Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells

Thomas Shum, Bilal Omer, Haruko Tashiro, Robert L. Kruse, Dimitrios L. Wagner, Kathan Parikh, Zhongzhen Yi, Tim Sauer, Daofeng Liu, Robin Parihar, Paul Castillo, Hao Liu, Malcolm K. Brenner, Leonid S. Metelitsa, Stephen Gottschalk, Cliona M. Rooney

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1238-1247
Number of pages10
JournalCancer Discovery
Volume7
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells'. Together they form a unique fingerprint.

  • Cite this

    Shum, T., Omer, B., Tashiro, H., Kruse, R. L., Wagner, D. L., Parikh, K., Yi, Z., Sauer, T., Liu, D., Parihar, R., Castillo, P., Liu, H., Brenner, M. K., Metelitsa, L. S., Gottschalk, S., & Rooney, C. M. (2017). Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discovery, 7(11), 1238-1247. https://doi.org/10.1158/2159-8290.CD-17-0538