Transcript Co-Administration of 4-1BB Agonist Antibody

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 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-CTLA4 Antibodies”.
I will be talking about investigational
therapeutics.
HPV Induced Cancers
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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
E6 Peptides
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E7 Peptides
80
60
40
20
Treated
(Recurrence+)
Treated
(Recurrence-)
Untreated
(HPV+CIN+)
0
Control
(HPV-/CIN-)
% Population with positive
HPV-specific immunity
100
E6 peptide:
– 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
Day 6 Day 15 Day 19
PBS
Regression of TC-1 tumors in FRT
Vaccine
Vaccine+
α-4-1BB
Vaccine+
α-CTLA4
Shailbala Singh
4-1BB agonist antibody vaccine amplification :
a paradigm for therapeutic vaccines?
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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
Curran Lab:
Sastry Lab:
Michael A. Curran
K. Jagannadha Sastry
Todd Bartkowiak
Shailbala Singh
Casey Ager
Guojun Yang
Midan Ai
Pratha Budhani
Ashvin Jaiswal
Beata Kaplan-Lerman
Jie Sheng
James P. Allison