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The development of CAR design for tumor CAR-T cell therapy.

ABSTRACT: In recent years, the chimeric antigen receptor modified T cells (Chimeric antigen receptor T cells, CAR-T) immunotherapy has developed rapidly, which has been considered the most promising therapy. Efforts to enhance the efficacy of CAR-based anti-tumor therapy have been made, such as the improvement of structures of CAR-T cells, including the development of extracellular antigen recognition receptors, intracellular co-stimulatory molecules and the combination application of CARs and synthetic small molecules. In addition, effects on the function of the CAR-T cells that the space distance between the antigen binding domains and tumor targets and the length of the spacer domains have are also being investigated. Given the fast-moving nature of this field, it is necessary to make a summary of the development of CAR-T cells. In this review, we mainly focus on the present design strategies of CAR-T cells with the hope that they can provide insights to increase the anti-tumor efficacy and safety.

SUBMITTER: Xu D

PROVIDER: S-EPMC5862632 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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The development of CAR design for tumor CAR-T cell therapy.

Xu Dandan D Jin Guoliang G Chai Dafei D Zhou Xiaowan X Gu Weiyu W Chong Yanyun Y Song Jingyuan J Zheng Junnian J

Oncotarget 20180112 17

In recent years, the chimeric antigen receptor modified T cells (Chimeric antigen receptor T cells, CAR-T) immunotherapy has developed rapidly, which has been considered the most promising therapy. Efforts to enhance the efficacy of CAR-based anti-tumor therapy have been made, such as the improvement of structures of CAR-T cells, including the development of extracellular antigen recognition receptors, intracellular co-stimulatory molecules and the combination application of CARs and synthetic s ...[more]

PMID: 29568411

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Project description:T-cells genetically engineered to express a chimeric antigen receptor (CAR) have shown remarkable results in patients with B-cell malignancies, including B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and mantle cell lymphoma, with some promising efficacy in patients with multiple myeloma. However, the efficacy of CAR T-cell therapy is still hampered by local immunosuppression and significant toxicities, notably cytokine release syndrome (CRS) and neurotoxicity. The tumor microenvironment (TME) has been identified to play a major role in preventing durable responses to immunotherapy in both solid and hematologic malignancies, with this role exaggerated in solid tumors. The TME comprises a diverse set of components, including a heterogeneous population of various cells and acellular elements that collectively contribute towards the interplay of pro-immune and immunosuppressive signaling. In particular, macrophages, myeloid-derived suppressor cells, regulatory T-cells, and cell-free factors such as cytokines are major contributors to local immunosuppression in the TME of patients treated with CAR T-cells. In order to create a more favorable niche for CAR T-cell function, armored CAR T-cells and other combinatorial approaches are being explored for potential improved outcomes compared to conventional CAR T-cell products. While these strategies may potentiate CAR T-cell function and efficacy, they may paradoxically increase the risk of adverse events due to increased pro-inflammatory signaling. Herein, we discuss the mechanisms by which the TME antagonizes CAR T-cells and how innovative immunotherapy strategies are being developed to address this roadblock. Furthermore, we offer perspective on how these novel approaches may affect the risk of adverse events, in order to identify ways to overcome these barriers and expand the clinical benefits of this treatment modality in patients with diverse cancers. Precise immunomodulation to allow for improved tumor control while simultaneously mitigating the toxicities seen with current generation CAR T-cells is integral for the future application of more effective CAR T-cells against other malignancies.

Dataset Information

The development of CAR design for tumor CAR-T cell therapy.

Publications

The development of CAR design for tumor CAR-T cell therapy.

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