Chimeric Antigen Receptor T Cells Engineered to Secrete CD40 Agonist Antibodies Enhance Antitumor Efficacy

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2021 Feb 19

PMID 33602263

Citations 12

Authors

Yajun Zhang

Pei Wang

Tengjiao Wang

Yuan Fang

Yongmei Ding

Qijun Qian

Affiliations

Soon will be listed here.

Abstract

Background: Although chimeric antigen receptor (CAR)-T cell therapy has been remarkably successful for haematological malignancies, its efficacy against solid tumors is limited. The combination of CAR-T cell therapy with immune checkpoint inhibitors (CPIs), such as PD-1, PD-L1, and CTLA-4 antibodies, is a promising strategy for enhancing the antitumor efficacy of CAR-T cells. However, because most patients acquire resistance to CPIs, investigating other strategies is necessary to further improve the antitumor efficacy of CAR-T cell therapy for solid tumors. Recently, CD40 agonist antibodies showed potential antitumor efficacy by activating the CD40 pathway.

Results: Based on the piggyBac transposon system, rather than the widely used viral vectors, we constructed a meso3-CD40 CAR-T targeting region III of mesothelin (MSLN) that possessed the ability to secrete anti-CD40 antibodies. Compared with meso3 CAR-T cells, which did not secrete the anti-CD40 antibody, meso3-CD40 CAR-T cells secreted more cytokines and had a relatively higher proportion of central memory T (T) cells after stimulation by the target antigen. In addition, compared with meso3 CAR-T cells, meso3-CD40 CAR-T cells had a more powerful cytotoxic effect on target cells at a relatively low effector-to-target ratio. More importantly, we demonstrated that the antitumor activity of meso3-CD40 CAR-T cells was enhanced in a human ovarian cancer xenograft model in vivo.

Conclusions: In conclusion, these results highlight anti-CD40-secreting CAR-T cells generated by nonviral vectors as a potential clinical strategy for improving the efficacy of CAR-T cell therapies.

Citing Articles

Optimizing CAR-T cell therapy for solid tumors: current challenges and potential strategies.

Ai K, Liu B, Chen X, Huang C, Yang L, Zhang W J Hematol Oncol. 2024; 17(1):105.

PMID: 39501358 PMC: 11539560. DOI: 10.1186/s13045-024-01625-7.

Therapeutic targets of armored chimeric antigen receptor T cells navigating the tumor microenvironment.

Li X, Chen T, Li X, Zhang H, Li Y, Zhang S Exp Hematol Oncol. 2024; 13(1):96.

PMID: 39350256 PMC: 11440706. DOI: 10.1186/s40164-024-00564-w.

Protein ubiquitination in ovarian cancer immunotherapy: The progress and therapeutic strategy.

Guo H, Wei J, Zhang Y, Wang L, Wan J, Wang W Genes Dis. 2024; 11(6):101158.

PMID: 39253578 PMC: 11382211. DOI: 10.1016/j.gendis.2023.101158.

Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment.

Chen Q, Sun Y, Li H Discov Oncol. 2024; 15(1):289.

PMID: 39023820 PMC: 11258118. DOI: 10.1007/s12672-024-01159-x.

Challenges of Anti-Mesothelin CAR-T-Cell Therapy.

Zhai X, Mao L, Wu M, Liu J, Yu S Cancers (Basel). 2023; 15(5).

PMID: 36900151 PMC: 10000068. DOI: 10.3390/cancers15051357.

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