We found that cells with high expression levels of GFP showed high expression levels of Her2-CAR or CD19-CAR ( Figure S1A), suggesting that the expression of GFP is proportional to the expression of the CAR. Flow cytometry analyses of the CAR signals found that the transduction efficiency of recombinant lentivirus ranged from 64.44% to 79.86% ( Figure 1B), suggesting that CAR-fusion protein can express efficiently in the effector cells after recombinant lentivirus infection. The recombinant lentiviruses with the CAR constructs were packaged and purified to appropriate concentrations. ĬD3-positive T cells were isolated with magnetic beads from healthy donor peripheral blood with signed consent. Further, with the tumor homing effects of CAR T cells, autocrine PD-1/PDL1 antibodies show local effects and reduce the risk of irAEs. To take advantage of both CAR T cells and ICB antibodies, CAR T cells were engineered to secrete the PD-1 antibody, which can enhance anti-tumor activity of T cells by autocrine and paracrine pathways. However, these PD-1 mutant CAR T cells cannot impact the TME effects on immune suppression and exhaustion of endogenous immune cells. In mouse xenograft models of glioma, pleural mesothelioma, and ovarian and colorectal cancers, the tumor load was reduced and the effector function of CAR T cells was much improved after PD-1 gene disruption. Alternatively, the disruption of PD-1 gene in CAR T cells by shRNAs or the CRISPR-Cas9 technique eliminates the functions of PD-1. Systemic treatment regimen with PD-1/PDL1 antibody injection may induce immune-related adverse effects (irAEs) that bring patients great pain and even risk of life. Therefore, it is of high interest to avoid CAR T cell exhaustion during cancer treatment. These TME signals collectively lead to CAR T cell exhaustion, including a gradual decrease in the anti-tumor activity, the decline of T cell proliferation, and an increase in T cell death. In the tumor microenvironment (TME), CAR T cells are constantly exposed to tumor antigens, soluble immune regulatory factors, hypoxia conditions, and regulatory leukocytes including macrophages and dendritic cells. However, nearly half of the patients experience tumor recurrence after anti-CD19 CAR T cells treatment, and CAR T cells are much less successful in the treatment of solid tumors. Anti-CD19 CAR T cells are already used for the treatment of leukemia with a high success rate. ![]() As such, 4-1BB CAR T with autocrine PD-L1 scFv antibody combined the power of CAR T cells and the immune checkpoint inhibitor, thereby increasing the anti-tumor immune function and CAR T persistence, providing a cell therapy solution for a better clinical outcome.Ĭhimeric antigen receptor (CAR) T cells are T cells engineered with a designed synthetic receptor, which targets specific antigens of tumor cells and activates T cells without the aid of MHC molecules. Importantly, we found that CAR T exhaustion was largely diminished by autocrine PD-L1 scFv antibody in vivo. ![]() CAR T cells with autocrine PD-L1 scFv antibody demonstrate enhanced anti-tumor activity in solid tumors and hematologic malignancies by blocking the PD-1/PD-L1 signaling. The antitumor activity and exhaustion of CAR T cells were investigated in vitro and in a xenograft cancer model using NCG mice. Here, we studied T cells engineered with autocrine PD-L1 scFv and 4-1BB-containing CAR. However, it remains largely unclear whether autocrine single-chain variable fragments (scFv) PD-L1 antibody can improve 4-1BB-based CAR T cell anti-tumor activity and revert CAR T cell exhaustion. Tumor treatment with a combination of programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockage and CD28-based CAR T cells has been intensively studied. Exhaustion of chimeric antigen receptor (CAR) T cells is one of the limitations for CAR T efficacy in solid tumors and for tumor recurrence after initial CAR T treatment.
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