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- Open Access
Poxvirus-based active immunotherapy synergizes with immune checkpoint inhibitors to cause tumor regression and extend survival in preclinical models of cancer
Journal for ImmunoTherapy of Cancervolume 2, Article number: P124 (2014)
Combining poxvirus-based immunotherapies which "step on the gas" to activate tumor antigen-specific T cell immune responses with immune checkpoint inhibitors (ICIs) which "release the brakes" on the immune system is a promising direction for enhancing cancer immunotherapy. Evidence for the potential clinical benefit from combination immunotherapy was obtained in a Phase I dose escalation trial. Cohorts of prostate cancer (mCRPC) patients were treated with a fixed dose of PROSTVAC, a poxvirus-based active immunotherapy, plus escalating doses of Ipilimumab, an anti-CTLA-4 ICI. The median overall survival (mOS) of 31.6 months  from the combined cohorts was notably longer than the mOS of mCRPC patients from an independent randomized Phase II study (PROSTVAC alone 25.1 months versus placebo 16.6 months; the most pronounced survival benefit (8.5 months) in mCRPC to date) . This potentially synergistic combination of PROSTVAC and Ipilimumab warrants further exploration.
We modeled the benefit of combining poxvirus-based immunotherapy with CTLA-4 blockade using MVA-BN-HER2, which is being developed for breast cancer. In preclinical studies a dramatic increase in mOS was observed in a therapeutic CT26-HER2 lung metastasis model when mice were treated with MVA-BN-HER2 plus CTLA-4 blockade compared to either treatment alone. The improved survival with the combination therapy was accompanied by a striking increase in the magnitude and functional quality of tumor infiltrating HER-2 specific CD8 T cells .
Additional ICIs are identified in our preclinical studies as promising candidates for combining with poxvirus-based immunotherapies. Immune checkpoint protein expression is normally induced on activated T cells to regulate activity, and we found that MVA-BN-HER2 treatment resulted in activated CD8 T cells and elevated expression of PD-1, TIM-3, or ICOS. However, immune checkpoint proteins are chronically elevated on exhausted T cells in an immunosuppressive tumor microenvironment. In untreated tumor-bearing mice, a potentially exhausted T cell phenotype was found on CD4 and CD8 T cells characterized by increased expression or co-expression of PD-1, TIM-3, and LAG-3. We compared treatment of MVA-BN-HER2 alone or in combination with ICI antibodies against these immune checkpoint molecules in solid or metastatic CT26-HER2 tumor models. Improved survival was observed with several different combinations, and synergistic efficacy was indicated using the Chou-Talalay method . These studies provide data and rationale for combining poxvirus-based immunotherapies with a variety of ICIs in the clinic.
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