Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

Xiaohui Wang,Xiang Xu,Weidong Han,Wei Qiu,Zhiqiang Wu,Ping Chen

doi:10.1007/s11684-020-0746-0

Xiaohui Wang, Xiang Xu + Show 4 more

Open Access

https://doi.org/10.1007/s11684-020-0746-0

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Abstract

Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

Highlights

Along with surgery, chemotherapy, and radiotherapy, immunotherapy is considered an important pillar of cancer treatment
Varying methods have been explored to deliver chemokine receptors into chimeric antigen receptor (CAR) T cells because effective trafficking is interrupted by the mismatch between the chemokine receptors expressed by CAR T cells and the chemokines expressed by tumors [23]
This group generated an anti-epidermal growth factor receptor (EGFR)-hmLIGHT fusion protein against EGFR-expressing tumor tissues. This fusion protein caused complete regression of EGFR-expressing tumors. These results demonstrate that LIGHT overcomes tumor resistance to programmed cell death-1 (PD-1) by sufficiently increasing T cell infiltration and by generating memory cells

Summary

Introduction

Chemotherapy, and radiotherapy, immunotherapy is considered an important pillar of cancer treatment. In addition to the above cytokines, the IL-7 signal is a potent stimulator of T cell proliferation and expansion [61], and the expression of IL-7Rα improves the function and efficacy of CAR T cells in solid tumor environments.

Results

Conclusion