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.

项目摘要/摘要 免疫疗法可引起高度突变癌患者的一部分持久的缓解。然而， 大多数癌症是适度的突变，无法应对当前的免疫疗法。这是 尤其是由磷脂酰肌醇3-激酶激活突变引起的恶性肿 亚基α（PIK3CA），这是人类中最常见的驾驶员癌基因。突变PIK3CA取消 表现出对常规疗法的耐药性，包括化学疗法，马疗治疗和抗体。 创新的新方法将免疫疗法的治疗潜力带到PIK3CA突变的癌症是 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 杰出的患者反应者可以解决成功免疫疗法的机制。这些分析 揭示了来自响应者的T细胞经常识别新抗原（NEOAGS） - 源自 患者独特完成人白细胞抗原的蛋白质突变蛋白质产物 （HLA）分子。在> 99％的病例中，NEOAGS是单个患者独有的，因为它们是由 不影响癌细胞适应性的乘客突变，因此受到克隆的影响 异质性。 NEOAG克隆异质性已成为免疫疗法抗药性的主要原因。我们 假设在突变体Pik3ca中衍生自热点突变的克隆表达的NEOAG可以是 免疫原性，可以使用T细胞受体（TCR）进行治疗靶向。支持我们 假设，我们通过质谱法（MS）屏幕发现了共享的NEOAG。 突变PIK3CA自然处理并在普遍的HLA等位基因的背景下进行。我们已经称为 这个独特的抗原“公共” NEOAGS的子集是因为它们特定于癌症，但由 患者，可以使用现成的试剂。使用新颖的TCR发现平台，我们成功地 生成了针对此PIK3CA公共NEOAG的多个T细胞克隆，检索了其独特的TCR基因 序列和外源转移的公共NEOAG反应性向非特异性T细胞。这些结果证实 MS识别的公共NEOAG的免疫原性，并能够开发基于TCR的基因 疗法。在这些初步数据的基础上，我们建议在AIM 1中开发一种新型的治疗方法 使用TCR基因转移和适应性免疫疗法表达PIK3CA公共NEOAG的癌症。在AIM 2中， 我们将在癌症患者中建立频率，免疫室化和潜在途径 对PIK3CA公共NEOAG特有的T细胞的抗性。在AIM 3中，我们将解决物理基础 PIK3CA公共NEOG免疫原性通过研究公共NEOAG/HLA的物理和结构特性 分子，野生型对应物以及它们与TCR形成的复合物。在一起，这项工作将 阐明人类NEOAG免疫原性的基本原则，使创新的新 目前缺乏现代疗法的常见上皮癌的精确免疫基因组方法。