Description
The B16F10 mouse melanoma is a unique preclinical model resembling many human tumors that are highly aggressive, poorly immunogenic, and have high metastatic potential. These attributes make this model clinically relevant and ideal for testing potential immunotherapies. In these studies, a clinical stage oncolytic immunotherapy developed by Vaxiion Therapeutics, called VAX014, is being tested as a locally administered therapy for B16F10. This therapy is a novel E. coli derivative, known as recombinant bacterial minicells (rBMCs), that target and deliver therapeutic molecules directly to tumor cells. VAX014 rBMCs incorporate invasin, a rBMC surface protein that targets integrins expressed on tumor cells, and perfringolysin O, an oncolytic bacterial toxin that facilitates tumor cell membrane lysis and death. In vitro studies demonstrate rapid VAX014-mediated oncolysis of B16F10, which set the stage for in vivo anti-tumor efficacy studies against intradermal B16F10 in immune-competent mice. All mice treated intra-tumorally 1x/week with VAX014 responded either completely (58%, n=22, p<0.0001) or partially (42%, n=16, p<0.0001) with an overall enhanced survival compared to saline treatment (p<0.0001). When survivors were re- challenged with B16F10 on the opposite flank and no additional treatment was given, >60% (n=32, p<0.0001) had reduced tumor growth, suggesting generation of anti-tumor adaptive immunity in response to therapy. Depletion of CD8+ cells prior to treatment resulted in a total loss of VAX014 efficacy (n=11, p<0.0001) whereas depletion of Natural Killer (NK) cells resulted in a significant reduction in efficacy (n=12, p<0.05), suggesting that both cytotoxic T cells and NK cells play a critical role in VAX014-mediated tumor clearance. Flow cytometry was then utilized to identify potential differences in immune cell populations within the tumor microenvironment (TME) between actively responding and rebounding tumors vs. saline treated controls. Consistent with depletion study results, responding tumors had a significant increase in immune cells, particularly CD8+ cells, compared to rebounding tumors (p<0.05). To date, these results support that VAX014 stimulates CD8+ and NK cell mediated anti-tumor immunity in this poorly immunogenic model of melanoma, inducing complete tumor regression in the majority of mice. These data encourage future studies on the investigation of VAX014 as a locally delivered immunotherapy for melanoma patients.
