TY - JOUR
T1 - Adenovirotherapy Delivering Cytokine and Checkpoint Inhibitor Augments CAR T Cells against Metastatic Head and Neck Cancer
AU - Rosewell Shaw, Amanda
AU - Porter, Caroline E.
AU - Watanabe, Norihiro
AU - Tanoue, Kiyonori
AU - Sikora, Andrew
AU - Gottschalk, Stephen
AU - Brenner, Malcolm
AU - Suzuki, Masataka
N1 - Funding Information:
The authors would like to thank Catherine Gillespie in the Center for Cell and Gene Therapy at Baylor College of Medicine for editing the paper, Walter Mejia in the Center for Cell and Gene Therapy at Baylor College of Medicine for graphical design of the video abstract, and Dr. Brendan Lee in the Department of Molecular and Human Genetics at Baylor College of Medicine for support of the project. This work was supported by NIH grants R00HL098692 (to M.S.), T32HL092332 (to A.R.S.), and P30-CA125123 (to the Human Tissue Acquisition and Pathology Core) and a BCM Head and Neck seed grant and the Concern Foundation (to M.S.). This work was also supported by NIH grant P01 CA094237 (to M.K.B. and S.G.). K.T. was supported by the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation of the Japan Society for the Promotion of Science .
Funding Information:
This research was supported by Tessa Therapeutics, Pte, Ltd.
Publisher Copyright:
© 2017 The American Society of Gene and Cell Therapy
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-specific CAR T cells, which alone are insufficient to cure solid tumors. We tested multiple cytokines in conjunction with PD-L1-blocking antibody and found that Ad-derived IL-12p70 prevents the loss of HER2.CAR-expressing T cells at the tumor site. Accordingly, we created a construct encoding the PD-L1-blocking antibody and IL-12p70 (CAd12_PDL1). In head and neck squamous cell carcinoma (HNSCC) xenograft models, combining local treatment with CAd12_PDL1 and systemic HER2.CAR T cell infusion improved survival to >100 days compared with approximately 25 days with either approach alone. This combination also controlled both primary and metastasized tumors in an orthotopic model of HNSCC. Overall, our data show that CAd12_PDL1 augments the anti-tumor effects of HER2.CAR T cells, thus controlling the growth of both primary and metastasized tumors. Rosewell Shaw et al. combine their binary oncolytic adenoviral vector with chimeric antigen receptor-modified T cells to overcome the inherent limitations of each agent. Locally injected adenovirus expressing both PDL1 checkpoint antibody and IL-12 augments the systemic anti-tumor activity of HER2.CAR-T cells, improving survival from human head and neck cancer xenografts.
AB - In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-specific CAR T cells, which alone are insufficient to cure solid tumors. We tested multiple cytokines in conjunction with PD-L1-blocking antibody and found that Ad-derived IL-12p70 prevents the loss of HER2.CAR-expressing T cells at the tumor site. Accordingly, we created a construct encoding the PD-L1-blocking antibody and IL-12p70 (CAd12_PDL1). In head and neck squamous cell carcinoma (HNSCC) xenograft models, combining local treatment with CAd12_PDL1 and systemic HER2.CAR T cell infusion improved survival to >100 days compared with approximately 25 days with either approach alone. This combination also controlled both primary and metastasized tumors in an orthotopic model of HNSCC. Overall, our data show that CAd12_PDL1 augments the anti-tumor effects of HER2.CAR T cells, thus controlling the growth of both primary and metastasized tumors. Rosewell Shaw et al. combine their binary oncolytic adenoviral vector with chimeric antigen receptor-modified T cells to overcome the inherent limitations of each agent. Locally injected adenovirus expressing both PDL1 checkpoint antibody and IL-12 augments the systemic anti-tumor activity of HER2.CAR-T cells, improving survival from human head and neck cancer xenografts.
KW - CAR T cell therapy
KW - adenovirotherapy
KW - head and neck cancer
KW - oncolytic virus
KW - orthotopic animal model
UR - http://www.scopus.com/inward/record.url?scp=85030467955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030467955&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2017.09.010
DO - 10.1016/j.ymthe.2017.09.010
M3 - Article
C2 - 28974431
AN - SCOPUS:85030467955
VL - 25
SP - 2440
EP - 2451
JO - Molecular therapy : the journal of the American Society of Gene Therapy
JF - Molecular therapy : the journal of the American Society of Gene Therapy
SN - 1525-0016
IS - 11
ER -