Reversible Transgene Expression Reduces Fratricide and Permits 4-1BB Costimulation of CAR T Cells Directed to T-cell Malignancies

被引:87
作者
Mamonkin, Maksim [1 ,2 ]
Mukherjee, Malini [1 ,3 ,4 ]
Srinivasan, Madhuwanti [1 ]
Sharma, Sandhya [1 ,5 ]
Gomes-Silva, Diogo [1 ,6 ]
Mo, Feiyan [1 ,5 ]
Krenciute, Giedre [1 ,3 ]
Orange, Jordan S. [2 ,3 ,4 ,5 ]
Brenner, Malcolm K. [1 ,3 ,5 ]
机构
[1] Texas Childrens Hosp, Baylor Coll Med, Houston Methodist Hosp, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
[4] Texas Childrens Hosp, Ctr Human Immunobiol, Houston, TX 77030 USA
[5] Baylor Coll Med, Interdept Grad Program Translat Biol & Mol Med, Houston, TX 77030 USA
[6] Univ Lisbon, Inst Super Tecn, Lisbon, Portugal
关键词
CHIMERIC ANTIGEN RECEPTOR; INTERCELLULAR-ADHESION MOLECULE-1; NATURAL-KILLER-CELLS; KAPPA-B; IMMUNOLOGICAL SYNAPSE; ANTITUMOR-ACTIVITY; EFFECTOR FUNCTION; INTERFERON-GAMMA; IN-VIVO; ACTIVATION;
D O I
10.1158/2326-6066.CIR-17-0126
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 CAR T 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. (C) 2017 AACR.
引用
收藏
页码:47 / 58
页数:12
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