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: 10363712
• 负责人: Christopher Austin Klebanoff
• 金额: $ 52.71万
• 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/10363712
• 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; 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 免疫疗法在一组高度突变的癌症患者中诱导持久缓解。然而， 大多数癌症都是适度突变的，对目前的免疫治疗没有反应。这是 尤其是由磷脂酰肌醇3-激酶催化突变激活引起的恶性肿瘤 亚基阿尔法(PIK3CA)，人类最常见的突变驱动癌基因。突变的PIK3CA癌症 表现出对常规治疗的抵抗力，包括化疗、激素治疗和抗体。 为PIK3CA突变癌症带来免疫治疗潜力的创新新方法是 因此迫切需要。我们和其他人之前进行了详细的免疫监测研究 杰出的患者应答人员，以解决成功的免疫治疗的机制。这些分析 研究发现，来自应答者的T细胞经常识别新抗原(NeoAgs)--来源于 由患者独特的人类白细胞抗原补体呈现的体细胞突变蛋白产物 (HL A)分子。在99%的病例中，NeoAgs只针对单个患者，因为它们是由 乘客突变不会影响癌细胞的健康，因此会受到克隆的影响 异质性。NeoAg克隆异质性已成为免疫治疗抵抗的主要原因。我们 假设来源于突变体PIK3CA热点突变的克隆表达的NeoAgs可能是 免疫原性，并服从于使用T细胞受体(TCR)的治疗性靶向。为了支持我们的 假设，我们通过质谱仪(MS)筛选发现，一个共享的NeoAg来自 突变的PIK3CA是在流行的HLA等位基因的背景下自然处理和呈现的。我们将其命名为 这一独特的抗原亚集是公共的，因为它们是癌症特异性的，但由 患者，使现成的试剂得以使用。使用一个新的TCR发现平台，我们成功地 产生了多个针对该PIK3CA公共NeoAg的T细胞克隆，检索到了它们唯一的TCR基因 序列，并将公共NeoAg反应性外源转移到非特异性T细胞。这些结果证实了 MS鉴定的公共NeoAgs的免疫原性及TCR基因的开发 治疗。在这些初步数据的基础上，我们在目标1中建议开发一种新的治疗方法 使用TCR基因转移和过继免疫治疗表达PIK3CA公共NeoAg的癌症。在目标2中， 我们将在癌症患者中建立频率、免疫分区和潜在的途径 PIK3CA公共NeoAg对T细胞的抵抗力。在目标3中，我们将解决 PIK3CA通过研究公共NeoAg/HLA的物理和结构特性来研究公共NeoAg的免疫原性 分子，它们的野生型对应物，以及它们与TCR形成的复合体。共同努力，这项工作将 阐明在人类中管理NeoAg免疫原性的基本原则，使创新的新 目前缺乏根治性治疗的常见上皮性癌症的精确免疫基因组方法。