TY - JOUR
T1 - Enhancing the potency and specificity of engineered T cells for cancer treatment
AU - Sukumaran, Sujita
AU - Watanabe, Norihiro
AU - Bajgain, Pradip
AU - Raja, Kanchana
AU - Mohammed, Somala
AU - Fisher, William E.
AU - Brenner, Malcolm
AU - Leen, Ann M.
AU - Vera, Juan F.
N1 - Funding Information:
This work was supported by grants from the NIH-NCI (P01 CA094237, P50 CA126752, P50 CA186784), a Pancreatic Cancer Action Network Translational Research Grant (16-65-LEEN), the V Foundation for Cancer Research (T2016-006), the Elsa U. Pardee Foundation, and the National Pancreas Foundation, as well as the Adrienne Helis Malvin Medical Research Foundation in collaboration with Baylor College of Medicine. J.F. Vera is supported by a Mentored Research Scholars Grant in Applied and Clinical Research (MRSG-14-197-01–LIB) from the American Cancer Society. The authors acknowledge the editorial assistance provided by Catherine Gillespie as well as Walter Mejia for helping with the artwork and formatting of figures and tables for the manuscript. The authors would also like to thank Texas Children’s Hospital for the use of the Small Animal Imaging Facility, the Mouse Metabolism and Phenotyping core (NIH UM1HG006348 and NIH 1R01DK114356), the Metabolomics core supported by the CPRIT Core Facility Award (RP120092) and P30 Cancer Center Support Grant (NCI-CA125123), and the support of the Flow Cytometry and Cell and Vector Production shared resources in the Dan L. Duncan Comprehensive Cancer Center. M.K. Brenner, A.M. Leen, and J.F. Vera are supported by P50 CA126752 and P50 CA186784. W.E. Fisher, M.K. Brenner, A.M. Leen, and J.F. Vera are supported by P01 CA094237. W.E. Fisher and A.M. Leen’s research is supported by the 2016 Pancreatic Cancer Action Network Translational Research Grant (16-65-LEEN) and The V Foundation for Cancer Research (T2016-006). J.F. Vera is supported by a Mentored Research Scholars Grant in Applied and Clinical Research (MRSG-14-197-01–LIB) from the American Cancer Society. N. Watanabe and J.F. Vera were supported by the Elsa U. Pardee Foundation. The National Pancreas Foundation provided support to S. Sukumaran, N. Watanabe, and A.M. Leen.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/8
Y1 - 2018/8
N2 - The adoptive transfer of chimeric antigen receptor (CAR)–modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in “on-target, off-tumor” toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize prostate stem cell antigen, TGFβ, and IL4, and whose endodomains recapitulate physiologic T-cell signaling by providing signals for activation, costimulation, and cytokine support, produce potent antitumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFβ and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g., PD-L1, IL10, and IL13). SIGNIFICANCE: This proof-of-concept study demonstrates how sophisticated engineering approaches can be utilized to both enhance the antitumor efficacy and increase the safety profile of transgenic T cells by incorporating a combination of receptors that ensure that cells are active exclusively at the tumor site.
AB - The adoptive transfer of chimeric antigen receptor (CAR)–modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in “on-target, off-tumor” toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize prostate stem cell antigen, TGFβ, and IL4, and whose endodomains recapitulate physiologic T-cell signaling by providing signals for activation, costimulation, and cytokine support, produce potent antitumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFβ and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g., PD-L1, IL10, and IL13). SIGNIFICANCE: This proof-of-concept study demonstrates how sophisticated engineering approaches can be utilized to both enhance the antitumor efficacy and increase the safety profile of transgenic T cells by incorporating a combination of receptors that ensure that cells are active exclusively at the tumor site.
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UR - http://www.scopus.com/inward/citedby.url?scp=85053252928&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-17-1298
DO - 10.1158/2159-8290.CD-17-1298
M3 - Article
C2 - 29880586
AN - SCOPUS:85053252928
SN - 2159-8274
VL - 8
SP - 972
EP - 987
JO - Cancer Discovery
JF - Cancer Discovery
IS - 8
ER -