Combining the potency of a neoantigen-expressing DNA vector, an anti-CTLA-4 antibody, and an attenuated poxvirus in a personalized immunization platform: Preclinical studies of ODI-2001.

Abstract

e14674 Background: Immune checkpoint inhibitors (ICI) have transformed cancer treatment. Their impressive effectiveness is crucially dependent on pre-existing neoepitope-specific immune responses. ODI-2001 aims at increasing the immune response against tumors by combining a DNA expressing multiple neoepitopes of the tumor, a MVA vaccinia virus as physiologic adjuvant and DNA carrier, and an anti-CTLA4 antibody as amplifier of the immune response. Methods: ODI-2001 was administered by repeated subcutaneous injections after tumor cells implantation in mice melanoma model B16F10 and colorectal cancer model CT26, and both before and after implantation in breast cancer model 4T1. In B16F10 model combination of ODI-2001 with anti-PD1 was assessed also. Neoepitopes were chosen from literature in B16F10 and CT26 models. In 4T1 model they were predicted using a dedicated neoepitope prediction algorithm (ImmunoEngine, myNEO, Gent, Belgium). Tumor volume and mice survival were assessed over time. Tumors were also analysed by immunofluorescence for immune cell infiltration. Each experiment received approval from the ethics committee for animals. Results: A significant improvement in survival was observed in mice treated with ODI-2001 in B16F10, and CT26 syngeneic mice models. In B16F10 the combination of ODI-2001 with anti-PD1 antibody demonstrated synergistic activity and a significant improvement in survival, while anti-PD1 alone or combined with anti-CTLA-4 failed to show any therapeutic effect (ODI-2001 + anti-PD1 vs. anti-CTLA-4 + anti-PD1 p<0.01). ODI-2001 treatment was associated with tumor rejections in the three animal models. In 4T1 model the ImmunoEngine epitope prediction algorithm demonstrated an improved efficacy as compared to a set of neoepitopes chosen from the literature. In B16F10, following immunization with ODI-2001, an increased CD8 immune cell infiltration of the tumor was documented. ODI-2001 was well tolerated by the treated animals. Conclusions: These data demonstrate a significant antitumoral activity of ODI-2001 as a neoantigen immunization platform across different preclinical cancer models, both in monotherapy and combined with anti-PD1. ODI-2001 represents a promising option to induce de novo cancer-specific immune responses, potentially increasing the proportion of patients responding to immunotherapy treatments. Based on this preclinical program a phase I with ODI-2001 in patients with advanced colorectal carcinoma is currently under preparation.