A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

Abstract

Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).

Targeting myeloid-derived suppressor cells in tumor immunotherapy: Current, future and beyond

“…PD-L1 axis is a key immunosuppressive signal provided by tumor cells and MDSCs in TME, which limits CAR-T cell function. Some studies designed the CAR-T cells secreting anti-PD-L1 single-chain variable fragment (scFv) or generated a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) (165)(166)(167). The former CAR-T cells secreting anti-PD-L1 scFv which could bind to PD-L1 on PD-L1 high tumor cells and MDSCs competitively and block their binding with anti-PD-L1 monoclonal antibodies, leading to increased efficacy (165).…”

“…The former CAR-T cells secreting anti-PD-L1 scFv which could bind to PD-L1 on PD-L1 high tumor cells and MDSCs competitively and block their binding with anti-PD-L1 monoclonal antibodies, leading to increased efficacy (165). The latter CAR-T cells can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal, displayed superior fitness and enhanced functions in culture medium, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models (166). Furthermore, a phase I clinical trial related to this study, was initiated in patients with pleural or peritoneal metastasis (NCT04684459).…”

CAR designs for solid tumors: overcoming hurdles and paving the way for effective immunotherapy

“…By merging inhibitory signals with immune-activating signals, these fusion receptors play a crucial role in enhancing the functionality of T cells within the challenging tumor microenvironment. In a recent study, it was demonstrated that CAR-T cells targeting HER2 and coexpressing CSR specific for PD-L1 exhibited superior fitness and enhanced functions in xenograft models (Ma et al 2022 ). Further investigations revealed upregulated expression of genes associated with T-cell activation, proliferation, and cytotoxicity in these CAR-T cells.…”

CAR-T cell immunotherapy for ovarian cancer: hushing the silent killer

“…Such studies accentuate the importance of PD-L1 in solid tumors, especially ovarian cancer. In 2022, Ma and colleagues reported that the tumoricidal efficacy of 2 nd generation HER2-redirected CAR-Ts was hampered by the component of malignant pleural effusion (MPE) or malignant ascites (MA), leading to a compromised expansion and cytokine production ability of the CAR-Ts ( 74 ). These researchers investigated the reason for this occurrence and identified a high-level expression of PD-L1 by the cells of MPE/MA for this negative impact ( 74 ).…”