Dataset Information

Chemokine Receptors CCR6 and PD1 Blocking scFv E27 Enhances Anti-EGFR CAR-T Therapeutic Efficacy in a Preclinical Model of Human Non-Small Cell Lung Carcinoma.

ABSTRACT: Chimeric antigen receptor (CAR)-T cells, a therapeutic agent for solid tumors, are not completely effective due to a lack of infiltration of T cells into the tumor site and immunity caused by Programmed Death Receptor 1(PD1). Here, an epidermal growth factor receptor (EGFR) CAR-T cell was engineered to express the chemokine receptor CCR6 and secrete PD1 blocking Single-chain antibody fragment (scFv) E27 to enhance their anti-tumor effects. The findings showed that CCR6 enhanced the migration of EGFR CAR-E27-CCR6 T cells in vitro by the Transwell migration assay. When incubated with tumor cells, EGFR CAR-E27-CCR6 T cells specifically exerted potent cytotoxicity and produced high levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), and interferon-γ (IFN-γ). A non-small cell lung carcinoma (NSCLC) cell line-derived xenograft model was constructed by implanting modified A549 cell lines into immunodeficient NOD.Prkdc^scidIl2rg^em1/Smoc (NSG) mice. In comparison with traditional EGFR CAR-T cells, live imaging indicated that EGFR CAR-E27-CCR6 T cells displayed superior anti-tumor function. In addition, the histopathological examination of mouse organs showed no obvious organic damage. Our findings confirmed that PD1 blocking and CCR6 can enhance the anti-tumor function of EGFR CAR-T cells in an NSCLC xenograft model, providing an effective treatment strategy to improve the efficacy of CAR-T in NSCLC.

SUBMITTER: Wang J

PROVIDER: S-EPMC10056525 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chemokine Receptors CCR6 and PD1 Blocking scFv E27 Enhances Anti-EGFR CAR-T Therapeutic Efficacy in a Preclinical Model of Human Non-Small Cell Lung Carcinoma.

Wang Jing J Wang Yanan Y Pan Hanyu H Zhao Lin L Yang Xinyi X Liang Zhiming Z Shen Xiaoting X Zhang Jing J Yang Jinlong J Zhu Yuqi Y Xun Jingna J Liang Yue Y Lin Qinru Q Liang Huitong H Li Min M Zhu Huanzhang H

International journal of molecular sciences 20230312 6

Chimeric antigen receptor (CAR)-T cells, a therapeutic agent for solid tumors, are not completely effective due to a lack of infiltration of T cells into the tumor site and immunity caused by Programmed Death Receptor 1(PD1). Here, an epidermal growth factor receptor (EGFR) CAR-T cell was engineered to express the chemokine receptor CCR6 and secrete PD1 blocking Single-chain antibody fragment (scFv) E27 to enhance their anti-tumor effects. The findings showed that CCR6 enhanced the migration of ...[more]

PMID: 36982500

Similar Datasets

Project description:BackgroundChimeric antigen receptor (CAR)-T cells can induce powerful immune responses in patients with hematological malignancies but have had limited success against solid tumors. This is in part due to the immunosuppressive tumor microenvironment (TME) which limits the activity of tumor-infiltrating lymphocytes (TILs) including CAR-T cells. We have developed a next-generation armored CAR (F i-CAR) targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is expressed at high levels in a range of aggressive tumors including poorly prognostic triple-negative breast cancer (TNBC). The F i-CAR-T is designed to release an anti-PD-1 checkpoint inhibitor upon CAR-T cell activation within the TME, facilitating activation of CAR-T cells and TILs while limiting toxicity.MethodsTo bolster potency, we developed a F i-CAR construct capable of IL-2-mediated, NFAT-induced secretion of anti-PD-1 single-chain variable fragments (scFv) within the tumor microenvironment, following ROR1-mediated activation. Cytotoxic responses against TNBC cell lines as well as levels and binding functionality of released payload were analyzed in vitro by ELISA and flow cytometry. In vivo assessment of potency of F i-CAR-T cells was performed in a TNBC NSG mouse model.ResultsF i-CAR-T cells released measurable levels of anti-PD-1 payload with 5 h of binding to ROR1 on tumor and enhanced the cytotoxic effects at challenging 1:10 E:T ratios. Treatment of established PDL1 + TNBC xenograft model with F i-CAR-T cells resulted in significant abrogation in tumor growth and improved survival of mice (71 days), compared to non-armored CAR cells targeting ROR1 (F CAR-T) alone (49 days) or in combination with systemically administered anti-PD-1 antibody (57 days). Crucially, a threefold increase in tumor-infiltrating T cells was observed with F i-CAR-T cells and was associated with increased expression of genes related to cytotoxicity, migration and proliferation.ConclusionsOur next-generation of ROR1-targeting inducible armored CAR platform enables the release of an immune stimulating payload only in the presence of target tumor cells, enhancing the therapeutic activity of the CAR-T cells. This technology provided a significant survival advantage in TNBC xenograft models. This coupled with its potential safety attributes merits further clinical evaluation of this approach in TNBC patients.

Dataset Information

Chemokine Receptors CCR6 and PD1 Blocking scFv E27 Enhances Anti-EGFR CAR-T Therapeutic Efficacy in a Preclinical Model of Human Non-Small Cell Lung Carcinoma.

Publications

Chemokine Receptors CCR6 and PD1 Blocking scFv E27 Enhances Anti-EGFR CAR-T Therapeutic Efficacy in a Preclinical Model of Human Non-Small Cell Lung Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets