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Vollständiger Abstract

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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.

Abstract: PubMed · Datensatz