Novel Chimeric CTLA-4 B-cell Epitope Peptide Vaccines Demonstrate Effective Antitumor Immunity with/without PD1/PDL1 Blockade in Multiple Syngeneic Murine Models of Breast and Colorectal Cancers

Abstract

Cancer immunotherapy with checkpoint inhibitors has resulted in impressive clinical results in several cancer indications. Despite this success, only a fraction of patients show durable and complete response to blockade by ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb. We identified four CTLA-4 peptide sequences from which engineered chimeric B-cell epitope constructs incorporating a "promiscuous" T-cell epitope elicited highly immunogenic anti-CTLA-4 natural polyclonal antibodies by immunization. Combination of CTLA-4 peptide vaccine with other checkpoint inhibitor vaccines PD1-Vaxx or PDL1-Vaxx was investigated in several breast and colon carcinoma BALB/c syngeneic models (CT26, 4T1, and D2F2). CTLA-4 vaccines showed significant tumor suppression and prolonged survival rates as compared with anti-mouse CTLA-4 mAb 9H10. The resulting antipeptide antibodies suppressed tumor proliferation and migration similar to ipilimumab. We focused on one CTLA-4 epitope sequence 130 to 150 that embodies the "MYPPPY" motif that ipilimumab binds to. Combination of MVF-CTLA-4 (130-150) with either PD1-Vaxx or PDL1-Vaxx showed synergistic activity. The 130 to 150 peptide mimic demonstrated that the polyproline type II helix motif showed inhibition of tumor growth and therapeutic efficacy in the syngeneic CT26/BALB/c model. Several CTLA-4 vaccines have been identified that show synergistic activities with other checkpoint inhibitor vaccines to PD1 and PDL1.