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Neoantigen vaccine and neoantigen-specific cell adoptive transfer therapy in solid tumors: Challenges and future directions.

ABSTRACT: The phenomenon of tumor hierarchy and genetic instability can be explained by the "two-hits theory" and results in the occurrence of many somatic mutations. The expression of nonsynonymous mutations results in the production of mutant proteins from tumor cells, namely tumor-specific antigens called neoantigens. Because neoantigens do not exist in healthy cells, they have the potential to stimulate antitumor immune responses by CD4+ and CD8+ T-cell activation without jeopardizing normal tissues. Immunotherapy has reshaped the cancer treatment paradigm in recent decades with the introduction of immune-checkpoint blockade therapy and transgenic T-cell receptor/chimeric antigen receptor T cells. However, these strategies performed poorly in solid tumors because of the obstacles of the immunosuppressive microenvironment caused by regulatory T cells and other suppressor cells. Therefore, other immunotherapeutic strategies are under development, such as personalized vaccines, to trigger de novo T-cell responses against neoantigens and lead to the amplification of tumor-specific T-cell subclones. Neoantigen epitope prediction algorithms have enabled the detection of neoantigens and the creation of tailored neoantigen vaccines as a result of the fast development of next-generation sequencing and cancer bioinformatics. Here we provide an overview of the current neoantigen cancer vaccines and adoptive T-cell transfer therapy with neoantigen-specific lymphocytes. We also discuss the challenges in developing neoantigen-targeted immunotherapeutic strategies for cancer.

SUBMITTER: Shen Y

PROVIDER: S-EPMC10686129 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Neoantigen vaccine and neoantigen-specific cell adoptive transfer therapy in solid tumors: Challenges and future directions.

Shen Yanwei Y Yu Lu L Xu Xiaoli X Yu Shaojun S Yu Zhuo Z

Cancer innovation 20220830 2

The phenomenon of tumor hierarchy and genetic instability can be explained by the "two-hits theory" and results in the occurrence of many somatic mutations. The expression of nonsynonymous mutations results in the production of mutant proteins from tumor cells, namely tumor-specific antigens called neoantigens. Because neoantigens do not exist in healthy cells, they have the potential to stimulate antitumor immune responses by CD4+ and CD8+ T-cell activation without jeopardizing normal tissues. ...[more]

PMID: 38090649

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Project description:Adoptive cell therapy using TCR-engineered T cells (TCR-T cells) represents a promising strategy for treating relapsed and metastatic cancers. We previously established methods to identify neoantigen-specific TCRs based on patients' PBMCs. However, in clinical practice isolation of PBMCs from advanced-stage cancer patients proves to be difficult. In this study, we substituted blood-derived T cells for tumor-infiltrating lymphocytes (TILs) and used an HLA-matched cell line of antigen-presenting cells (APCs) to replace autologous dendritic cells. Somatic mutations were determined in head and neck squamous cell carcinoma resected from two patients. HLA-A*02:01-restricted neoantigen libraries were constructed and transferred into HLA-matched APCs for stimulation of patient TILs. TCRs were isolated from reactive TIL cultures and functionality was tested using TCR- T cells in vitro and in vivo. To exemplify the screening approach, we identified the targeted neoantigen leading to recognition of the minigene construct that stimulated the strongest TIL response. Neoantigen peptides were used to load MHC-tetramers for T cell isolation and a TCR was identified targeting the KIAA1429D1358E mutation. TCR-T cells were activated, exhibited cytotoxicity, and secreted cytokines in a dose-dependent manner, and only when stimulated with the mutant peptide. Furthermore, comparable to a neoantigen-specific TCR that was isolated from the patient's PBMCs, KIAA1429D1358E-specific TCR T cells destroyed human tumors in mice. The established protocol provides the required flexibility to methods striving to identify neoantigen-specific TCRs. By using an MHC-matched APC cell line and neoantigen-encoding minigene libraries, autologous TILs can be stimulated and screened when patient PBMCs and/or tumor material are not available anymore. Abbreviations: Head and neck squamous cell carcinoma (HNSCC); adoptive T cell therapy (ACT); T cell receptor (TCR); tumor-infiltrating lymphocytes (TIL); cytotoxic T lymphocyte (CTL); peripheral blood mononuclear cell (PBMC); dendritic cell (DC); antigen-presenting cells (APC).

Dataset Information

Neoantigen vaccine and neoantigen-specific cell adoptive transfer therapy in solid tumors: Challenges and future directions.

Publications

Neoantigen vaccine and neoantigen-specific cell adoptive transfer therapy in solid tumors: Challenges and future directions.

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