A Vaccine Enhances CAR-T Cell Efficacy against Solid Tumors

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized care in some blood cancers, but establishing these treatments in solid tumors has been difficult. Reinhard, Rengstl, Oehm, and colleagues developed a CAR targeting claudin 6 (CLDN6), a transmembrane tight-junction protein that their findings suggest is normally expressed only in fetal tissues in humans but is highly overexpressed in some tumor types. When treated with CLDN6-targeting human CAR-T cells, mice xenografted with human tumor-cell lines exhibited complete tumor regression, whereas control-treated tumors progressed rapidly. To enhance engraftment and persistence of the CAR-T cells, a major barrier to treatment of solid tumors with CAR-T cell therapies, the authors employed a liposomal CLDN6-encoding vaccine (CLDN6-LPX) to enhance CLDN6-specific T-cell expansion. In vitro, exposure to CLDN6-LPX triggered display of CLDN6 on dendritic cells that led to stimulation, cytokine secretion, and proliferation of cocultured CLDN6 CAR-T cells. Correspondingly, in vivo intravenous injection of CLDN6-LPX increased surface expression of CLDN6 on splenic dendritic cells. Further, mice engrafted with CLDN6 CAR-T cells exhibited increased proportions of CLDN6 CAR-T cells following CLDN6-LPX treatment. CLDN6-LPX caused a marked expansion of circulating CLDN6 CAR-T cells in vivo, even when the number of CAR-T cells transferred was small. Additionally, CLDN6-LPX was capable of causing reexpansion of CLDN6 CAR-T cells after prolonged treatment-free intervals, revealing memory formation. Further, in mice bearing large Lewis lung tumors or colon carcinomas, adoptive cell transfer with subtherapeutic doses of CLDN6 CAR-T cells caused complete regression of large tumors and greater median survival when CLDN6-LPX was added to the treatment regimen, and the combination treatment also caused complete tumor regression in xenografted mice. This study illustrates the potential not only of using CLDN6 as a CAR-T target, but also of combining vaccines such as CLDN6-LPX with CAR-T therapy.

Reinhard K, Rengstl B, Oehm P, Michel K, Billmeier A, Hayduk N, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 2020 Jan 2 [Epub ahead of print].

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