Identification and assessment of unconventional tumor-associated antigens as potential targets for cytotoxic T-cell based immunotherapy of cancer

鉴定和评估非常规肿瘤相关抗原作为基于细胞毒性 T 细胞的癌症免疫疗法的潜在靶标

• 批准号: 10365225
• 负责人: PATRICK HWU
• 金额: $ 59.67万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365225
• 关键词: Antigen Targeting; Antigens; Applications Grants; BRAF gene; Bioinformatics; Cancer Patient; Categories; Cell surface; Cellular immunotherapy; Clinical; Cytolysis; Cytotoxic T-Lymphocytes; DNA; Data; Detection; Development; Disease; Engineering; Epitopes; Foundations; Genetic; Goals; Human; Immune; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Interleukin-2; Intervention; Introns; Knowledge; Leukocytes; Light; MAP Kinase Gene; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Melanoma Cell; Methodology; Methods; Minority; Mitogen-Activated Protein Kinases; Nature; Oncogenic; Pathway interactions; Patients; Peptide Vaccines; Peptides; Phosphopeptides; Post-Translational Protein Processing; Proteomics; RNA Editing; RNA Splicing; Refractory; Reporting; Research; Safety; Source; Specificity; T cell therapy; T-Cell Receptor; T-Lymphocyte; Techniques; Therapeutic; Translating; Tumor Antigens; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Vaccines; Work; base; bioinformatics pipeline; cancer immunotherapy; cancer therapy; cancer type; cytotoxic; design; driver mutation; immunogenic; immunogenicity; innovation; melanoma; multicatalytic endopeptidase complex; neoplastic cell; next generation; novel; personalized immunotherapy; success; therapeutic target; transcriptome sequencing; transcriptomics; tumor; tumor infiltrating lymphocyte therapy; tumor specificity

PROJECT SUMMARY / ABSTRACT: Cytotoxic T lymphocyte (CTL)-based immunotherapies have shown great success in the treatment of patients with several different cancer types. CTLs recognize peptide antigens presented at the tumor cell surface by HLA class I molecules, triggering specific tumor cell lysis. Defining the nature of such tumor- associated antigens (TAAs) can directly facilitate therapeutic tumor targeting through a number of interventions, including personalized vaccines, endogenous T cell infusion, or TCR-engineered immunotherapies. However, only a minority of human TAAs can be confidently identified using conventional proteomic methodologies. Recent evidence suggests this may be due to the fact that most of the immunopeptidome is comprised of peptides derived from ‘non-canonical’ sources such as those derived from translated introns, RNA editing, proteasome splicing, or containing post-translational modifications. Although these represent potentially high value tumor targets, few of these have yet been validated as bona fide TAAs. However, overcoming the challenges inherent in non-canonical TAA identification holds the promise of significantly expanding the landscape of targetable antigens for cancer patients. The specific objective of this project is to identify and assess non-canonical TAAs as potential therapeutic targets for melanoma, as a necessary prerequisite and foundation for generating effective CTL- based immunotherapies for treating patients with this disease. It is our central hypothesis that unique, non- canonical TAAs can constitute shared immunotherapeutic CTL targets, and that those TAAs induced downstream of oncogenic driver mutations such as BRAF(V600E) will show greater tumor specificity and refractoriness to antigen loss. We have formulated this hypothesis based on preliminary data showing that potentially targetable non-canonical TAA peptides can be identified using an integration of highly sensitive mass spectrometry (MS) combined with genetic sequencing analysis and a novel, in-house bioinformatics pipeline. We have also shown that constitutive oncogenic MAPK pathway activation leads to dramatic global tumor immunopeptidome shifts that appear to potentially involve thousands of non-canonical TAAs. There is a strong clinical rationale for this antigen discovery work since it will directly facilitate the development of novel, CTL-based therapies with the potential to benefit large numbers of cancer patients. The proposed work is innovative, because it will explore different categories of non-canonical TAAs in cancer and assess their immunogenicity and potential therapeutic value as shared cancer targets. It will also shed light on the transcriptomic and proteomic changes that occur upon oncogenic-mediated MAPK pathway activation, and how this influences the tumor immunopeptidome. Lastly, fulfilling the outlined objectives will have an important positive clinical impact, because they will facilitate development of the next generation of novel antigen-specific CTL-based immunotherapies for melanoma patients, and possibly also patients with other cancer types.

项目摘要/摘要：