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 复发的上皮性卵巢癌(EOC)患者预后较差，复发后中位数 存活约30个月，治疗选择有限，因此呈现出根本未得到满足的 医疗需要。广泛肿瘤类型的免疫治疗的进展提供了希望 免疫学方法可能会改善卵巢癌患者的预后。尤其是一种免疫疗法 称为嵌合抗原受体(CAR)的T细胞疗法通过以下方式重新训练免疫系统以靶向癌症 识别特定的癌症标志物。EOC对有效的CAR T细胞免疫治疗提出了几个挑战， 包括肿瘤部位较差的浸润、活化、功能不全和这些T细胞在肿瘤内的持久性 恶劣的腹膜肿瘤微环境。此外，缺乏有效的CAR T细胞靶点 晚期EOC肿瘤细胞表面。我们的目标是开发有效的治疗转移性卵巢癌的方法， 特别关注CAR T细胞疗法在治疗腹膜转移方面的区域应用。TAG72已经严重超标了- 在卵巢上皮性癌和其他实体瘤中表达，而在正常组织中很少或根本没有表达，使其成为理想的靶点 接受CAR T细胞治疗。我们希望之城的团队已经开发并完成了TAG72的实验室测试- 靶向CAR T细胞疗法。我们的临床前数据也支持TAG72 CAR T卓越的抗肿瘤活性 细胞可能是通过腹膜腔给药而不是全身静脉给药。 由于CAR抗原T细胞可直接、即时地进入肿瘤细胞。假设是地区性的- 注射TAG72-CAR T细胞将是安全的和中介的抗肿瘤效果，这将在 具体目标如下：1)评价TAG72-CAR T区域性腹膜腔内分娩的安全性和可行性 1期临床试验中晚期卵巢癌患者的细胞；2)评估CAR T细胞介导的免疫状况 可能指示治疗反应或耐药性的变化；以及3)研究肿瘤耐药性的途径 和CAR T细胞诱导的肿瘤演变。我们的计划包含了对预适应的创新使用 我们实体肿瘤CAR T细胞治疗的方案，CAR T细胞给药的区域路线，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 同时潜在地最小化限制TAG72-CAR T持久性和/或功能的免疫反应 细胞。这一方法意义重大，因为它将扩大我们对EOC和其他实体肿瘤的治疗组合。