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.

摘要 越来越多的证据表明，实体瘤中对免疫检查点阻断（ICB）的临床反应是 由T细胞识别“新抗原”介导，当含有氨基酸的肽被 癌症特异性突变存在于主要组织相容性复合体（MHC）蛋白上。因此，战略 独立于ICB或与ICB同时增强这种T细胞应答可能具有治疗益处。之前 关于新抗原反应性T细胞的工作集中在直接识别呈递的抗原的CD8+ T细胞上 肿瘤细胞表达的I类MHC。然而，有新的证据表明，CD4+ T细胞应答 针对由专职抗原呈递细胞（APC）上的II类MHC呈递的新抗原， 常见，有助于小鼠模型中的肿瘤排斥反应，并且在用 过继转移的肿瘤浸润淋巴细胞。我最近发现了CD4+ T细胞特异性的复发性 癌症患者BRAF、KRAS、Her2和EGFR的驱动突变，并克隆了特异性T细胞 受体（TCR）用于表达这些突变并具有这些突变的患者的过继免疫治疗。 正确的MHC等位基因驱动突变是理想的免疫治疗靶点，因为与大多数新抗原不同， 它们是随机的且具有患者特异性，它们被积极选择用于克隆和同质表达， 在多名患者中发现。我们和其他人已经表明，驱动突变特异性CD4+ T细胞应答 通常存在，并且这些T细胞可以在肿瘤中局部扩增，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反应， 通过直接破坏肿瘤细胞、激活先天免疫细胞和刺激CD8+ T细胞 CD4+ T细胞在抗肿瘤免疫中的作用机制在很大程度上是未知的。 人类肿瘤的高维单细胞分析显示了CD4+ T细胞的异质性， 与刺激相关的活化、耗竭、细胞溶解潜能和分化状态， 抑制细胞免疫反应，但这些人群中的哪一个含有小的亚群， 新抗原特异性CD4+ T细胞是未知的。在具体目标1中，我们将讨论频率、激活和 肿瘤中新抗原特异性CD4+ T细胞的分化状态，以更好地了解这些细胞是否以及如何分化。 细胞可能有助于抗肿瘤免疫。然后，我们将使用我们发现的TCR，可以重定向 CD4+ T细胞对常见BRAF V600E突变的特异性，以询问过继细胞转移是否 新抗原特异性CD4+ T细胞在第一次人体I期临床试验中是安全的。这 试验将提供机会询问过继转移的CD4+ T细胞是否可以介导治疗性 作用，并解决了CD4+ T细胞介导抗肿瘤免疫的潜在机制。如果成功，这 这种方法可以应用于更多患者中的其他目标。