Unique potential of 4-1BB agonist antibody to promote durable regression of HPV+ tumors when combined with an E6/E7 peptide vaccine (TUM2P.1016)

Abstract

Abstract Antibody modulation of T cell co-inhibitory (e.g. CTLA-4) or co-stimulatory (e.g. 4-1BB) receptors promotes clinical responses to a variety of cancers. Therapeutic cancer vaccination, in contrast, has produced limited clinical benefit. The E6 and E7 onco-proteins of human papilloma virus drive the majority of genital and oropharyngeal cancers. We discovered 15-19 amino acid peptides from HPV16 E6/E7 for which T cell immunity correlates with disease-free survival in patients treated for high-grade cervical neoplasia. We report that intra-nasal vaccination with these peptides and the adjuvant alpha-galactosylceramide elicits systemic and mucosal T cell responses leading to reduced HPV+ TC-1 tumor growth and prolonged survival in mice. We hypothesized that the inability of these T cells to fully reject established tumors resulted from suppression in the tumor which could be ameliorated through checkpoint modulation. Combining this vaccine with checkpoint blockade produced only modest benefit; however, co-administration with a 4-1BB agonist antibody promoted durable regression of 100% of established genital HPV+ tumors. The vaccine/α4-1BB combination promoted the highest CD8+ versus regulatory FoxP3+ T cell ratios, elicited much higher infiltration by E7-specific CTL, and evoked higher densities of highly cytotoxic TcEO CD8 (>70-fold) and ThEO CD4 (>17-fold) phenotype T cells. Activation of 4-1BB may have a unique capacity to potentiate therapeutic cancer vaccines.