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Pre-Treatment with Dacarbazine Sensitizes B16 Melanoma to CAR T Cell Therapy in Syngeneic Mouse Model
Egor A Emelianov1, Elizaveta R Naberezhnaya1, Andrey S Logvinov1
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
Abstract:
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.
Insights
Combining dacarbazine (DTIC) chemotherapy with adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) improved melanoma tumor control and survival in mice.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T cell therapy shows promise in hematologic cancers but faces challenges in solid tumors like melanoma.
- Factors limiting CAR T cell efficacy in solid tumors include heterogeneous antigen expression and an immunosuppressive tumor microenvironment (TME).
- Combining chemotherapy with CAR T cell therapy may enhance antitumor activity by improving T cell infiltration and disrupting the TME.
Purpose of the Study:
- To evaluate the efficacy of combining dacarbazine (DTIC) chemotherapy with epidermal growth factor receptor (EGFR) targeted CAR T cell therapy in a B16 melanoma mouse model.
- To assess the impact of cyclophosphamide (CPA) pre-conditioning on the combination therapy.
Main Methods:
- Developed a syngeneic B16 melanoma mouse model expressing a human/murine hybrid EGFR.
- Administered DTIC chemotherapy followed by EGFR-specific murine CAR T cells (EGFR mCAR T cells) after CPA pre-conditioning.
- Compared the combination therapy to monotherapy with DTIC or EGFR mCAR T cells alone.
Main Results:
- The combination of DTIC chemotherapy and EGFR mCAR T cells resulted in superior tumor control compared to monotherapy.
- Mice receiving the combination therapy exhibited significantly prolonged survival.
- CPA pre-conditioning was utilized prior to CAR T cell administration.
Conclusions:
- Combined DTIC chemotherapy and EGFR mCAR T cell therapy is a potentially effective strategy for melanoma treatment.
- This combination approach may overcome limitations of CAR T cell monotherapy in solid tumors.
- Further investigation into this combined therapeutic strategy for human melanoma is warranted.
