PARP Inhibitors plus Anlotinib as Bridging Therapy for Armored CAR‐T Cells in Ovarian Cancer Enhances Infiltration and Antitumor Efficacy

Abstract

ABSTRACT Chimeric antigen receptor (CAR)‐T cell therapy is largely ineffective in most solid tumors, partially because of inadequate intratumoral trafficking. Bridging therapy, administered between leukapheresis and CAR‐T cell infusion, offers a distinct opportunity to control the disease and precondition the tumor microenvironment without directly exposing CAR‐T cells to concomitant drugs. Here, a poly (ADP‐ribose) polymerase (PARP) inhibitor combined with anlotinib is evaluated as bridging therapy for ovarian cancer. In immunocompetent mice bearing ovarian tumors, this regimen induces durable intratumoral T cell accumulation associated with activation of the cGAS‐STING pathway, vascular normalization, and reduced fibrillar collagen deposition. Furthermore, TGFβ‐resistant, dual‐target mesothelin (MSLN)/CD19 CAR‐T cells are engineered using a bait‐and‐switch strategy. Niraparib plus anlotinib administered as bridging therapy before CAR‐T cell infusion enhances CAR‐T cell infiltration and antitumor activity across multiple preclinical ovarian cancer models. These findings inform an ongoing phase I clinical trial (NCT05141253) evaluating the safety of these engineered CAR‐T cells following bridging therapy in patients with refractory MSLN‐positive solid tumors. Collectively, our findings support a clinically actionable bridging therapy with translational potential for potentiating CAR‐T cell therapy in ovarian cancer and highlight bridging therapy as a translational approach to improve CAR‐T cell access and efficacy in solid tumors.