Co-administration of 4-1BB agonist antibody converts a therapeutic HPV E6/E7 vaccine into a curative therapy Michael A. Curran, Ph.D. MD Anderson Cancer.

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Presentation transcript:

Co-administration of 4-1BB agonist antibody converts a therapeutic HPV E6/E7 vaccine into a curative therapy Michael A. Curran, Ph.D. MD Anderson Cancer Center Department of Immunology

I will be talking about investigational therapeutics. I have research collaborations with Bristol Myers Squibb, Astrazeneca, Adimab, and Threshold. I receive royalties from the patent “Methods and Compositions for Localized Secretion of anti-CTLA-4 Antibodies”. I will be talking about investigational therapeutics.

HPV Induced Cancers HPV E6/E7 oncoproteins are causative for cervical, vulvar, vaginal, penile, anal, and oropharyngeal cancers Each year ~20,000 HPV-driven cancers occur in women with cervical cancer the most common Each year ~12,000 HPV-driven cancers occur in men with oropharyngeal cancer most common As immunologically foreign proteins which are critical for maintenance of the transformed phenotype, E6 and E7 are ideal vaccine targets.

Responses to specific E6/E7 peptides predict recurrence-free survival in HPV Q15L (43-57) QLLRREVYDFAFRDL E7 peptide: Q19D (44-62) QAEPDRAHYNIVTFCCKCD Shailbala Singh

An intra-nasal HPV E6/E7 : α-GalCer vaccine slows growth of TC-1 tumors Shailbala Singh

4-1BB agonist antibody and HPV E6/E7 vaccine synergize in curing TC-1 tumors Todd Bartkowiak, M.S.

Diverse adjuvant effects of checkpoint blockade with HPV vaccination Todd Bartkowiak, M.S.

Intra-tumoral CD8/Treg ratios are dramatically elevated in Vax + α4-1BB group Todd Bartkowiak, M.S.

Enhanced CD8/Treg ratios result from both decreased Treg and increased CD8 T cells Todd Bartkowiak, M.S.

Vax + α4-1BB promotes high density tumor infiltration by E7-specific CD8 T cells Todd Bartkowiak, M.S.

Both HPV Vax/adjuvant and α4-1BB contribute to enhanced tumor T cell response Todd Bartkowiak, M.S.

4-1BB agonist antibodies also activate APCs helping to generate ThEO/TcEO T cells Spleen ThEO T Cells Tumor ThEO T Cells Curran M A et al. J Exp Med 2013;210:743-755

Highly cytotoxic ThEO/TcEO phenotype T cells are abundant in tumors of α4-1BB treated mice

Vaccine + α4-1BB regresses tumors established in the mucosa of the female reproductive tract Regression of TC-1 tumors in FRT Shailbala Singh

4-1BB agonist antibody vaccine amplification : a paradigm for therapeutic vaccines? Outside of HPV E6/E7, current therapeutic vaccination trials include Her2, Muc1, NY-ESO, hTERT, Survivin, PAP, PSA, Mesothelin, et. al. Future studies will seek to confirm whether the advantages of 4-1BB agonist antibody as a vaccine potentiator are specific to HPV E6/E7 or are consistent across the therapeutic cancer vaccination landscape.

Acknowledgements James P. Allison Curran Lab: Sastry Lab: Michael A. Curran Todd Bartkowiak Casey Ager Midan Ai Pratha Budhani Ashvin Jaiswal Beata Kaplan-Lerman Jie Sheng Sastry Lab: K. Jagannadha Sastry Shailbala Singh Guojun Yang James P. Allison