In situ APMV-4 vaccination primes systemic response to subtherapeutic dosing of aCTLA-4 in colorectal carcinoma.

Abstract

Background: Colorectal carcinoma (CRC) is frequently typified by chronic inflammation and high levels of immunosuppression that render it resistant to immunotherapy. The multimodal immunostimulatory mechanisms of oncolytic virotherapy make it an attractive strategy for priming tumors for immune-checkpoint blockade (ICB). Here, we present an emerging oncolytic virotherapeutic, rAPMV-4, with previously described efficacy in preclinical models of CRC and melanoma.

Methods: We expand on the established efficacy of APMV-4 by characterizing responses to the virotherapy in preclinical single and bilateral MicroSatellite Stable CRC tumor models. To investigate local and systemic effects of the virus, we characterized responses in tumors, draining lymph nodes, and sera using RNA-seq, high-dimensional flow cytometry, and cytokine analysis.

Results: rAPMV-4 induced rapid, yet transient, interferon signaling, and early signatures of antigen presentation and T cell activation. Comparison with a human CRC cohort revealed a transcriptomic shift induced by the virus from a mesenchymal CMS4 to an "immune-high" CMS1 subtype predicted to respond well to ICB. Leveraging these signatures of response and resistance to the virotherapy, we designed a rational combinatorial approach with low-dose anti-CTLA-4, which reversed Treg activation and alleviated CD4 and CD8 dysfunction, leading to more potent systemic tumor elimination.

Conclusions: This work supports the further clinical development of rAPMV-4, either alone or in combination, as an efficacious therapy for CRC.