Molecular mechanisms of T cell responses to a clonal neoantigen resulting from a mutated driver oncogene.

T 细胞对由突变的驱动癌基因产生的克隆新抗原作出反应的分子机制。

• 批准号: 10185280
• 负责人: Christopher Austin Klebanoff
• 金额: $ 53.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185280
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adoptive Immunotherapy; Affinity; Alleles; Antibodies; Antigens; Autoantigens; Avidity; Binding; Bioinformatics; Biometry; Biophysics; Blood specimen; Cancer Etiology; Cancer Patient; Carcinoma; Catalytic Domain; Cessation of life; Clone Cells; Complement; Complex; DNA Sequence Alteration; Data; Disease remission; Exhibits; Frequencies; Gene Transfer; Genomic approach; Genomics; Genotype; Growth; HLA Antigens; Heterogeneity; Human; Immune; Immune response; Immunologic Monitoring; Immunologics; Immunotherapy; Kinetics; Knowledge; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Memory; Molecular; Mutate; Mutation; Neoplasm Metastasis; Oncogenes; Pathway interactions; Patients; Peptides; Pre-Clinical Model; Privatization; Process; Property; Proteins; Reagent; Resistance; Somatic Mutation; Structure; T cell response; T-Cell Development; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Testing; Time; Toxic effect; Tumor Antigens; Viral; Viral Antigens; Work; X-Ray Crystallography; base; cancer cell; chemotherapy; conventional therapy; cost efficient; curative treatments; exhaustion; fitness; gain of function mutation; gene therapy; genetically modified cells; genome sequencing; hormone therapy; immunogenic; immunogenicity; individual patient; inhibitor/antagonist; innovation; multidisciplinary; mutant; neoantigens; novel; novel strategies; novel therapeutic intervention; patient subsets; personalized immunotherapy; programmed cell death protein 1; response; structural biology; therapeutic target; translational approach; tumor; tumor immunology

PROJECT SUMMARY/ABSTRACT Immunotherapy induces durable remissions in a subset of patients with highly mutated cancers. However, most cancers are modestly mutated and fail to respond to current immunotherapy treatments. This is especially true for malignancies caused by activating mutations in phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA), the most commonly mutated driver oncogene in humans. Mutant PIK3CA cancers exhibit resistance to conventional treatments, including chemotherapy, hormonal therapy, and antibodies. Innovative new approaches that bring the curative potential of immunotherapy to PIK3CA mutated cancers are therefore urgently needed. We and others previously performed detailed immune monitoring studies of exceptional patient responders to resolve the mechanisms of successful immunotherapy. These analyses revealed that T cells from responders often recognize neoantigens (NeoAgs) - peptides derived from the protein products of somatic mutations presented by a patient’s unique complement of human leukocyte antigen (HLA) molecules. In >99% of cases, NeoAgs are exclusive to an individual patient because they result from passenger mutations that do not contribute to cancer cell fitness and therefore are subject to clonal heterogeneity. NeoAg clonal heterogeneity has emerged as a major cause of immunotherapy resistance. We hypothesize that clonally expressed NeoAgs derived from hotspot mutations in mutant PIK3CA can be immunogenic and are amenable to therapeutic targeting using T cell receptors (TCRs). In support of our hypothesis, we discovered through a mass spectrometry (MS) screen that a shared NeoAg derived from mutant PIK3CA is naturally processed and presented in the context of a prevalent HLA allele. We have termed this unique subset of antigens “public” NeoAgs because they are cancer-specific yet expressed by groups of patients, enabling the use of off-the-shelf reagents. Using a novel TCR discovery platform, we successfully generated multiple T cell clones specific for this PIK3CA public NeoAg, retrieved their unique TCR gene sequences, and exogenously transferred public NeoAg reactivity to non-specific T cells. These results confirm the immunogenicity of MS-identified public NeoAgs and enable the development of TCR-based gene therapies. Building on these preliminary data, we propose in Aim 1 to develop a novel therapeutic approach for cancers expressing a PIK3CA public NeoAg using TCR gene transfer and adoptive immunotherapy. In Aim 2, we will establish in cancer patients the frequency, immune-compartmentalization, and potential pathways of resistance to T cells specific for a PIK3CA public NeoAg. In Aim 3, we will resolve the physical basis for PIK3CA public NeoAg immunogenicity by studying the physical and structural properties of public NeoAg/HLA molecules, their wild type counterparts, and the complexes they form with TCRs. Together, this work will elucidate the fundamental principles governing NeoAg immunogenicity in humans, enabling innovative new precision immune-genomic approaches for common epithelial cancers currently lacking curative treatments.

项目总结/摘要 免疫疗法在高度突变的癌症患者亚组中诱导持久缓解。然而，在这方面， 大多数癌症是适度突变的，并且对当前的免疫疗法治疗没有反应。这是 特别是对于由磷脂酰肌醇3-激酶催化活性突变引起的恶性肿瘤， 亚基α（PIK 3CA），人类中最常见的突变驱动癌基因。突变型PIK 3CA癌 表现出对常规治疗的抵抗力，包括化疗、激素治疗和抗体。 将免疫疗法的治愈潜力带到PIK 3CA突变癌症的创新新方法是 因此迫切需要。我们和其他人以前进行了详细的免疫监测研究， 特殊的患者应答者，以解决成功的免疫治疗的机制。这些分析 结果显示，来自应答者的T细胞通常识别新抗原（NeoAgs）--来源于 由患者的人类白细胞抗原的独特补体呈递的体细胞突变的蛋白质产物 (HLA)分子。在>99%的病例中，NeoAg是个体患者独有的，因为它们是由以下原因引起的： 乘客突变对癌细胞适应性没有贡献，因此易受克隆形成的影响。 异质性NeoAg克隆异质性已成为免疫疗法抗性的主要原因。我们 假设来源于突变型PIK 3CA中热点突变的克隆表达的NeoAg可以 免疫原性的，并且适合于使用T细胞受体（TCR）的治疗靶向。为支持我们的 假设，我们通过质谱（MS）筛选发现，一个共享的NeoAg来自 突变型PIK 3CA在普遍的HLA等位基因的背景下被天然加工和呈递。我们称之为 这种独特的抗原亚组“公开”NeoAg，因为它们是癌症特异性的，但由肿瘤细胞群表达。 患者，使得能够使用现成的试剂。使用新的TCR发现平台，我们成功地 产生了对这种PIK 3CA公共NeoAg特异性的多个T细胞克隆， 序列，并外源性转移公共NeoAg反应性到非特异性T细胞。这些结果证实 MS鉴定的公共NeoAg的免疫原性，并使得能够开发基于TCR的基因 治疗基于这些初步数据，我们在目标1中提出开发一种新的治疗方法， 使用TCR基因转移和过继性免疫疗法治疗表达PIK 3CA公共NeoAg的癌症。在目标2中， 我们将在癌症患者中确定免疫系统的频率、免疫区室化和潜在途径， 对PIK 3CA公共NeoAg特异性T细胞的抗性。在目标3中，我们将解决 通过研究公共NeoAg/HLA的物理和结构特性，PIK 3CA公共NeoAg免疫原性 分子，它们的野生型对应物，以及它们与TCR形成的复合物。这项工作将 阐明了人类NeoAg免疫原性的基本原理，使创新的 精确的免疫基因组方法，目前缺乏治愈性治疗的常见上皮癌。