| Autor: |
Poorebrahim M; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. mansour.poorebrahim@dkfz-heidelberg.de.; Targeted Tumor Vaccines Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany. mansour.poorebrahim@dkfz-heidelberg.de., Melief J; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Pico de Coaña Y; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., L Wickström S; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Cid-Arregui A; Targeted Tumor Vaccines Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany., Kiessling R; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. rolf.kiessling@ki.se. |
| Abstrakt: |
In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an "exhaustion-resistant" phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed. |
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