Dataset Information

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

ABSTRACT:

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 1×10⁷/100 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)×10⁹ in PV group and (1.97±0.11)×10⁹ 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.

SUBMITTER: Zhou X

PROVIDER: S-EPMC10932675 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Zhou Xin X Yang Minjie M Yu Jiaze J Tan Jingwen J Xu Nan N Zhou Yongjie Y Zhang Wen W Ma Jingqin J Zhang Zihan Z Friedlaender Alex A Taylor Justin J Yu Lei L Yan Zhiping Z

Journal of gastrointestinal oncology 20240228 1

<h4>Background</h4>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).<h4>Methods</h4>Seco ...[more]

PMID: 38482238

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Project description:CD19-targeted chimeric antigen receptor (CAR) engineered T/natural killer (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to "on-target off-tumor" toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK cells may permit prospective control of "on-target off-tumor" toxicity. To develop a commercial product for solid tumors, mesothelin was selected as an antigen target based on its association with poor prognosis and overexpression in multiple solid cancers. It was hypothesized that selecting, activating, and expanding cells ex vivo prior to mRNA CAR transfection would not be necessary, thus simplifying the complexity and cost of manufacturing. Now, the development of anti-human mesothelin mRNA CAR transfected peripheral blood lymphocytes (CARMA-hMeso) is reported, demonstrating the manufacture and cryopreservation of multiple cell aliquots for repeat administrations from a single human leukapheresis. A rapid, automated, closed system for cGMP-compliant transfection of mRNA CAR in up to 20 × 109 peripheral blood lymphocytes was developed. Here we show that CARMA-hMeso cells recognize and lyse tumor cells in a mesothelin-specific manner. Expression of CAR was detectable over approximately 7 days in vitro, with a progressive decline of CAR expression that appears to correlate with in vitro cell expansion. In a murine ovarian cancer model, a single intraperitoneal injection of CARMA-hMeso resulted in the dose-dependent inhibition of tumor growth and improved survival of mice. Furthermore, repeat weekly intraperitoneal administrations of the optimal CARMA-hMeso dose further prolonged disease control and survival. No significant off-target toxicities were observed. These data support further investigation of CARMA-hMeso as a potential treatment for ovarian cancer and other mesothelin-expressing cancers.

Project description:BackgroundStandard-of-care therapies for treating pediatric medulloblastoma have long-term side effects, even in children who are cured. One emerging modality of cancer therapy that could be equally effective without such side effects would be chimeric antigen receptor (CAR) T cells. Knowing that human epidermal growth factor receptor 2 (HER2) is overexpressed in many medulloblastomas and has been used as a CAR T target before, we sought to evaluate the efficacy of more sophisticated anti-HER2 CAR T cells, as well as the feasibility and efficacy of different routes of delivering these cells, for the treatment of pediatric medulloblastoma.MethodsDaoy, D283 and D425 medulloblastoma cell lines were characterized by flow cytometry to evaluate HER2 expression. Anti-tumor efficacy of HER2-BBz-CAR T cells in vitro was performed using cytokine release and immune cytotoxicity assays compared to control CD19 CAR T cells. In vivo, Daoy and D283 tumor cells were orthotopically implanted in the posterior fossa of NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice and treated with regional or intravenous HER2-BBz-CAR T cells or control CD19 CAR T cells. Non-human primates (NHPs) bearing ventricular and lumbar reservoirs were treated with target autologous cells bearing extracellular HER2 followed by autologous HER2-CAR T cells intraventricularly. Cerebrospinal fluid and blood were collected serially to measure the persistence of delivered cells and cytokines.ResultsHER2-BBz-CAR T cells effectively clear medulloblastoma orthotopically implanted in the posterior fossa of NSG mice via both regional and intravenous delivery in xenograft models. Intravenous delivery requires a log higher dose compared to regional delivery. NHPs tolerated intraventricular delivery of autologous cells bearing extracellular HER2 followed by HER2-BBz-CAR T cells without experiencing any systemic toxicity.ConclusionsHER2-BBz-CAR T cells show excellent pre-clinical efficacy in vitro and in mouse medulloblastoma models, and their intraventricular delivery is feasible and safe in NHPs. A clinical trial of HER2-BBz-CAR T cells directly delivered into cerebrospinal fluid should be designed for patients with relapsed medulloblastoma.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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