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

摘要 将CAR T细胞疗法应用于卵巢癌(OvCa)等实体肿瘤被广泛认为是一种主要的 这是一个机遇，但也是一个重大挑战，因此也是本提案的重点。在这里，我们寻求开发新的 使用叶酸受体-α(FR-α)特异性CAR T细胞治疗卵巢癌和其他实体肿瘤的临床策略 作为下一代CAR T细胞治疗的靶点。FRα是一种表面蛋白，在80%-90%的 OvCa病例，且预后不良。已知FRα是一种安全的、可用药的治疗靶点 铂耐药卵巢癌患者的抗体药物结合物和双特异性抗体武装T细胞试验， 临床有效率分别为26%和27%。这些药物在患者体内的寿命很短，因此 反应是不持久的；然而，CAR T细胞具有持续和维持活动的能力 活着。在多种临床前模型中，人FRαCAR T细胞对人肿瘤显示出强大的抗肿瘤活性 表达FRα的实体瘤移植瘤。在这里，我们建议检验慢病毒的中心假设 基因工程FRα特异性CAR T细胞可在慢性粒细胞白血病患者中实现有临床意义的肿瘤反应 复发性卵巢癌，无不良反应。我们建议(1)确定该方案的可行性、安全性和肿瘤 自体FR-α慢病毒CAR-T细胞腹腔注射对确诊患者的免疫应答 FRα-I期剂量递增试验中复发卵巢钙蛋白的过表达(NCT03585764)，(2)确定FRα FRCAR-α特异性CAR T细胞活性在治疗中的持续性、免疫效力及机制 患者了解卵巢微环境中的免疫反应和其他调节 CAR T细胞注射，以及(3)确定诱导系统免疫的范围、广度和持续时间 作为预期的未来组合疗法的基础。在这条线上，第二个假设是 依赖于时间表的肿瘤微环境预适应(TME)是有效的 心理治疗。在卵巢癌和其他癌症中，肿瘤相关巨噬细胞()的积聚与 不良转归及免疫治疗抵抗，提示衰竭或破损或好转 病人结局。我们现在已经开发出新的CAR T细胞技术，它可以介导深度和高度的 选择性去除免疫抑制的M2样TAMs。在临床前研究中，我们发现抗的CAR T 细胞增强内源性CD8+T细胞抗肿瘤反应，免除M1样巨噬细胞，重新培养 TME，并在三个独立的小鼠肿瘤模型中抑制体内肿瘤进展，提示 可以实现与FRαCAR T细胞疗法的协同作用，特别是作为一种制剂应用时 预适应疗法。我们准备通过评估和优化这一点来检验这个新的假设 新的耗竭方案等成熟的方法，在FRαCAR T细胞治疗的背景下 各种临床前肿瘤模型，使我们能够利用发现的新的有效组合作为 为卵巢癌和承载积聚的实体瘤患者进行下一代临床试验的桥梁。

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.