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

点击翻译按钮获取中文摘要

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.