A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine

Abstract

BackgroundProgrammed cell death protein 1 (PD-1) can attenuate chimeric antigen receptor-T (CAR-T) cell-mediated anti-tumoral immune responses. In this regard, co-administration of anti-PD-1 with CAR-T cells and PD-1 gene-editing of CAR-T cells have been suggested to disrupt this inhibitory axis. Herein, we aim to investigate the advantages and disadvantages of these two approaches and propose a novel strategy to ameliorate the prognosis of glioma patients.MethodsScopus, Embase, and Web of Science were systematically searched to obtain relevant peer-reviewed studies published before March 7, 2021. Then, the current study was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. The random-effect model was applied to evaluate the effect size of administrated agents on the survival of animal models bearing gliomas using RevMan version 5.4. The Cochran Q test and I2 were performed to assess the possible between-study heterogeneity. Egger’s and Begg and Mazumdar’s tests were performed to objectively assess potential asymmetry and publication bias using CMA version 2.ResultsAnti-PD-1 can substantially increase the survival of animal models on second-generation CAR-T cells. Also, PD-1 knockdown can remarkably prolong the survival of animal models on third-generation CAR-T cells. Regardless of the CAR-T generations, PD-1 gene-edited CAR-T cells can considerably enhance the survival of animal-bearing gliomas compared to the conventional CAR-T cells.ConclusionsThe single-cell sequencing of tumoral cells and cells residing in the tumor microenvironment can provide valuable insights into the patient-derived neoantigens and the expression profile of inhibitory immune checkpoint molecules in tumor bulk. Thus, single-cell sequencing-guided fourth-generation CAR-T cells can cover patient-derived neoantigens expressed in various subpopulations of tumoral cells and inhibit related inhibitory immune checkpoint molecules. The proposed approach can improve anti-tumoral immune responses, decrease the risk of immune-related adverse events, reduce the risk of glioma relapse, and address the vast inter-and intra-heterogeneity of gliomas.

PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cells in lung cancer brain metastasis.

“…[27,38,39] Within the context of CAR T-cell treatment PD-1 suppression can be achieved through the co-administration of PD-1 targeting monoclonal antibodies or the PD-1 gene editing of CAR T-cells. [40] In systemic tumor models, the additional value of PD-1 blockade to increase CAR T-cell e cacy has been debated. In a murine preclinical model for systemic melanoma, concurrent PD-1 blockade notably increased the persistence and e cacy of CAR T-cell treatment.…”

Are we ready for personalizedCAR‐Ttherapy?

“…It has been shown that PD-1 knock-out had a positive effect on CAR-T cell survival, but such manipulation can cause significant adverse reactions, thus the individual risk of gains and losses should be kept in mind. 13 Transforming growth factor β (TGF-β) negatively affects the efficacy of CAR-T therapy, as one of its functions in tumor microenvironment (TME) is immunosuppression limiting the role of T cells. 14 Tang et al 14 attempted to block TGF-β at the tumor site by using nano-techniques to deliver TGF-β inhibitors LY2157299 (LY), and obtained LY/ICG@HES-PCL nanoparticle.…”

“…Insufficient persistence of CAR T‐cells in vivo remains a significant clinical problem. It has been shown that PD‐1 knock‐out had a positive effect on CAR‐T cell survival, but such manipulation can cause significant adverse reactions, thus the individual risk of gains and losses should be kept in mind 13 . Transforming growth factor β (TGF‐β) negatively affects the efficacy of CAR‐T therapy, as one of its functions in tumor microenvironment (TME) is immunosuppression limiting the role of T cells 14 .…”

The Basis and Advances in Clinical Application of Cytomegalovirus-Specific Cytotoxic T Cell Immunotherapy for Glioblastoma Multiforme

“…It has been shown that the PD-1/PD-L1 axis contributes to CTL exhaustion and Treg augmentation, which protects tumor cells from CTL-mediated lysis ( 159 ). These findings call for more research into integrating anti-PD-L1 or genetically engineered T cells with PD-1 receptor blockade with CMV-specific ACT to maximize the clinical response of GB patients with predominant PD-L1 expression ( 160 ).…”