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The Weal and Woe of Costimulation in the Adoptive Therapy of Cancer with Chimeric Antigen Receptor (CAR)-Redirected T Cells

[ Vol. 13 , Issue. 7 ]

Author(s):

A. A. Hombach, A. Holzinger and H. Abken   Pages 1079 - 1088 ( 10 )

Abstract:


Adoptive cell therapy has shown impressive efficacy to combat cancer in early phase clinical trials, in particular when T cells engineered to specifically target tumor cells were applied. The patient's T cells are genetically equipped with a chimeric antigen receptor (CAR) which allows them to be redirected in a predefined manner towards virtually any target; by using an antibody-derived domain for binding, CAR T cells can be redirected in a major histocompatibility complex (MHC) dependent and independent fashion. The CAR also provides the stimuli required to induce and maintain T cell activation. Recent clinical data sustain the notion that strong costimulation in conjunction with the primary activation signal is crucial for lasting therapeutic efficacy of CAR T cells. However, costimulation is a double-edged sword and the impact of the individual costimuli to optimize T cell activation is still under debate; some general rules are emerging. The review summarizes how costimulation modulates, improves and prolongs the redirected anti-tumor T cell response and how the same costimulatory signals may contribute to unintended side effects including "cytokine storm" and T cell repression. Upcoming strategies to break the activation/repression circle by using CAR's with modified costimulatory signals are also discussed.

Keywords:

Adoptive cell therapy, cancer, chimeric antigen receptor, CD28, immunotherapy, T cell, OX40 (CD134), 4-1BB (CD137).

Affiliation:

Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Str. 21, D-50931 Cologne, Germany.



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