Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy

项目2：针对肺癌免疫治疗的新抗原

• 批准号: 10700908
• 负责人: STANLEY R. RIDDELL
• 金额: $ 34.66万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700908
• 关键词: Adjuvant; Adoptive Transfer; American; Antigen Presentation; 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-Cell Activation; T-Lymphocyte; TP53 gene; Therapeutic; Transgenes; Translating; Tumor Immunity; Tumor Promotion; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; WASP protein; antigen-specific T cells; antitumor effect; 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 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; vaccine platform; vector

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 免疫疗法抑制剂（ICI）的免疫疗法正在改变许多癌症的治疗 包括非小细胞肺癌（NSCLC），其中一小部分转移性疾病患者具有 重大反应。 ICI的抗肿瘤活性部分被CD4+和CD8+ T细胞介导 识别新抗原，这些新抗原是源自肿瘤细胞中表达基因突变的胡椒体， 由I类或II类MHC分子提出。这，大多数患者无法对ICI做出反应可能是由于 先前存在的肿瘤特异性T细胞反应不足，先前激活的T的不可逆功能障碍 细胞或局部免疫抑制机制。能够增强或诱发的DE NOVO的治疗疫苗 功能性T细胞对新抗原的反应可能是单独有益的，或者与ICI或其他 克服肿瘤微环境中免疫抑制的方式。假定的新抗原是 由于伯嫩高突变，在NSCLC中普遍存在，并且可能优于自我抗原作为疫苗靶标 因为能够响应的T细胞库不受中央耐受机制的影响。 此外，从理论上讲，多种新抗原可以由疫苗靶向，这可以克服 肿瘤上抗原和MHC表达的异质性，以及单个新抗原的质量。多种的 可以使用肿瘤的整个外显子组测序来鉴定候选新抗原，以检测编码突变， 和预测可能与MHC分子结合的肽的算法。治疗的最初临床应用 黑色素瘤中的新抗原疫苗最近提供了原则证明，并揭示了这种潜力 个性化癌症免疫疗法的方法。 我们已经开发了一种新型方法来进行新抗原疫苗接种，该方法利用了 自体T细胞设计为表达癌症特异性突变（TVAX）。该策略是由 来自我们实验室的临床数据表明，人类T细胞表达翻译编码的收养转移 外蛋白诱导潜在的CD8+和CD4+ T细胞反应，特有的转化产物是 即使在免疫力严重损害的患者中，也会增加随后的输注。 T细胞提供 个性化药物的多功能平台，包括基于细胞的疫苗，因为它们很容易 在CGMP条件下经过一定的修改和扩展 到淋巴结位点以启动免疫反应的抗原。这个项目将翻译这个 在临床前模型和NSCLC患者中，向新抗原疫苗接种的独特方法。