title: Combined vaccination and immunostimulatory antibodies provides durable cure of murine melanoma and induces transcriptional changes associated with positive outcome in human melanoma patients.
abstract: We have developed a recombinant adenovirus vaccine encoding dopachrome tautomerase (rHuAd5-hDCT) that produces robust DCT-specific immunity, but only provides modest suppression of murine melanoma. In the current study, an agonist antibody against 4-1BB was shown to enhance rHuAd5-hDCT efficacy and evoke tumor regression, but most tumors ultimately relapsed. The vaccine triggered upregulation of the immune inhibitory PD-1 signaling pathway and PD-1 blockade dramatically enhanced the rHuAd5-hDCT + anti-4-1BB strategy, resulting in complete regression of growing tumors in > 70% of recipients. The impact of the combined anti-4-1BB/anti-PD-1 treatment did not manifest as a dramatic enhancement in either the magnitude or functionality of DCT-specific tumor infiltrating lymphocytes relative to either treatment alone. Rather, a synergistic enhancement in intratumoral cytokine expression was observed, suggesting that the benefit of the combined therapy was a local event within the tumor. Global transcriptional analysis revealed immunological changes within the tumor following the curative vaccination, which extended beyond the T cell compartment. We identified an immune signature of 85 genes associated with clearance of murine melanoma that correlated with improved survival outcome in two independent cohorts of human melanoma patients. Our data reinforce the concept that successful vaccination must overcome local hurdles in the tumor microenvironment that are not manifest within the periphery. Further, tumor rejection following vaccination involves more than simply T cells. Finally, the association of our immune signature with positive survival outcome in human melanoma patients suggests that similar vaccination strategies may be promising for melanoma treatment.
authors: Department of Pathology and Molecular Medicine; McMaster University; Hamilton, ON Canada.
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