1. 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

2. 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.

3. 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.

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

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

6. 4-1BB agonist antibody and HPV E6/E7 vaccine synergize in curing TC-1 tumors
Todd Bartkowiak, M.S.

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

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

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

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

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

13. 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:

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

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

16. 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.

17. 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