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Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):E5290-9. doi: 10.1073/pnas.1514418112. Epub 2015 Sep 8.

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

Author information

1
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030.
2
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
3
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030 mcurran@mdanderson.org jallison@mdanderson.org.

Abstract

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.

KEYWORDS:

4-1BB; HPV; cancer vaccine; checkpoint blockade; immunotherapy

PMID:
26351680
PMCID:
PMC4586868
DOI:
10.1073/pnas.1514418112
[Indexed for MEDLINE]
Free PMC Article

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