Advanced Materials and Delivery Systems for Enhancement of Chimeric Antigen Receptor Cells

Li, Tingxuan; Luo, Ran; Su, Lina; Lv, Feng; Mei, Lin; Yu, Yongkang

doi:10.1002/smtd.202300880

Cited by 3 publications

(1 citation statement)

References 158 publications

(144 reference statements)

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“…Given this low therapeutic window, novel approaches are necessary to reduce systemic CAR T-cell concentrations. One method to avoid the circulating load of CAR T-cell in solid tumors might be regional delivery ( 23 ). In CRLM, research has shown that regional hepatic artery delivery of CAR T-cell to liver metastases outperformed systemic delivery ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice

Zhou,

Yang,

et al. 2024

J Gastrointest Oncol

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Background Liver metastasis is the major cause of colorectal cancer related death. Mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T-cell therapy has been illustrated effective and safe through regional delivery of breast cancer, ovarian cancer and malignant mesothelioma tumors. Herein, we investigated the safety, efficacy, and immune microenvironment of regional delivery of MSLN (CAR) T-cell in the treatment of colorectal carcinoma liver metastases (CRLM). Methods Second-generation MSLN CAR T-cells were administered by portal vein (PV) or caudal vein (CV, systemic administration) delivery in an orthotopic MSLN + CRLM nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/γc −/− (NSG) mouse model. A total of 20 mice were randomly divided into control group, non-transduced T cell (NT)-CV group, NT-PV group, MSLN CAR T-cell CV (MSLN-CV) group, and MSLN CAR T-cell PV (MSLN-PV) group, with each group containing four mice to examine the safety and efficacy. The bioluminescence intensity (BLI) of tumor burden, tumor tissue macroscopic and microscopic observation were used to evaluate treatment efficacy. The safety was examined by body weight, survival time, and vital organ damage of mice. CAR T-cell infiltration and cytokine concentration were analyzed by flow cytometry, and immunostaining. The change of immune microenvironment between regional delivery and systemic delivery was investigated on an immune reconstructed CRLM patient-derived xenograft (PDX) model. Additionally, T cell subsets and immunosuppressive markers were examined. Results PV administration of 1×10 7 /100 μL MSLN CAR T-cells in 20 NSG mice was well tolerated, and no overt toxicity was observed. The tumor burden in the PV group was obviously alleviated. The BLI was (0.73±0.52)×10 9 in PV group and (1.97±0.11)×10 9 in CV group (P<0.05), CD8 + granzyme B (GB) + T cell percentage (MSLN-CV 4.42%±0.47% vs. MSLN-PV 13.5%±4.67%, P<0.01) and cytokine concentration were obviously increased in the MSLN-PV group. In the immune reconstituted CRLM PDX model, intratumor (IT) delivery of MSLN CAR T-cells exhibited much more infiltration of CD4 + and CD8 + T cells accompanied with elevated expression levels of PD-1, LAG-3, and TIM-3. Conclusions Regional delivery of MSLN-targeted CAR T-cell therapy has encouraging results in the orthotopic CRLM NSG mouse model and PDX model, and converts the tumor microenvironment from cold to hot. This study may provide a new therapeutic approach for CRLM. Further clinical study is needed.

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Section: Discussionmentioning

confidence: 99%

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice

Zhou,

Yang,

et al. 2024

J Gastrointest Oncol

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Bioactive-material-programmed CAR-T cell living drug for augmented immunotherapy against tumors

Huang,

Tang,

Yin

et al. 2024

Cell Reports Physical Science

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RNA technology and nanocarriers empowering in vivo chimeric antigen receptor therapy

Cai,

Chen,

Liu

et al. 2024

Immunology

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The remarkable success of mRNA‐based coronavirus 2019 (COVID‐19) vaccines has propelled the advancement of nanomedicine, specifically in the realm of RNA technology and nanomaterial delivery systems. Notably, significant strides have been made in the development of RNA‐based in vivo chimeric antigen receptor (CAR) therapy. In comparison to the conventional ex vivo CAR therapy, in vivo CAR therapy offers several benefits including simplified preparation, reduced costs, broad applicability and decreased potential for carcinogenic effects. This review summarises the RNA‐based CAR constructs in in vivo CAR therapy, discusses the current applications of in vivo delivery vectors and outlines the immune cells edited with CAR molecules. We aim for the conveyed messages to contribute towards the advancement of in vivo CAR application.

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Advanced Materials and Delivery Systems for Enhancement of Chimeric Antigen Receptor Cells

Cited by 3 publications

References 158 publications

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice

Bioactive-material-programmed CAR-T cell living drug for augmented immunotherapy against tumors

RNA technology and nanocarriers empowering in vivo chimeric antigen receptor therapy

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