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Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor-Based Cellular Therapy.

ABSTRACT: T cell reactivity to tumor-specific neoantigens can drive endogenous and therapeutically induced antitumor immunity. However, most tumor-specific neoantigens are unique to each patient (private) and targeting them requires personalized therapy. A smaller subset of neoantigens includes epitopes that span recurrent mutation hotspots, translocations, or gene fusions in oncogenic drivers and tumor suppressors, as well as epitopes that arise from viral oncogenic proteins. Such antigens are likely to be shared across patients (public), uniformly expressed within a tumor, and required for cancer cell survival and fitness. Although a limited number of these public neoantigens are naturally immunogenic, recent studies affirm their clinical utility. In this review, we highlight efforts to target mutant KRAS, mutant p53, and epitopes derived from oncogenic viruses using T cells engineered with off-the-shelf T cell receptors. We also discuss the challenges and strategies to achieving more effective T cell therapies, particularly in the context of solid tumors.

SUBMITTER: Martinov T

PROVIDER: S-EPMC10470615 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor-Based Cellular Therapy.

Martinov Tijana T Greenberg Philip D PD

Annual review of cancer biology 20230125 1

T cell reactivity to tumor-specific neoantigens can drive endogenous and therapeutically induced antitumor immunity. However, most tumor-specific neoantigens are unique to each patient (private) and targeting them requires personalized therapy. A smaller subset of neoantigens includes epitopes that span recurrent mutation hotspots, translocations, or gene fusions in oncogenic drivers and tumor suppressors, as well as epitopes that arise from viral oncogenic proteins. Such antigens are likely to ...[more]

PMID: 37655310

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Project description:BackgroundPhenotypic transition is a common resistance mechanism of targeted therapy. While transformations from lung adenocarcinoma (LUAD) to small-cell lung cancer or squamous-cell carcinoma have been extensively studied, the conversion into sarcomatoid carcinoma (SC) is rarely reported.MethodsGenetic and histological examinations were systematically performed on tumor re-biopsy samples obtained from patients with advanced EGFR-mutant LUAD who progressed on EGFR-tyrosine kinase inhibitors (TKIs). EGFR wild-type patients were also identified who underwent the rare transformation from adenocarcinoma to SC following the ineffectiveness of inhibitors that target distinct driver oncogenes. Furthermore, we also retrospectively collected 42 cases diagnosed with primary pulmonary SC as a comparison cohort to comprehensively characterize the biological events and clinical outcomes of transformed SC.ResultsThe sarcomatoid transformation mediated drug resistance in 2.5 % and 4.8 % of patients after failure on the first/second, and third-generation EGFR-TKIs. Transformation of sarcomatoid carcinoma is characterized by a higher frequency of TP53, RB1, and MET genetic alterations compared to cases lacking histological transformation; the PI3K signaling pathway was also significantly activated. Fifteen individuals were identified with a rare transition from adenocarcinoma to SC, consisting of seven cases with EGFR-activating mutations and eight cases without EGFR mutations. All sarcomatoid-transformed samples not only retained their original driver mutations but also shared specific genetic alterations with primary LUAD. Moreover, transformed sarcomatoid carcinomas mimic the primary SC in terms of immunochemical and molecular features.ConclusionsThe transformation from lung adenocarcinoma to SC is a resistance mechanism wildly applied to inhibitors targeting different driver oncogenes. Immunotherapy plus chemotherapy shows potential to benefit patients with sarcomatoid transformation and warrants further study in larger cohorts.

Dataset Information

Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor-Based Cellular Therapy.

Publications

Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor-Based Cellular Therapy.

Similar Datasets

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