Gp96-Ig/Costimulator (OX40L, ICOSL, or 4-1BBL) Combination Vaccine Improves T-cell Priming and Enhances Immunity, Memory, and Tumor Elimination

G. Fromm, S. de Silva, L. Giffin, X. Xu, J. Rose, T. H. Schreiber
2016 Cancer immunology research  
The excitement in the field of immuno-oncology over the last several years, driven largely by the clinical success of checkpoint inhibitors, is tempered by the fact that only 10-40% of patients respond to these drugs given as monotherapy. It is widely believed that to improve efficacy and patient outcome, new approaches that combine treatments with more than one functionality are needed. We have developed a next generation cellular vaccine platformreferred to as ComPACT (COMbination Pan-Antigen
more » ... Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T cell costimulation (Fc-OX40L), into a single tumor cell line that secretes them both (recently published in Cancer Immunology Research, 2016). ComPACT primes both antigen-specific CD4+ and CD8+ T cells, and stimulates activation of CD127 + KLRG-1memory precursor cells. Systemic administration of OX40 antibodies led to proliferation of non-specific CD4+ T cells, Tregs and systemic inflammatory cytokine production. Importantly, ComPACT led to high frequencies of IFNγ + , TNFα + , granzyme-b + and IL-2 + antigenspecific CD8+ T cells at both priming and boosting, which enhanced rejection of established murine melanoma (B16.F10) and colon cancer (CT26) tumors and increased overall survival. Here, we have assessed ComPACT in a 3 rd tumor model (MC38colorectal carcinoma) and show that it synergizes effectively with PD1 and PD-L1 antagonist antibody therapies, amplifying antigenspecific T cells, programming a memory response, and eliminating tumors. ComPACT/αPD1 or αPD-L1 combinations may therefore translate into an efficacious approach to treat human cancers.
doi:10.1158/2326-6066.cir-15-0228 pmid:27364122 fatcat:kpklw3p5bzegbldrmo6z3cx4om