CAR molecular design: TLR2 total stimulation signal improves the function of CAR T cells to kill tumors.

Recently, Leukemia, an authoritative journal in the field of leukemia, published the latest research results of the Li Peng Research Group of the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences online.
the study constructed a third-generation chimeric antigen receptor (CAR) molecule containing TLR2 co-stimulation signals, and demonstrated that TLR2 co-stimulation signals improve the function of CAR T cells to kill tumors.
this study provides a theoretical basis for the combined effects of natural and adaptive immunity in CAR T cell therapy, and opens up new ideas for CAR molecular design.
the results were completed by doctoral students Lai Yunxin and Wei Xinru under the guidance of their mentor Li Peng.
CAR T cell therapy is the most influential treatment in the field of tumor immunotherapy in recent years, in which CAR T for CD19 has been very effective in clinical trials.
CAR molecules give T-cell-specific identification of killer tumor cells, and the membrane molecule has an antigen-identifying ScFv segment outside the cell, which contains a domain that transmits the killer function of active T-cells and mediated T-cells.
design of THE CAR molecules is critical to the ultimate efficacy of CAR T.
the total stimulation molecules such as CD28, 41-BB provide the necessary assistance for the function of CAR T cells.
however, CAR T cell therapy does not play a significant role in targeting other antigens or solid tumors, so the design of CAR molecules also requires new co-stimulation molecules to enhance and maintain the function of CAR T cells on hematomas and solid tumors.
interaction between natural and adaptive immunity is an important mode for the body's immune system to function.
To learn from and simulate this pattern in CAR molecules, the study introduced the in-cell signaling domain of TLR2, an important recepton of the natural immune system, into CAR molecules, and constructed CAR molecules including TLR2, 1928zT2 and m28zT2, for B-cell leukemia, which expresses CD19, and mesothelin solid tumors, respectively.
inosernoid results show that the addition of TLR2 promotes the killing of CAR T cells against leukemia cells and solid tumor cells, as well as the secretion of antigen-induced cytokines IL2, IFN-g and GM-CSF.
In vivo experiments on humanized xeogelogic transplantation (PDX) models built in immunodeficiency mice showed that 1928zT2 T cells with TLR2 had stronger anti-leukemia cell action and secretion cytokine function than 1928z T cells, and promoted the survival of B-cell leukemia PDX mice; In the
mechanism study, the study used RNA-seq to compare gene expression of CAR T cells in the case of antigen stimulation or non-stimulation after TLR2 was added, and the results showed that the genes that TLR2 can be increased were related to cell adhesion and migration, and in vitro cell invasion experiments also showed that TLR2 could enhance the migration ability of CAR T cells.
the potential toxicity of CAR T cells is one of the major barriers to clinical application, the addition of TLR2 enhances the lethality of CAR T, but may also increase the toxicity of CAR T cells.
To verify the safety and effectiveness of 1928zT2 T cells containing TLR2 in the human body, the study also conducted a clinical trial in a patient with B-cell acute leukemia: after returning 5e4/kg of low-dose 1928zT2 T cells to patients, the patient quickly developed an answer and was cleared of leukemia cells in about 20 days, with test results showing complete remission at 51 days.
therefore, clinical results show that the design of TLR2 to join CAR molecules is safe and effective.
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