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Protocol to assess the antitumor efficacy of an immunotherapeutic peptide in syngeneic orthotopic glioma mouse models.

ABSTRACT: Understanding the glioblastoma (GBM) immune microenvironment and development of clinical treatment drugs rely on suitable preclinical GBM models. Here, we present a protocol to establish syngeneic orthotopic glioma mouse models. We also describe the steps to intracranially deliver immunotherapeutic peptides and monitor the treatment response. Finally, we show how to assess the tumor immune microenvironment with treatment outcomes. For complete details on the use and execution of this protocol, please refer to Chen et al. (2021).¹.

SUBMITTER: Chen A

PROVIDER: S-EPMC10037209 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Protocol to assess the antitumor efficacy of an immunotherapeutic peptide in syngeneic orthotopic glioma mouse models.

Chen Apeng A Chao Yapeng Y Zou Han H McCarl Lauren H LH Kohanbash Gary G Hu Baoli B

STAR protocols 20230119 1

Understanding the glioblastoma (GBM) immune microenvironment and development of clinical treatment drugs rely on suitable preclinical GBM models. Here, we present a protocol to establish syngeneic orthotopic glioma mouse models. We also describe the steps to intracranially deliver immunotherapeutic peptides and monitor the treatment response. Finally, we show how to assess the tumor immune microenvironment with treatment outcomes. For complete details on the use and execution of this protocol, p ...[more]

PMID: 36861832

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Project description:Claudin 18.2 (CLDN18.2)-targeting chimeric antigen receptor (CAR)-modified T cells are one of the few cell therapies currently producing an impressive therapeutic effect in treating solid tumors; however, their long-term therapeutic efficacy is not satisfactory with a short duration of response. Transgenic expression of interleukin (IL)-15 has been reported to promote T-cell expansion, survival, and function and enhance the antitumor activity of engineered T cells in vitro and in vivo. Therefore, this study aimed to explore whether IL-15 modification would increase the antitumor activity of CLDN18.2-targeting CAR-modified T (CAR-T) cells in immunocompetent murine tumor models. CLDN18.2-specific CAR-T cells with (H9 CAR-IL15) or without transgenic IL-15 expression (H9 CAR) were generated by retroviral transduction of mouse splenic T cells. In vitro, compared with H9 CAR T cells, H9 CAR-IL15 T cells exhibited better expansion and viability in the absence of antigen stimulation, with a less differentiated and T-cell exhausted phenotype; although IL-15 modification did not affect the production of effector cytokines and cytotoxic activity in the short-term killing assay, it moderately improved the in vitro recursive killing activity of CAR-T cells against CLDN18.2-expressing tumor cells. In vivo, H9 CAR T cells showed no antitumor activity against CLDN18.2-expressing pancreatic tumors in immunocompetent mice without lymphodepleting pretreatment; however, H9 CAR-IL15 T cells produced significant tumor-suppressive effects. Furthermore, H9 CAR-IL15 T cells exhibited greater in vivo expansion and tumor infiltration when combined with lymphodepleting preconditioning, resulting in superior antitumor activity in two murine tumor models and a survival advantage in one tumor model. We further demonstrated that recurrent tumors following H9 CAR-IL15 T-cell therapy downregulated CLDN18.2 expression, suggesting immune escape through the selection of antigen-negative cells under persistent CAR-T-cell immune pressure. In conclusion, our findings provide preclinical evidence supporting the clinical evaluation of IL-15-expressing CLDN18.2 CAR-T cells in patients with CLDN18.2-positive tumors.

Dataset Information

Protocol to assess the antitumor efficacy of an immunotherapeutic peptide in syngeneic orthotopic glioma mouse models.

Publications

Protocol to assess the antitumor efficacy of an immunotherapeutic peptide in syngeneic orthotopic glioma mouse models.

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