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: 10686943
• 负责人: SAUL PRICEMAN
• 金额: $ 69万
• 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/10686943
• 关键词: Aftercare; Antigens; Antitumor Response; Ascites; Breast; CAR T cell therapy; Catheters; Cells; Central Nervous System; Characteristics; Cities; Clinical; Clinical Research; Clinical Trials; Data; Disease; Dose; Epithelial ovarian cancer; Evolution; Future; Gene Expression; Goals; Greater sac of peritoneum; Hematologic Neoplasms; 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; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mediating; Medical; Neoplasm Metastasis; Normal tissue morphology; Pathway interactions; Patient-Focused Outcomes; Patients; Peritoneal; Phase; Phase I Clinical Trials; Phenotype; Platinum; Positioning Attribute; Primary Brain Neoplasms; Prognosis; Progression-Free Survivals; Recommendation; Recurrence; Regimen; Relapse; Resistance; Route; Safety; Sampling; Site; Solid Neoplasm; Surface; Surface Antigens; T cell therapy; T-Lymphocyte; TAG-72 Antigen; Testing; Therapeutic; Translating; Work; antitumor effect; 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; timeline; 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.

项目总结