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),
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