TY - JOUR
T1 - Reversible transgene expression reduces fratricide and permits 4-1BB Costimulation of CAR T cells directed to T-cell malignancies
AU - Mamonkin, Maksim
AU - Mukherjee, Malini
AU - Srinivasan, Madhuwanti
AU - Sharma, Sandhya
AU - Gomes-Silva, Diogo
AU - Mo, Feiyan
AU - Krenciute, Giedre
AU - Orange, Jordan S.
AU - Brenner, Malcolm
N1 - Funding Information:
This study was supported by a grant from the NIH, NCI (P50 CA126752), by the ASH Scholar Award (to M. Mamonkin), and by a Stand Up To Cancer - St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113; to M.K. Brenner). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. The authors also appreciate the support of shared resources in the Cancer Center (support grant NCIP30CA125123). The imaging work was supported by R01AI067946 (to J.S. Orange).
Funding Information:
This study was supported by a grant from the NIH, NCI (P50 CA126752), by the ASH Scholar Award (to M. Mamonkin), and by a Stand Up To Cancer – St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113; to M.K. Brenner). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. The authors also appreciate the support of shared resources in the Cancer Center (support grant NCIP30CA125123). The imaging work was supported by R01AI067946 (to J.S. Orange). The authors thank Catherine Gillespie for editing the article.
Publisher Copyright:
©2017 American Association for Cancer Research.
PY - 2018/1
Y1 - 2018/1
N2 - T cells expressing second-generation chimeric antigen receptors (CARs) specific for CD5, a T-cell surface marker present on normal and malignant T cells, can selectively kill tumor cells. We aimed to improve this killing by substituting the CD28 costimulatory endodomain (28.z) with 4-1BB (BB.z), as 28.z CD5 CART cells rapidly differentiated into short-lived effector cells. In contrast, 4-1BB costimulation is known to promote development of the central memory subpopulation. Here, we found BB.z CD5 CAR T cells had impaired growth compared with 28.z CD5.CAR T cells, due to increased T-cell-T-cell fratricide. We demonstrate that TRAF signaling from the 4-1BB endodomain upregulated the intercellular adhesion molecule 1, which stabilized the fratricidal immunologic synapse between CD5 CAR T cells. As the surviving BB.z CD5 CAR T cells retained the desired central memory phenotype, we aimed to circumvent the 4-1BB-mediated toxicity using a regulated expression system that reversibly inhibits CAR expression. This system minimized CAR signaling and T-cell fratricide during in vitro expansion in the presence of a small-molecule inhibitor, and restored CAR expression and antitumor function of transduced T cells in vivo. These studies reveal a mechanism by which 4-1BB costimulation impairs expansion of CD5 CAR T cells and offer a solution to mitigate this toxicity.
AB - T cells expressing second-generation chimeric antigen receptors (CARs) specific for CD5, a T-cell surface marker present on normal and malignant T cells, can selectively kill tumor cells. We aimed to improve this killing by substituting the CD28 costimulatory endodomain (28.z) with 4-1BB (BB.z), as 28.z CD5 CART cells rapidly differentiated into short-lived effector cells. In contrast, 4-1BB costimulation is known to promote development of the central memory subpopulation. Here, we found BB.z CD5 CAR T cells had impaired growth compared with 28.z CD5.CAR T cells, due to increased T-cell-T-cell fratricide. We demonstrate that TRAF signaling from the 4-1BB endodomain upregulated the intercellular adhesion molecule 1, which stabilized the fratricidal immunologic synapse between CD5 CAR T cells. As the surviving BB.z CD5 CAR T cells retained the desired central memory phenotype, we aimed to circumvent the 4-1BB-mediated toxicity using a regulated expression system that reversibly inhibits CAR expression. This system minimized CAR signaling and T-cell fratricide during in vitro expansion in the presence of a small-molecule inhibitor, and restored CAR expression and antitumor function of transduced T cells in vivo. These studies reveal a mechanism by which 4-1BB costimulation impairs expansion of CD5 CAR T cells and offer a solution to mitigate this toxicity.
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UR - http://www.scopus.com/inward/citedby.url?scp=85040458768&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-17-0126
DO - 10.1158/2326-6066.CIR-17-0126
M3 - Article
C2 - 29079655
AN - SCOPUS:85040458768
VL - 6
SP - 47
EP - 58
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 1
ER -