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: 10378482
• 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/10378482
• 关键词: Address; Adoptive Cell Transfers; Adoptive Immunotherapy; Adoptive Transfer; Alleles; Amino Acids; 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; 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; V(D)J Recombination; Work; antitumor effect; cancer cell; cancer therapy; cell motility; dimensional analysis; driver mutation; engineered T cells; exhaustion; experience; fighting; first-in-human; high dimensionality; immune activation; immune checkpoint blockade; in vivo; insight; melanoma; 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，实体肿瘤对免疫检查点阻断(ICB)的临床反应是 由T细胞对含有氨基酸的多肽改变时产生的新抗原的识别所介导 癌症特异性突变出现在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细胞反应，可能对治疗有好处。之前 对新抗原反应性T细胞的研究主要集中在CD8+T细胞上，CD8+T细胞直接识别提呈的抗原 肿瘤细胞表达的I类MHC。然而，有新的证据表明，CD4+T细胞的反应 针对专职抗原提呈细胞(APC)上II类MHC递呈的新抗原， 在小鼠模型中常见，有助于肿瘤排斥反应，在癌症患者中治疗有效 过继转移肿瘤浸润性淋巴细胞。我最近发现CD4+T细胞是复发的特异性细胞 癌症患者BRAF、KRAS、Her2和EGFR的驱动突变，并克隆了特定的T细胞 受体(TCR)用于表达这些突变的患者的过继免疫治疗 正确的MHC等位基因。驱动程序突变是理想的免疫治疗靶点，因为与大多数新抗原不同 它们是随机的和患者特有的，它们被阳性选择进行克隆和同源表达，并 在多个患者身上都有发现。我们和其他人已经证明，司机突变特异性的CD4+T细胞反应 普遍存在，而且这些T细胞可以在肿瘤中局部扩张，这表明它们识别 体内的肿瘤抗原。在小鼠模型中，肿瘤抗原特异性的CD4+T细胞可以介导肿瘤排斥反应 通过直接破坏肿瘤细胞，激活天然免疫细胞，刺激CD8+T细胞 但CD4+T细胞在人类抗肿瘤免疫中的作用机制很大程度上还不清楚。 对人类肿瘤的高维单细胞分析显示，在以下方面，CD4+T细胞的异质性 与刺激相关的激活、衰竭、细胞溶解潜力和分化状态与 抑制细胞免疫反应，但这些群体中哪一个包含 新抗原特异性的CD4+T细胞是未知的。在具体目标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细胞是否以及如何 细胞可能参与了抗肿瘤免疫。然后，我们将使用我们发现的TCR将 CD4+T细胞对常见的BRAF V600E突变的特异性探讨 在人类第一阶段临床试验中，新抗原特异性的CD4+T细胞可以是安全的。 试验将使人们有机会询问过继转移的CD4+T细胞是否可以介导治疗 CD4+T细胞在介导抗肿瘤免疫中的作用和潜在机制。如果成功，这将是 该方法可应用于更多患者的其他靶点。