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Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy

项目2：针对肺癌免疫治疗的新抗原

基本信息

批准号：
10174871
负责人：
STANLEY R. RIDDELL
金额：
$ 26.34万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174871
关键词：
Adjuvant Adoptive Transfer American Antigens Autoantigens Autologous Avidity Binding Bioinformatics CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cancer Vaccines Cells Clinical Data Code Cyclic GMP Data Dendritic Cells Disease Disease Progression Engineering Failure Fred Hutchinson Cancer Research Center Functional disorder Future Genes Granulocyte-Macrophage Colony-Stimulating Factor Heterogeneity Histocompatibility Antigens Class II Human Immune checkpoint inhibitor Immune response Immunity Immunologic Monitoring Immunosuppression Immunotherapy Induced Mutation Infusion procedures Interleukin-12 KRAS2 gene Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Methods Modality Modeling Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Patients Peptides Phase I Clinical Trials Physiologic pulse Pre-Clinical Model Production Proteins RNA Safety Signal Transduction Site T cell response T-Lymphocyte TP53 gene Therapeutic Transgenes Translating Tumor Immunity Vaccinated Vaccination Vaccine Therapy Vaccines base cGMP production cancer immunotherapy central tolerance checkpoint inhibition checkpoint therapy clinical application clinical translation cohort design engineered T cells exome exome sequencing genetic approach immune checkpoint immune function immunogenicity improved inhibiting antibody innovation lymph nodes melanoma mortality mouse model neoantigen vaccination neoantigen vaccine neoantigens neoplastic cell novel novel strategies novel therapeutics patient subsets personalized approach personalized medicine prediction algorithm response subcutaneous therapeutic vaccine transcriptome sequencing tumor tumor microenvironment tumor-immune system interactions vector

项目摘要

Project Summary/Abstract – Project 2 Immunotherapy with immune checkpoint inhibitors (ICI) is revolutionizing the treatment of many cancers, including non-small cell lung cancer (NSCLC) where a small subset of patients with metastatic disease have significant responses. The antitumor activity of ICI is thought in part to be mediated by CD4+ and CD8+ T cells that recognize neoantigens, which are peptides derived from mutations in expressed genes in tumor cells and presented by class I or II MHC molecules. Thus, the failure of most patients to respond to ICI may result from an insufficient pre-existing tumor-specific T cell response, irreversible dysfunction of previously activated T cells, or local immunosuppressive mechanisms. A therapeutic vaccine capable of boosting or inducing de novo functional T cell responses to neoantigens could be beneficial alone, or in combination with ICI or other modalities that overcome immunosuppression in the tumor microenvironment. Putative neoantigens are prevalent in NSCLC due to the high mutation burden, and may be superior to self-antigens as vaccine targets because the T cell repertoire capable of responding is not affected by central tolerance mechanisms. Moreover, multiple neoantigens can theoretically be targeted by a vaccine, which could overcome heterogeneity in antigen and MHC expression on tumors, and in the quality of a single neoantigen. Multiple candidate neoantigens can be identified using whole exome sequencing of tumors to detect coding mutations, and algorithms that predict peptides likely to bind to MHC molecules. Initial clinical applications of therapeutic neoantigen vaccines in melanoma have recently provided proof-of-principle, and revealed the potential of this personalized approach to cancer immunotherapy. We have developed a novel approach to neoantigen vaccination that utilizes the systemic administration of autologous T cells engineered to express cancer-specific mutations (Tvax). This strategy was suggested by clinical data from our lab showing that adoptive transfer of human T cells expressing transgenes encoding foreign proteins induced potent CD8+ and CD4+ T cell responses specific for the transgene product that were boosted by subsequent infusions, even in patients with severely compromised immunity. T cells provide a versatile platform for personalized medicines, including cell based vaccines because they can be easily genetically modified and expanded in cGMP conditions, safely administered systemically, and traffic efficiently to lymph node sites to deliver antigens where immune responses are initiated. This project will translate this unique approach for vaccination to neoantigens in preclinical models and patients with NSCLC.

项目摘要/摘要-项目2