Secretion of bispecific protein of anti-PD-1 fused with TGF-β trap enhances antitumor efficacy of CAR-T cell therapy

Abstract

Despite the remarkable success of chimeric antigen receptor-modified T (CAR-T) cell therapy for blood malignancies, the clinical efficacy of this novel therapy in solid tumor treatment is largely limited by the immunosuppressive tumor microenvironment (TME). For instance, immune checkpoints (e.g., programmed cell death protein 1 [PD-1]/programmed death ligand 1 [PD-L1]) in TME play an important role in inhibiting T cell proliferation and functions. Transforming growth factor β (TGF)-β secreted by cancer cells in TME induces regulatory T cells (Tregs) and inhibits cytotoxic T cells. To overcome the inhibitory effect of immune checkpoints, we have previously engineered CAR-T cells to secrete anti-PD-1 to block the PD-1/PD-L1 pathway activity, a step demonstrating superior antitumor efficacy compared with conventional CAR-T cells. In this study, we engineered CAR-T cells that secrete bispecific trap protein co-targeting PD-1 and TGF-β, with the aim of further improving antitumor immunity. Compared with conventional CAR-T cells and anti-PD-1-secreting CAR-T cells, data from in vitro and in vivo experiments showed that CAR-T cells with trap protein secretion further attenuated inhibitory T cell signaling, enhanced T cell persistence and expansion, and improved effector function and resistance to exhaustion. In the xenograft mouse model, CAR-T cells with trap protein secretion exhibited significantly enhanced antitumor immunity and efficacy. With these observations, we demonstrate the potential of trap protein self-secreting CAR-T cells as a potent therapy for solid tumors.

Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment

“…TGF-β has been shown to increase PD-1 expression on immune cells, while anti-PD-1 increases tumor cell pSMAD3 and can induce immunosuppression ( Baas et al, 2016 ; Park et al, 2016 ; Dodagatta-Marri et al, 2019 ; Wu et al, 2020 ). Thus, blockade of TGF-β signaling enhances the effects of PD-1 inhibitors or overcomes primary resistance to PD-1 blockade in silico and in vivo ( Terabe et al, 2017 ; Strauss et al, 2018 ; Chen et al, 2021 ; Siewe and Friedman, 2021 ).…”

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma

“…Studies have found the critical role of TGF-β signaling pathway in regulating cell growth, apoptosis, and differentiation, which also participates in the tumorigenesis and metastasis of HCC [69][70][71][72]. More importantly, lncRNA can regulate the progress of HCC by mediating the TGF-β signal pathway in HCC to play the role of miRNA sponge.…”

Genetic Modification of Cytokine Signaling to Enhance Efficacy of CAR T Cell Therapy in Solid Tumors

“…In another study using CRL5826 positive melanoma cells, Tang and colleagues have demonstrated that knocking out the endogenous TGFβRII in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T cells ( 27 ). Secretion of bispecific protein of anti-PD-1 fused with TGF-β trap has also shown to enhances antitumor efficacy of CAR T cells through attenuating inhibitory T cell signaling, enhancing T cell persistence and expansion, and improving effector function and resistance to exhaustion in a prostate cancer xenograft mouse model ( 32 ). It has been well-documented that overexpression of cytokines (e.g.…”