Abstract
Chimeric antigen receptor (CAR) T cell therapy has had limited efficacy for solid tumors, largely due to a lack of selectively and highly expressed surface antigens. To avoid reliance on a tumor’s endogenous antigens, here we describe a method of tumor-selective delivery of surface antigens using an oncolytic virus to enable a generalizable CAR T cell therapy. Using CD19 as our proof of concept, we engineered a thymidine kinase-disrupted vaccinia virus to selectively deliver CD19 to malignant cells, and thus demonstrated potentiation of CD19 CAR T cell activity against two tumor types in vitro. In an immunocompetent model of B16 melanoma, this combination markedly delayed tumor growth and improved median survival compared with antigen-mismatched combinations. We also found that CD19 delivery could improve CAR T cell activity against tumor cells that express low levels of cognate antigen, suggesting a potential application in counteracting antigen-low escape. This approach highlights the potential of engineering tumors for effective adoptive cell therapy.
Highlights
Chimeric antigen receptor (CAR) tumor cells (T cells) therapy has emerged as a promising curative cancer immunotherapy, with CD19-targeting CAR T cells having achieved durable remissions in the setting of therapy-resistant B cell malignancies.[1]
MCD19 CAR T Cells Exhibit Activity against mCD19-Positive Melanoma Cells To characterize the activity of primary murine CD19 CAR T cells against solid tumors that uniformly express mCD19, we first stably expressed mCD19 and a TurboRFP/Renilla luciferase (TR) fusion protein in the B16 mouse melanoma cell line (Figure S1)
CD19 CAR T cell toxicity was dependent on antigen density, with a B16-mCD19low cell line exhibiting a diminished response compared with a B16-mCD19high cell line (p = 0.0116; n = 5 for each condition) (Figure 1B)
Summary
Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising curative cancer immunotherapy, with CD19-targeting CAR T cells having achieved durable remissions in the setting of therapy-resistant B cell malignancies.[1] Translating these successes to solid tumors is arguably the most pressing challenge facing the field.[2]. Solid tumors present several challenges for effective CAR T cell therapy, which have limited the success of efforts to date. Solid tumors are often populated with myeloid-derived suppressor cells that contribute to an immunosuppressive, anti-inflammatory microenvironment that can inhibit T cell function and proliferation.[3] Second, lineage-restricted antigens such as CD19 are uniformly expressed and B cell aplasia is a clinically manageable phenotype, identifying solid tumor CAR targets that are both uniformly and selectively expressed on malignant cells to prevent “off-tumor, on-target” toxicities has proven problematic.[4] CAR T cell recognition of target cells is highly dependent on antigen density, suggesting that even solid tumors that do express tumor-associated targets may still be unresponsive to therapy should they express low levels of antigen.[5,6,7]
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