Co-administration of 4-1BB agonist antibody converts a therapeutic HPV E6/E7 vaccine into a curative...

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 CenterDepartment 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-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

0

20

40

60

80

100

120

Q15L Q19D Q15L Q19D

Recurrence-free With recurrence

% P

os

itiv

e p

op

ula

tio

n

IFN-g IL-12 IL-4 IL-10

0

20

40

60

80

100

Co

ntr

ol

(H

PV

-/C

IN-)

Un

tre

ate

d

(HP

V+

CIN

+)

Tre

ate

d

(Re

cu

rre

nc

e-)

Tre

ate

d

(Re

cu

rre

nc

e+)

% P

op

ula

tio

n w

ith

po

sit

ive

H

PV

-sp

eci

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imm

un

ity

E6 Peptides E7 Peptides

• 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


Intra-tumoral CD8/Treg ratios are dramatically elevated in Vax + α4-

1BB group


Enhanced CD8/Treg ratios result from both decreased Treg and

increased CD8 T cells


Vax + α4-1BB promotes high density tumor infiltration by E7-

specific CD8 T cells


Both HPV Vax/adjuvant and α4-1BB contribute to enhanced tumor

T cell response


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 tractDay 6 Day 15 Day 19

PBS

Vaccine

Vaccine+ α-4-1BB

Vaccine+ α-CTLA4

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

Curran 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

Co-administration of 4-1BB agonist antibody converts a therapeutic HPV E6/E7 vaccine into a curative...

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