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Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors.

ABSTRACT: Cancer elimination in humans can be achieved with immunotherapy that relies on T lymphocyte-mediated recognition of tumor antigens. Several types of these antigens have been recognized based on their cellular origins and expression patterns, while their detection has been greatly facilitated by recent achievements in next-generation sequencing and immunopeptidomics. Some of them have been targeted in clinical trials with various immunotherapy approaches, while many others remain untested. Here, we discuss molecular identification of different tumor antigen types, and the clinical safety and efficacy of targeting them with immunotherapy. Additionally, we suggest strategies to increase the efficacy and availability of antigen-directed immunotherapies for treatment of patients with metastatic cancer.

SUBMITTER: Leko V

PROVIDER: S-EPMC7737225 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors.

Leko Vid V Rosenberg Steven A SA

Cancer cell 20200820 4

Cancer elimination in humans can be achieved with immunotherapy that relies on T lymphocyte-mediated recognition of tumor antigens. Several types of these antigens have been recognized based on their cellular origins and expression patterns, while their detection has been greatly facilitated by recent achievements in next-generation sequencing and immunopeptidomics. Some of them have been targeted in clinical trials with various immunotherapy approaches, while many others remain untested. Here, ...[more]

PMID: 32822573

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Project description:BackgroundDespite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors.MethodsTumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models.ResultsOur results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated.ConclusionsWe have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.

Dataset Information

Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors.

Publications

Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors.

Similar Datasets

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