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

27 Citations (Scopus)

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

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Interleukin-7 Receptors
T-Lymphocytes
Neoplasms
Interleukin-7
T-Cell Antigen Receptor
Cytokines
Antigens
Antigen Receptors
Cytokine Receptors
Glioblastoma
Cell- and Tissue-Based Therapy
Neuroblastoma
Heterografts
Immunotherapy
Cell Survival
Cell Proliferation
Lymphocytes

ASJC Scopus subject areas

  • Oncology

Cite this

Shum, T., Omer, B., Tashiro, H., Kruse, R. L., Wagner, D. L., Parikh, K., ... 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

Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. / Shum, Thomas; Omer, Bilal; Tashiro, Haruko; Kruse, Robert L.; Wagner, Dimitrios L.; Parikh, Kathan; Yi, Zhongzhen; Sauer, Tim; Liu, Daofeng; Parihar, Robin; Castillo, Paul; Liu, Hao; Brenner, Malcolm K.; Metelitsa, Leonid S.; Gottschalk, Stephen; Rooney, Cliona M.

In: Cancer Discovery, Vol. 7, No. 11, 01.11.2017, p. 1238-1247.

Research output: Contribution to journalArticle

Shum, T, Omer, B, Tashiro, H, Kruse, RL, Wagner, DL, Parikh, K, Yi, Z, Sauer, T, Liu, D, Parihar, R, Castillo, P, Liu, H, Brenner, MK, Metelitsa, LS, Gottschalk, S & Rooney, CM 2017, 'Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells', Cancer Discovery, vol. 7, no. 11, pp. 1238-1247. https://doi.org/10.1158/2159-8290.CD-17-0538
Shum, Thomas ; Omer, Bilal ; Tashiro, Haruko ; Kruse, Robert L. ; Wagner, Dimitrios L. ; Parikh, Kathan ; Yi, Zhongzhen ; Sauer, Tim ; Liu, Daofeng ; Parihar, Robin ; Castillo, Paul ; Liu, Hao ; Brenner, Malcolm K. ; Metelitsa, Leonid S. ; Gottschalk, Stephen ; Rooney, Cliona M. / Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. In: Cancer Discovery. 2017 ; Vol. 7, No. 11. pp. 1238-1247.
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