Therapeutic applications of CD4+ T cells specific for oncogenic driver mutations

致癌驱动突变特异性 CD4 T 细胞的治疗应用

• 批准号: 10640078
• 负责人: Joshua R Veatch
• 金额: $ 19.41万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-04 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640078
• 关键词: Address; Adoptive Cell Transfers; Adoptive Immunotherapy; Adoptive Transfer; Alleles; Amino Acids; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autologous; BRAF gene; Biopsy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Patient; Cell physiology; Cells; Clinical; Clinical Trials; Correlative Study; Epidermal Growth Factor Receptor; Frequencies; HLA Antigens; Heterogeneity; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Immunologics; Immunotherapy; Infiltration; Inflammation; KRAS2 gene; Knowledge; Learning; Major Histocompatibility Complex; Malignant Neoplasms; Measures; Mediating; Minority; Mutate; Mutation; Oncogenic; Patient Transfer; Patients; Peptides; Phase I Clinical Trials; Phenotype; Play; Population; Process; RNA analysis; Recurrence; Role; Safety; Sampling; Signal Transduction; Site; Solid Neoplasm; Specificity; Surface; T cell response; T-Cell Receptor; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Effect; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Work; antigen-specific T cells; antitumor effect; cancer cell; cancer infiltrating T cells; cancer therapy; dimensional analysis; driver mutation; engineered T cells; exhaustion; experience; fighting; first-in-human; high dimensionality; immune activation; immune checkpoint blockade; in vivo; insight; melanoma; migration; mouse model; neoantigens; neoplastic cell; protein complex; response; single cell analysis; single-cell RNA sequencing; transcriptome; tumor; tumor microenvironment

Abstract Increasing evidence indicates that clinical responses to immune checkpoint blockade (ICB) in solid tumors are mediated by T-cell recognition of “neoantigens” created when peptides containing amino acids altered by cancer specific mutations are presented on major histocompatibility complex (MHC) proteins. Thus, strategies to augment such T-cell responses independent of, or concurrent with ICB, could be of therapeutic benefit. Prior work on neoantigen-reactive T cells has focused on CD8+ T cells which directly recognize antigens presented on class I MHC expressed by tumor cells. However, there is emerging evidence that CD4+ T cell responses directed against neoantigens presented by class II MHC on professional antigen presenting cells (APC) are common, contribute to tumor rejection in mouse models, and are effective in cancer patients treated with adoptively transferred tumor infiltrating lymphocytes. I recently discovered CD4+ T-cells specific for recurrent driver mutations in BRAF, KRAS, Her2 and EGFR in cancer patients, and have cloned the specific T cell receptors (TCRs) to use for adoptive immunotherapy of patients that express these mutations and have the correct MHC alleles. Driver mutations make ideal immunotherapy targets because, unlike most neoantigens that are random and patient specific, they are positively selected for clonal and homogenous expression and are found in multiple patients. We and others have shown that driver mutation-specific CD4+ T cell responses are commonly present, and that these T cells can be expanded locally in tumors, suggesting they recognize tumor antigens in vivo. In mouse models, tumor antigen-specific CD4+ T cells can mediate tumor rejection through direct destruction of tumor cells, activation of innate immune cells, and stimulation of CD8+ T cell responses, but the mechanisms of action by CD4+ T cells in human antitumor immunity are largely unknown. High dimensional single cell analysis of human tumors has shown heterogeneity of CD4+ T cells with regards to activation, exhaustion, cytolytic potential, and differentiation states associated with stimulation versus suppression of cellular immune responses, but which of these populations contain the small subset of neoantigen specific CD4+ T cells is unknown. In specific aim 1 we will address the frequency, activation, and differentiation state of neoantigen specific CD4+ T cells in tumors to better understand whether and how these cells might contribute to antitumor immunity. We will then use our discovery of a TCR that can redirect the specificity of CD4+ T cell to the common BRAF V600E mutation to ask whether adoptive cell transfer of neoantigen-specific CD4+ T cells can be safe in a first in human phase I clinical trial in specific aim 2. This trial will give the opportunity for asking whether adoptively transferred CD4+ T cells can mediate therapeutic effects and address potential mechanisms for CD4+ T cells to mediate antitumor immunity. If successful, this approach could be applied to additional targets in larger number of patients.

抽象的 越来越多的证据表明，实体瘤中对免疫障碍物封锁（ICB）的临床反应是 当T细胞对“新抗原”的识别介导的“新抗原”时，当含有氨基酸的肽改变了 癌症特异性突变在主要的组织相容性复合物（MHC）蛋白上呈现。那，策略 增加与ICB无关或与ICB并发的这种T细胞响应可能具有治疗益处。事先的 在新抗原反应性T细胞上的工作集中在CD8+ T细胞上，CD8+ T细胞直接识别出呈现的抗原 在I类MHC上由肿瘤细胞表达。但是，有新的证据表明CD4+ T细胞反应 针对由II类MHC提出的针对专业抗原呈现细胞（APC）的新抗原是 常见，有助于小鼠模型中的肿瘤排斥，并且在接受治疗的癌症患者中有效 采用转移的肿瘤浸润淋巴细胞。我最近发现了针对经常性的CD4+ T细胞 癌症患者的BRAF，KRAS，HER2和EGFR的驾驶员突变，并克隆了特定的T细胞 用于表达这些突变并具有的患者的自适应免疫疗法，并具有 纠正MHC等位基因。驾驶员突变成为理想的免疫疗法靶标，因为与大多数新抗原不同 它们是随机和患者的特定于患者的，它们被积极选择用于克隆和同质表达，并且 在多个患者中发现。我们和其他人已经表明驱动器突变特异性CD4+ T细胞响应 通常存在，并且这些T细胞可以在肿瘤中局部扩展，这表明它们识别 体内肿瘤抗原。在小鼠模型中，肿瘤抗原特异性CD4+ T细胞可以介导肿瘤排斥 通过直接破坏肿瘤细胞，活化的先天免疫球和CD8+ T细胞的刺激 反应，但是CD4+ T细胞在人类抗肿瘤免疫学中的作用机理在很大程度上尚不清楚。 人类肿瘤的高维单细胞分析已显示CD4+ T细胞的异质性 激活，精疲力尽，溶质电位和与刺激相关的分化状态 细胞免疫反应的抑制 新抗原特异性CD4+ T细胞未知。在特定目标1中，我们将解决频率，激活和 肿瘤中新抗原特异性CD4+ T细胞的分化状态，以更好地了解这些状态是否以及如何 细胞可能有助于抗肿瘤免疫。然后，我们将使用可以重定向的TCR发现 CD4+ T细胞对普通BRAF V600E突变的特异性询问是否适应性细胞转移是否转移 新抗原特异性的CD4+ T细胞在人类I期临床试验中的第一个特定目标2可以安全。 试验将有机会询问是否适当转移的CD4+ T细胞可以介导治疗 影响和解决CD4+ T细胞的潜在机制介导抗肿瘤免疫。如果成功，这 方法可以应用于大量患者的其他靶标。