TY - JOUR
T1 - Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells
AU - Shum, Thomas
AU - Omer, Bilal
AU - Tashiro, Haruko
AU - Kruse, Robert L.
AU - Wagner, Dimitrios L.
AU - Parikh, Kathan
AU - Yi, Zhongzhen
AU - Sauer, Tim
AU - Liu, Daofeng
AU - Parihar, Robin
AU - Castillo, Paul
AU - Liu, Hao
AU - Brenner, Malcolm K.
AU - Metelitsa, Leonid S.
AU - Gottschalk, Stephen
AU - Rooney, Cliona M.
N1 - Funding Information:
This work was supported by P01CA094237, 1RO1CA173750, an Alex’s Lemonade Stand Foundation Reach grant as well as T32DK060445 and HL092332 that supported Thomas Shum. This work was funded in part by the Howard Hughes Medical Institutes Med into Grad Initiative. It was also supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574) and the expert assistance of Joel M. Sederstrom.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/11
Y1 - 2017/11
N2 - Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefi ts but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modifi ed T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7Rcoexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specifi c T-cell therapies against cancer. SIGnIFICAnCE: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development.
AB - Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefi ts but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modifi ed T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7Rcoexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specifi c T-cell therapies against cancer. SIGnIFICAnCE: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development.
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U2 - 10.1158/2159-8290.CD-17-0538
DO - 10.1158/2159-8290.CD-17-0538
M3 - Article
C2 - 28830878
AN - SCOPUS:85032977547
SN - 2159-8274
VL - 7
SP - 1238
EP - 1247
JO - Cancer Discovery
JF - Cancer Discovery
IS - 11
ER -