Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer

自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验

• 批准号: 10576370
• 负责人: Daniel J. Powell
• 金额: $ 65.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576370
• 关键词: Acute Lymphocytic Leukemia; Address; Adoptive Transfer; Adult; Antibody Therapy; Antibody-drug conjugates; Antigens; Antitumor Response; Area; Autologous; Biological; Bispecific Antibodies; CAR T cell therapy; CD19 gene; CD8-Positive T-Lymphocytes; Cancer Patient; Child; Chronic Lymphocytic Leukemia; Clinical; Clinical Investigator; Clinical Trials; Cyclophosphamide; Development; Disease; Dose; Education; Engineering; Enrollment; Exhibits; FOLR1 gene; Foundations; Future; G-Protein-Coupled Receptors; Hematologic Neoplasms; Human; Immune response; Immunologics; Immunosuppression; Immunotherapy; In complete remission; Industrialization; Infusion procedures; Injections; Intraperitoneal Injections; Investments; Lead; Lentivirus; Ligands; Macrophage; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Membrane Proteins; Modeling; Mus; Outcome; Ovarian; Patient Selection; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Phenotype; Platinum; Positioning Attribute; Pre-Clinical Model; Prognosis; Recurrence; Regimen; Reproducibility; Research; Resistance; Safety; Schedule; Solid Neoplasm; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic; Toxic effect; Treatment Protocols; Tumor Immunity; Tumor-associated macrophages; Woman; anticancer activity; cancer cell; chimeric antigen receptor; chimeric antigen receptor T cells; cohort; combinatorial; effective therapy; experience; immune checkpoint; immunoreaction; improved; in vivo; intraperitoneal; next generation; novel; objective response rate; overexpression; phase I trial; pre-clinical; preclinical study; preconditioning; response; safety and feasibility; synergism; therapeutic target; tumor; tumor microenvironment; tumor progression; tumor xenograft

Abstract Applying CAR T cell therapy to solid tumors such as ovarian cancer (OvCa) is widely considered a major opportunity but also a major challenge and thus the focus of this proposal. Here, we seek to develop new clinical strategies for OvCa and other solid tumors using CAR T cells specific for folate receptor-alpha (FRα), as the target of next generation CAR T cell therapy. FRα is a surface protein that is expressed in 80-90% of OvCa cases and associated with poor prognosis. FRα is known to be a safe, “druggable” therapeutic target in trials of antibody drug conjugates and bispecific antibody armed T cells in platinum-resistant OvCa patients, with clinical response rates of 26% and 27%, respectively. These agents are short-lived in patients and thus responses are non-enduring; CAR T cells however have the capacity for persistence and maintained activity in vivo. In multiple preclinical models, human FRα CAR T cells exhibit potent anti-tumor efficacy against human solid tumor xenografts that express FRα. Here, we propose to test the central hypothesis that lentivirus engineered FRα-specific CAR T cells can achieve clinically meaningful tumor responses in patients with recurrent OvCa without untoward toxicity. We propose to (1) determine the feasibility, safety and tumor response following intraperitoneal injection of autologous FRα lentivirus CAR T cells in patients with confirmed FRα-overexpressing recurrent OvCa in a phase I dose escalation trial (NCT03585764), (2) determine FRα CAR persistence, immunological potency and mechanism of FRα-specific CAR T cell activity in treated patients to understand the immune reaction and other modulations in the OvCa microenvironment following CAR T cell injection, and (3) determine the scope, breadth, and duration of induced systemic immune responses, as a foundation for anticipated future combinatorial therapies. In this line, a secondary hypothesis is that schedule-dependent preconditioning of the tumor microenvironment (TME) is a requirement for effective therapy. In OvCa and other cancers, tumor associated macrophage (TAM) accumulation is associated with poor outcome and resistance to immunotherapy, suggesting that TAM depletion or disruption may improve patient outcome. We have now developed novel CAR T cell technology that mediates deep and highly selective depletion of immunosuppressive M2-like TAMs. In preclinical studies, we find that anti-TAM CAR T cells augment endogenous CD8+ T cell antitumor responses, spares M1-like macrophages, re-educates the TME, and inhibits tumor progression in vivo in three independent mouse tumor models, suggesting that synergy with FRα CAR T cell therapy may be achieved, particularly when applied as a preparative preconditioning regimen. We are positioned to test this novel hypothesis by evaluating and optimizing this novel TAM depletion regimen, and other established approaches, in the context of FRα CAR T cells therapy in various preclinical tumor models, allowing us to capitalize on the discovery of a novel effective combination as a bridge to next generation clinical trials for patients with OvCa and solid tumors bearing TAM accumulation.

抽象的 将CAR T细胞疗法应用于卵巢癌（OvCa）等实体瘤被广泛认为是一个主要的治疗方法 机遇也是重大挑战，因此我们在此提出新的建议。 使用叶酸受体-α (FRα) 特异性的 CAR T 细胞治疗 OvCa 和其他实体瘤的临床策略， 作为下一代 CAR T 细胞疗法的靶标，FRα 是一种表面蛋白，在 80-90% 的细胞中表达。 众所周知，OvCa 病例和预后不良相关的 FRα 是一种安全、“可用药”的治疗靶点。 抗体药物偶联物和双特异性抗体武装 T 细胞在铂耐药 OvCa 患者中的试验， 临床反应率分别为 26% 和 27%，这些药物在患者体内的寿命较短，因此。 CAR T 细胞的反应是非持久的，但具有持久性和维持活性的能力 在多个临床前模型中，人 FRα CAR T 细胞对人类表现出强大的抗肿瘤功效。 在这里，我们建议测试慢病毒的中心假设。 工程化的 FRα 特异性 CAR T 细胞可以在患有以下疾病的患者中实现具有临床意义的肿瘤反应 复发性 OvCa 无不良毒性 我们建议 (1) 确定可行性、安全性和肿瘤。 确诊患者腹腔注射自体 FRα 慢病毒 CAR T 细胞后的反应 I 期剂量递增试验中 FRα 过度表达复发性 OvCa (NCT03585764)，(2) 确定 FRα 治疗中 FRα 特异性 CAR T 细胞活性的 CAR 持久性、免疫效力和机制 患者了解 OvCa 微环境中的免疫反应和其他调节 CAR T细胞注射，以及（3）确定诱导的全身免疫的范围、广度和持续时间 反应，作为预期未来组合疗法的基础在这一点上，有一个次要假设。 肿瘤微环境（TME）的时间依赖性预处理是有效性的必要条件 在 OvCa 和其他癌症中，肿瘤相关巨噬细胞 (TAM) 的积累与肿瘤相关巨噬细胞 (TAM) 的积累有关。 不良结果和对免疫治疗的抵抗，表明 TAM 耗尽或破坏可能会改善 我们现在已经开发出新型 CAR T 细胞技术，可以深度、高度介导患者的治疗效果。 在临床前研究中，我们发现抗 TAM CAR T 选择性耗尽免疫抑制性 M2 样 TAM。 细胞增强内源性 CD8+ T 细胞抗肿瘤反应，保留 M1 样巨噬细胞，重新教育 TME，并在三个独立的小鼠肿瘤模型中抑制体内肿瘤进展，表明 可以实现与 FRα CAR T 细胞疗法的协同作用，特别是作为制剂应用时 我们准备通过评估和优化这一新假设来检验这一新假设。 在 FRα CAR T 细胞治疗的背景下，新的 TAM 消除方案和其他既定方法 各种临床前肿瘤模型，使我们能够利用新的有效组合的发现 为患有 TAM 积累的 OvCa 和实体瘤患者搭建下一代临床试验的桥梁。