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.

项目概要 复发性上皮性卵巢癌 (EOC) 患者的预后较差，复发后中位数为 生存期约为 30 个月，治疗选择有限，因此存在根本性的未满足问题 医疗需要。多种肿瘤类型免疫治疗的进展带来了希望 免疫学方法可以改善 EOC 患者的预后。特别是，一种免疫疗法 称为嵌合抗原受体（CAR）的 T 细胞疗法通过重新训练免疫系统来靶向癌症 识别特定的癌症标志物。 EOC 对有效的 CAR T 细胞免疫疗法提出了一些挑战， 包括肿瘤部位浸润不良、活化、功能不足以及这些 T 细胞在肿瘤细胞内的持续存在。 腹膜肿瘤微环境恶劣。此外，目前还缺乏有效的 CAR T 细胞靶标。 晚期EOC肿瘤细胞的表面。我们的目标是开发针对转移性 EOC 的有效疗法， 特别关注区域性 CAR T 细胞疗法治疗腹膜转移。 TAG72 非常过分 在 EOC 和其他实体瘤中表达，而在正常组织中很少或不表达，使其成为理想的靶点 用于 CAR T 细胞治疗。我们 City of Hope 的团队已开发并完成了 TAG72- 的实验室测试 靶向 CAR T 细胞疗法。我们的临床前数据还支持 TAG72 CAR T 具有卓越的抗肿瘤活性 细胞通过腹膜内递送进行区域性施用，而不是通过静脉内递送进行全身性施用，可能 由于抗原CAR T细胞能够直接、立即接触到肿瘤细胞。假设从区域来看—— 施用的 TAG72-CAR T 细胞将是安全的并介导抗肿瘤作用，这将在 以下具体目标： 1) 评估 TAG72-CAR T 区域腹腔内递送的安全性和可行性 一期临床试验中晚期 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耐药性的变化； 3）研究肿瘤耐药途径 以及 CAR T 细胞诱导的肿瘤进化。我们的计划创新性地采用了预处理 我们的实体瘤 CAR T 细胞治疗方案、CAR T 细胞给药的区域路线以及全面的 优化的 TAG72-CAR 构建体。这些功能旨在提高靶向 TAG72+ 的效力和选择性 肿瘤，同时可能最大限度地减少限制 TAG72-CAR T 持久性和/或功能的免疫反应 细胞。这种方法意义重大，因为它将扩大我们针对 EOC 和其他实体瘤的治疗组合。