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Click on the translational medicine website above to subscribe to our dry goods | Reliable | Practical Recently, the team of Professor Zhu Huanzhang of Fudan University reported that in the NSG mouse lung cancer CDX model, the chemokine receptor CCR2b can promote the CAR T cells targeting mesothelin to tumors The migration of tissues, thereby enhancing its anti-tumor function, this is the first time that chemokine receptors combined with CAR T cell therapy have been applied to the study of non-small cell lung cancer (NSCLC), bringing new hopes for the advancement of clinical treatment of solid tumors .
The research was published in the internationally renowned journal "Frontiers in Immunology", entitled "Chemokine receptor CCR2b enhanced anti-tumor function of chimeric antigen receptor T cells targeting mesothelin in a non-small-cell lung carcinoma model".
At present, clinical trials of chimeric antigen receptor (CAR) T cells in the treatment of hematological tumors have achieved encouraging results.
However, in the field of solid tumors, the effects of CAR T cells are not ideal.
The reasons and lack of Tumor-specific antigens, insufficient survival and expansion of T cells, low migration efficiency of T cells to tumor tissues and immunosuppressive tumor microenvironment are related to factors.
To this end, the researchers first fused CCR2b/CCR4 with mesothelin-targeted Msln-CAR to construct the Msln-CCR2b/CCR4-CAR co-expression vector, and infect human primary CD3 T cells by lentivirus to prepare Msln-CCR2b/ CCR4-CAR T cells can efficiently express CAR and CCR2b/CCR4.
Figure 1.
Chemokine receptor CCR2b/CCR4 enhances the anti-tumor pattern of Msln-CAR T cells.
Transwell experiments prove that CCR2b and CCR4 can promote the migration of CAR T cells in vitro.
The modified lung cancer cell line was incubated with CAR T cells, and efficient cell killing and cytokine secretion were detected in vitro.
A CDX model of lung cancer in NSG mice transplanted with A549-MLM was further constructed.
Seven days after tumor cell transplantation, the mice were randomly divided into Msln-CCR2b-CAR, Msln-CAR and PBS groups, and the effector cells were transplanted twice.
35 days after tumor cell transplantation, in vivo imaging of mice showed that 60% of the tumor cells in the Msln-CAR group were completely cleared, while the Msln-CCR2b-CAR group reached a 100% clearance rate.
Compared with the PBS group, the tumor weight in the CAR T cell treatment group was significantly reduced (P<0.
001).
IHC analysis of tumor tissues showed that the expression of CCR2b increased the number of CD3 T cells that migrated and infiltrated the tumor tissue by a factor of two.
In addition, pathological examination of the heart, liver, spleen, lung, kidney, etc.
of mice showed no obvious organic lesions.
The above results confirm that the new Msln-CCR2b-CAR has a complete tumor clearance ability and is related to its higher tumor tissue homing activity, showing the potential for further clinical transformation and development.
Figure 2.
In the NSG mouse lung cancer CDX model, CCR2b enhances the anti-tumor effect of Msln-CAR T cells.
In recent years, the Zhu Huanzhang team has made some progress in preclinical research on gene editing therapy. In 2013, it was the first internationally proposed and confirmed the feasibility of gene editing to target the removal of HIV provirus "cutting weeds and roots" treatment strategy (Nucleic Acids Res.
, 2013, 41:7771-82), and obtained the first gene editing treatment of diseases Chinese invention patent; successfully achieved inducible zinc finger nuclease (ZFN) targeted removal of nearly 9.
8 kb HIV provirus (Molecular Therapy-Nucleic Acids, 2018, 12, 67-74).
Early in the world, using the three major technologies of gene editing technology, we have successively obtained ZFP, TALE, and dCas9 gene therapy vector systems that can target permanent silencing or interfere with HIV latency (Molecular Therapy, 2016, 24:508-21; Molecular Therapy-Nucleic Acids, 2017, 17:233-42; Gene Ther, 2014, 21:490-95; AIDS Res Hum Retroviruses, 2015, 98-106).
In 2020, the CRISPR-Cas9 library large-scale gene knockout technology was used to screen the HIV-1 latent-related gene PEBP1 for the first time (EMBO Rep, 2020, e49305).
Tumor immunotherapy for hematomas and solid tumors has also been studied, and CAR T cells targeting CD19, mesothelin and EGFR have been constructed, and they have been humanized from multiple perspectives in combination with immune checkpoints and chemokine receptors.
The anti-tumor function of CAR T cells is enhanced in mice.
Doctor Wang Yanan from the School of Life Sciences of Fudan University is the first author of the paper, and Professor Zhu Huanzhang is the corresponding author of the paper.
Relevant research has been funded by the National Infectious Disease Major Special Project, the National Natural Science Foundation of China NSFC-NIH Cooperation Project and the National Natural Science Foundation of China General Project.
Link to the paper: https://
The research was published in the internationally renowned journal "Frontiers in Immunology", entitled "Chemokine receptor CCR2b enhanced anti-tumor function of chimeric antigen receptor T cells targeting mesothelin in a non-small-cell lung carcinoma model".
At present, clinical trials of chimeric antigen receptor (CAR) T cells in the treatment of hematological tumors have achieved encouraging results.
However, in the field of solid tumors, the effects of CAR T cells are not ideal.
The reasons and lack of Tumor-specific antigens, insufficient survival and expansion of T cells, low migration efficiency of T cells to tumor tissues and immunosuppressive tumor microenvironment are related to factors.
To this end, the researchers first fused CCR2b/CCR4 with mesothelin-targeted Msln-CAR to construct the Msln-CCR2b/CCR4-CAR co-expression vector, and infect human primary CD3 T cells by lentivirus to prepare Msln-CCR2b/ CCR4-CAR T cells can efficiently express CAR and CCR2b/CCR4.
Figure 1.
Chemokine receptor CCR2b/CCR4 enhances the anti-tumor pattern of Msln-CAR T cells.
Transwell experiments prove that CCR2b and CCR4 can promote the migration of CAR T cells in vitro.
The modified lung cancer cell line was incubated with CAR T cells, and efficient cell killing and cytokine secretion were detected in vitro.
A CDX model of lung cancer in NSG mice transplanted with A549-MLM was further constructed.
Seven days after tumor cell transplantation, the mice were randomly divided into Msln-CCR2b-CAR, Msln-CAR and PBS groups, and the effector cells were transplanted twice.
35 days after tumor cell transplantation, in vivo imaging of mice showed that 60% of the tumor cells in the Msln-CAR group were completely cleared, while the Msln-CCR2b-CAR group reached a 100% clearance rate.
Compared with the PBS group, the tumor weight in the CAR T cell treatment group was significantly reduced (P<0.
001).
IHC analysis of tumor tissues showed that the expression of CCR2b increased the number of CD3 T cells that migrated and infiltrated the tumor tissue by a factor of two.
In addition, pathological examination of the heart, liver, spleen, lung, kidney, etc.
of mice showed no obvious organic lesions.
The above results confirm that the new Msln-CCR2b-CAR has a complete tumor clearance ability and is related to its higher tumor tissue homing activity, showing the potential for further clinical transformation and development.
Figure 2.
In the NSG mouse lung cancer CDX model, CCR2b enhances the anti-tumor effect of Msln-CAR T cells.
In recent years, the Zhu Huanzhang team has made some progress in preclinical research on gene editing therapy. In 2013, it was the first internationally proposed and confirmed the feasibility of gene editing to target the removal of HIV provirus "cutting weeds and roots" treatment strategy (Nucleic Acids Res.
, 2013, 41:7771-82), and obtained the first gene editing treatment of diseases Chinese invention patent; successfully achieved inducible zinc finger nuclease (ZFN) targeted removal of nearly 9.
8 kb HIV provirus (Molecular Therapy-Nucleic Acids, 2018, 12, 67-74).
Early in the world, using the three major technologies of gene editing technology, we have successively obtained ZFP, TALE, and dCas9 gene therapy vector systems that can target permanent silencing or interfere with HIV latency (Molecular Therapy, 2016, 24:508-21; Molecular Therapy-Nucleic Acids, 2017, 17:233-42; Gene Ther, 2014, 21:490-95; AIDS Res Hum Retroviruses, 2015, 98-106).
In 2020, the CRISPR-Cas9 library large-scale gene knockout technology was used to screen the HIV-1 latent-related gene PEBP1 for the first time (EMBO Rep, 2020, e49305).
Tumor immunotherapy for hematomas and solid tumors has also been studied, and CAR T cells targeting CD19, mesothelin and EGFR have been constructed, and they have been humanized from multiple perspectives in combination with immune checkpoints and chemokine receptors.
The anti-tumor function of CAR T cells is enhanced in mice.
Doctor Wang Yanan from the School of Life Sciences of Fudan University is the first author of the paper, and Professor Zhu Huanzhang is the corresponding author of the paper.
Relevant research has been funded by the National Infectious Disease Major Special Project, the National Natural Science Foundation of China NSFC-NIH Cooperation Project and the National Natural Science Foundation of China General Project.
Link to the paper: https://
