Pre-Treatment with Dacarbazine Sensitizes B16 Melanoma to CAR T Cell Therapy in Syngeneic Mouse Model.

Adoptive cell therapy (ACT) with T cells modified with a chimeric antigen receptor (CAR T cells) has dramatically improved outcomes in hematologic cancers. However, its efficacy in solid tumors, such as melanoma, is hampered by several factors. These include heterogeneous expression of tumor-associated antigens (TAA) and an immunosuppressive, profibrotic tumor microenvironment (TME), which restricts cytotoxic CAR T cells trafficking into the tumor, as well as their persistence and cytolytic activity. As a result, responses to CAR T cell monotherapy in melanoma and other solid tumors are typically weak, transient or even absent. Emerging evidence suggests that combining traditional chemotherapy with CAR T cell therapy can enhance the antitumor activity of CAR T cells in solid malignancies. Partial tumor cell killing by chemotherapy improves access to TAA and disrupts the TME by affecting the global structure of the tumor tissue. Here, we developed an immunocompetent syngeneic B16 melanoma mouse model to test a combination of classical dacarbazine (DTIC) chemotherapy with ACT with murine CAR T cells. B16-F10 (next as B16) melanoma cells were modified to express a human/murine hybrid epidermal growth factor receptor (EGFR) recognized by a murine CAR bearing a single-chain variable fragment (scFv) derived from cetuximab, an anti-EGFR monoclonal antibody approved for the treatment of colorectal and certain other solid tumors. Prior to CAR T cells administration, cyclophosphamide (CPA) pre-conditioning was used. We demonstrated that DTIC therapy followed by infusion of murine CAR T cells targeting the human/murine hybrid EGFR (EGFR mCAR T cells) provided superior tumor control and prolonged survival compared to monotherapy with either DTIC or EGFR mCAR T cells alone. These findings support the potential feasibility of a combined therapeutic strategy for human melanoma involving DTIC treatment followed by EGFR CAR T cells infusion after CPA pre-conditioning.