Improved survival of chimeric antigen receptor‐engineered T (CAR‐T) and tumor‐specific T cells caused by anti‐programmed cell death protein 1 single‐chain variable fragment‐producing CAR‐T cells

Abstract

Chimeric antigen receptor‐engineered T (CAR‐T)‐cell therapy holds significant promise for the treatment of hematological malignancies, especially for B‐cell leukemia and lymphoma. However, its efficacy against non‐hematological malignancies has been limited as a result of several biological problems characteristic of the tumor microenvironment of solid tumors. One of the main hurdles is the heterogeneous nature of tumor‐associated antigens (TAA) expressed in solid tumors. Another hurdle is the inefficient activation and limited persistence of CAR‐T cells, mainly as a result of T‐cell exhaustion caused by immunosuppressive factors in the tumor microenvironment. In the present study, to address these problems, we engineered CAR‐T cells to produce antagonistic anti‐programmed cell death protein 1 (PD‐1) single‐chain variable fragment (scFv), by which PD‐1‐dependent inhibitory signals in CAR‐T cells and adjacent tumor‐specific non‐CAR‐T cells are attenuated. In mouse solid tumor models, PD‐1 scFv‐producing CAR‐T cells induced potent therapeutic effects superior to those of conventional CAR‐T cells, along with a significant reduction of apoptotic cell death not only in CAR‐T cells themselves but also in TAA‐specific T cells in the tumor tissue. In addition, the treatment with anti‐PD‐1 scFv‐producing CAR‐T cells resulted in an increased concentration of PD‐1 scFv in tumor tissue but not in sera, suggesting an induction of less severe systemic immune‐related adverse events. Hence, the present study developed anti‐PD‐1 scFv‐producing CAR‐T cell technology and explored its cellular mechanisms underlying potent antitumor efficacy.

Recent advances in CAR-T cell engineering

“…Therefore, the inhibitor of PD-1 reverses the effects of the TME to some extent and helps prevent T cell exhaustion. Although disrupting the PD-1 receptor using the clustered regularly interspaced short palindromic repeats (CRISPR)/CAS9 system enables CAR-T cells to resist the TME and increases the tumorkilling efficiency [90], the secreted PD-1 blocker rescues the "bystander" T cells and reconstructs the immune system in patients [91][92][93][94]. The PD-1 blocker showed the ability to rescue PD-1-overexpressing (exhausted) CAR-T cells [95], but ongoing clinical trials will reveal whether the secreted PD-1 blocker is effective in CAR-T cells.…”

Augmenting the Effectiveness of CAR-T Cells by Enhanced Self-Delivery of PD-1-Neutralizing scFv

“…To overcome the inhibitory effects of PD-1, synergistically administrating anti-PD-1 antibody or deleting PD-1 with CRISPR/cas9 have been extensively studied in CAR-T cells ( John et al, 2013 ; Rupp et al, 2017 ; Choi et al, 2019 ; Hu et al, 2019 ). Besides, constructing CAR-T cells that can produce PD-1-neutralizing proteins is also in action ( Li et al, 2017 ; Rafiq et al, 2018 ; Yin et al, 2018 ; Nakajima et al, 2019 ). In this study, we constructed mesothelin-specific CAR-T cells with optimized secretion of α-PD-1 scFv and checked the anti-tumor efficacy of CAR-T cells with α-PD-1 scFv in vitro and in vivo .…”

Anti‐tumor efficacy of human anti‐c‐met CAR‐T cells against papillary renal cell carcinoma in an orthotopic model

“…To overcome the immunosuppressive environment of tumor tissues, CAR-T cells with the capacity to produce anti-PD-1 scFv have been developed. 61,62 In another concept, to enhance infiltration, accumulation, and survival of CAR-T cells in solid tumors, we have recently reported CAR-T cells expressing IL-7 and CCL19 simultaneously. 63 It would also be reasonable to convert the conventional anti-c-met CAR-T cells employed in this study to such next-generation CAR systems to enhance anti-tumor capacity.…”