受体 (CAR) T 细胞的 1 期研究

• 批准号: 10523013
• 负责人: SAUL PRICEMAN
• 金额: $ 72.3万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523013
• 关键词: Aftercare; Antigens; Antitumor Response; Ascites; Brain; CAR T cell therapy; Catheters; Cells; Characteristics; Cities; Clinical; Clinical Research; Clinical Trials; Data; Disease; Dose; Epithelial ovarian cancer; Evolution; Future; Gene Expression; Goals; Greater sac of peritoneum; Hematologic Neoplasms; Hematology; Immune; Immune response; Immune system; Immunologic Monitoring; Immunologics; Immunotherapy; Infiltration; Inflammatory; Intravenous; Investigational New Drug Application; Laboratories; Lead; Light; Longevity; Malignant Neoplasms; Malignant neoplasm of ovary; Maximum Tolerated Dose; Mediating; Medical; Neoplasm Metastasis; Neuraxis; Normal tissue morphology; Pathway interactions; Patient-Focused Outcomes; Patients; Peritoneal; Phase; Phase I Clinical Trials; Phenotype; Platinum; Positioning Attribute; Prognosis; Progression-Free Survivals; Prostate; Recurrence; Regimen; Relapse; Resistance; Route; Safety; Sampling; Site; Solid Neoplasm; Surface; Surface Antigens; T cell therapy; T-Lymphocyte; TAG-72 Antigen; Testing; Therapeutic; TimeLine; Translating; Work; antitumor effect; base; cancer biomarkers; cancer therapy; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical candidate; clinical development; clinical translation; cytokine; design; effective therapy; engineered T cells; experience; first-in-human; human subject; improved; improved outcome; innovation; intraperitoneal; mouse model; neoplastic cell; overexpression; patient response; peripheral blood; peritoneal cancer; phase 1 study; phase I trial; pre-clinical; preclinical study; preconditioning; programs; protein expression; response; safety and feasibility; success; systemic toxicity; therapy resistant; trafficking; treatment response; tumor; tumor microenvironment

PROJECT SUMMARY Patients with recurrent epithelial ovarian cancer (EOC) have a poor prognosis with a post-relapse median survival of approximately 30 months and limited therapeutic options, thus presenting a fundamental unmet medical need. Progress in immunotherapy across a broad range of tumor types provides hope that immunological approaches may improve outcomes for patients with EOC. Particularly, a type of immunotherapy called chimeric antigen receptor (CAR) T cell therapy retrains the immune system to target cancers by recognizing specific cancer markers. EOC presents several challenges to effective CAR T cell immunotherapy, including poor tumor site infiltration, activation, inadequate function and persistence of these T cells within the harsh peritoneal tumor microenvironment. Additionally, there are a lack of effective CAR T cell targets on the surface of advanced EOC tumor cells. Our goal is to develop effective therapies against metastatic EOC, with a specific focus on regional delivery of CAR T cell therapies to treat peritoneal metastasis. TAG72 is highly over- expressed in EOC and other solid tumors with little or no expression in normal tissues, making it an ideal target for CAR T cell therapy. Our team at City of Hope has developed and completed laboratory testing of a TAG72- targeting CAR T cell therapy. Our preclinical data also supports superior anti-tumor activity when TAG72 CAR T cells are administered regionally by intraperitoneal delivery versus systemically by intravenous delivery, likely due to direct and immediate antigen CAR T cell access to tumor cells. The hypothesis is that regionally- administered TAG72-CAR T cells will be safe and mediate anti-tumor effects, which will be assessed in the following specific aims: 1) Evaluate safety and feasibility of regional intraperitoneal delivery of TAG72-CAR T cells in patients with advanced EOC in a phase 1 clinical trial; 2) Assess CAR T cell-mediated immune landscape changes that may indicate therapeutic response or resistance; and 3) investigate pathways of tumor resistance and CAR T cell-induced tumor evolution. Our program has incorporated an innovative use of pre-conditioning regimens to our solid tumor CAR T cell therapies, regional routes of CAR T cell administration, and a fully- optimized TAG72-CAR construct. These features aim to improve the potency and selectivity of targeting TAG72+ tumors while potentially minimizing immune responses that limit persistence and/or function of TAG72-CAR T cells. This approach is significant in that it will expand our therapeutic portfolio for EOC and other solid tumors.

项目摘要 复发性上皮卵巢癌（EOC）的患者的预后较差，而后中值的中位数 大约30个月的生存期和有限的治疗选择，从而提出了基本的未满足 医疗需求。在广泛的肿瘤类型中，免疫疗法的进展为您提供了希望 免疫方法可以改善EOC患者的预后。特别是一种免疫疗法 称为嵌合抗原受体（CAR）T细胞疗法将免疫系统重新培训以靶向癌症 识别特定的癌症标志物。 EOC提出了有效CAR T细胞免疫疗法的几个挑战， 包括肿瘤部位浸润不良，激活，功能不足和这些T细胞在 严酷的腹膜肿瘤微环境。此外，在 晚期EOC肿瘤细胞的表面。我们的目标是使用A开发有效的疗法，以抗转移EOC 特定的重点是切入腹膜转移的汽车T细胞疗法的区域递送。 TAG72高度超过 在EOC和其他实体瘤中表达，在正常组织中很少或没有表达，使其成为理想的目标 用于汽车T细胞疗法。我们希望市的团队已经开发并完成了TAG72-的实验室测试 靶向汽车T细胞疗法。当Tag72 Car T T 细胞是通过腹膜内递送而在区域内给予细胞的，而不是系统地通过静脉输送，可能 由于直接和直接的抗原汽车T细胞进入肿瘤细胞。假设是区域 施用的TAG72-CAR T细胞将是安全的，并介导了抗肿瘤作用，将在 以下具体目的：1）评估tag72型车T的区域腹膜递送的安全性和可行性 在1期临床试验中晚期EOC患者的细胞； 2）评估CAR T细胞介导的免疫景观 可能表明治疗反应或抗性的变化； 3）研究肿瘤耐药性的途径 和CAR T细胞诱导的肿瘤进化。我们的计划纳入了预先调节的创新使用 我们实体瘤CAR T细胞疗法的方案，CAR T细胞给药的区域途径以及完全 优化的TAG72-CAR结构。这些功能旨在提高靶向tag72+的效力和选择性 肿瘤虽然有可能最大程度地减少限制tag72-car t的持久性和/或功能的免疫反应 细胞。这种方法很重要，因为它将扩大我们针对EOC和其他实体瘤的治疗组合。