Antibody modulation of T-cell coinhibitory (e.g., CTLA-4) or costimulatory (e.g., 4-1BB) receptors promotes clinical responses to a variety of cancers. Therapeutic cancer vaccination, in contrast, has produced limited clinical benefit and no curative therapies. The E6 and E7 oncoproteins of human papilloma virus (HPV) drive the majority of genital cancers, and many oropharyngeal tumors. We discovered 15-19 amino acid peptides from HPV-16 E6/E7 for which induction of T-cell immunity correlates with disease-free survival in patients treated for high-grade cervical neoplasia. We report here that intranasal 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 microenvironment which could be ameliorated through checkpoint modulation. Combining this E6/E7 peptide vaccine with checkpoint blockade produced only modest benefit; however, coadministration with a 4-1BB agonist antibody promoted durable regression of established genital TC-1 tumors. Relative to other therapies tested, this combination of vaccine and α4-1BB promoted the highest CD8 + versus regulatory FoxP3 + T-cell ratios, elicited 2-to 5-fold higher infiltration by E7-specific CTL, and evoked higher densities of highly cytotoxic TcEO (T cytotoxic Eomesodermin) CD8 (>70-fold) and ThEO (T helper Eomesodermin) CD4 (>17-fold) T cells. These findings have immediate clinical relevance both in terms of the direct clinical utility of the vaccine studied and in illustrating the potential of 4-1BB antibody to convert therapeutic E6/E7 vaccines already in clinical trials into curative therapies.C ervical cancer is the second most common malignancy in women worldwide and continues to cause significant morbidity and mortality in the developing world, where screening and prevention programs remain rudimentary (1). The E6 and E7 oncoproteins of human papilloma virus (HPV) drive cervical cancer formation and are critical for maintenance of the transformed state (2). Beyond cervical cancer, HPV infection underlies 40% or greater of cases of oropharyngeal, anal, penile, vaginal, and vulvar cancers (3).The immunologically foreign nature of the HPV E6 and E7 proteins, coupled with their critical role in maintaining the oncogenic state, makes them ideal target antigens for therapeutic cancer vaccination. Whereas peptide-, protein-, viral-and DNAbased vaccines targeting E6 and E7 have been studied both preclinically and in clinical trials, most fail to induce regression of established HPV + tumors (4). To some degree, all of these vaccines succeed in eliciting peripheral E6/E7-specific T-cell responses; however, not all are proven to generate T cells capable of trafficking to the genital mucosa where cervical cancer develops. Whereas a number of these vaccines extend survival, few can induce regression of establishe...