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主要的 机会也是一个重大挑战，因此是该提案的重点。在这里，我们试图开发新的 使用叶酸受体-Alpha（FRα）的CAR T细胞的OVCA和其他实体瘤的临床策略， 作为下一代汽车T细胞疗法的目标。 FRα是一种表面蛋白，以80-90％的表达 OVCA病例，预后不良。众所周知，FRα是一个安全的“可药”治疗靶标 抗铂耐药性OVCA患者的抗体药物结合物和双特异性抗体T细胞的试验， 临床反应率分别为26％和27％。这些药物在患者中是短暂的，因此 反应是无关的；但是，汽车T细胞具有持久性和维持活性 体内。在多种临床前模型中，人类FRα汽车T细胞暴露了针对人的有效抗肿瘤效率 表达FRα的实体瘤异种移植物。在这里，我们建议检验慢病毒的中心假设 设计的FRα特异性汽车T细胞可以在患有临床意义的肿瘤反应中 反复发作的OVCA没有不良毒性。我们建议（1）确定可行性，安全性和肿瘤 腹膜内注射自体FRα慢病毒CAR T细胞的反应 在I期剂量升级试验（NCT03585764）中，过表达FRα的复发性OVCA，（2）确定FRα CAR持久性，FRα特异性CAR T细胞活性的免疫学效力和机制 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，（3）确定诱导全身免疫的范围，广度和持续时间 回应，作为预期的未来组合疗法的基础。在这一行中，次要假设 是肿瘤微环境（TME）的附表依赖性预处理是有效的 治疗。在OVCA和其他癌症中，肿瘤相关的巨噬细胞（TAM）积累与 结果不佳和对免疫疗法的抵抗力，表明TAM耗竭或破坏可能会改善 病人的结果。我们现在已经开发了新颖的汽车T细胞技术，可深入介导 免疫抑制M2样TAM的选择性耗竭。在临床前研究中，我们发现抗tam car t 细胞增强内源性CD8+ T细胞抗肿瘤反应，备用M1样巨噬细胞，重新教育 TME，并在三种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FRαCAR T细胞疗法的协同作用，尤其是当作为准备 预处理方案。我们可以通过评估和优化这一点来检验这一新假设 在FRαCAR T细胞治疗中，新型TAM部署方案和其他已建立的方法 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 OVCA和实体肿瘤患者的下一代临床试验的桥梁。