Augmenting T cell activity to weak tumor antigens and reversing myeloid cell-mediated T cell inhibition

增强 T 细胞对弱肿瘤抗原的活性并逆转骨髓细胞介导的 T 细胞抑制

基本信息

批准号：
9669010
负责人：
Eduardo V Davila
金额：
$ 36.65万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9669010
关键词：
Affinity Antigens Antitumor Response Avidity Binding Brain Neoplasms Cancer Vaccines Cell Survival Cell physiology Cell surface Cells Cellular immunotherapy Clinical Clinical Trials Cytotoxic T-Lymphocytes Data Exhibits Gene-Modified Goals Human In Vitro Institution Intracranial Melanoma Kinetics Ligands Link Major Histocompatibility Complex Mediating Molecular Mus Myeloid Cell Suppression Myeloid Cells Myeloid-derived suppressor cells Patients Property Publishing Receptor Activation Receptor Signaling Research Resistance Signal Transduction Site Skin Stress Survival Rate T Cell Receptor Signaling Pathway T cell response T cell therapy T-Cell Activation T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte Testing Time Toll-like receptors Translating Tumor Antigens base cancer therapy clinically relevant clinically significant cytotoxic CD8 T cells effective therapy engineered T cells extracellular immunogenic improved in vivo insight melanoma neoantigens neoplastic cell novel novel strategies patient subsets receptor receptor binding receptor expression research clinical testing response subcutaneous treatment strategy tumor vaccination strategy

项目摘要

Our long term goal is to develop a novel approach for treating established melanoma tumors by enhancing cytotoxic T cell responses towards weakly immunogenic and lowly expressed tumor antigens (TAgs) including neoantigens while simultaneously conferring T cells resistance to myeloid-derived suppressor cell (MDSC)– mediated suppression. In clinical trials, T cell-based immunotherapies have demonstrated tumor regression and increased survival rates. Yet despite these encouraging clinical results, durable antitumor responses are observed in only a subset of patients with advanced melanoma. This discrepancy stresses the need for more effective treatment strategies. T cell-based therapies are hindered in part by low T cell receptor (TCR) affinity and/or avidity and by the low expression of TAg on the tumor cell's surface. Additionally, the presence of MDSCs poses a major obstacle to generating effective and long-lived antitumor T cell responses. In our published and preliminary studies, activating MyD88 signaling in T cells, via toll like receptor engagement, augmented T cell responses and prolonged T cell survival. By fusing the CD8α (extracellular) to MyD88 (intracellular; CD8α:MyD88) molecule or by linking melanoma-reactive TCRs to MyD88 (TCR:MyD88) we have developed a novel platform that strongly activates MyD88 signaling in a TLR-independent, strictly TCR- dependent fashion. CD8α:MyD88 expression in T cells considerably amplifies responses to weak and suboptimal levels of TAg and in a TCR-dependent manner, and in preliminary studies has demonstrated the extraordinary property of differentiating MDSC's into cells that can enhance T cell responses. Importantly, the use of CD8α offers the unique feature in that it represents a `universal' approach to potentiating T cell responses, regardless of the patient's HLA type. Our central hypothesis is that T cells engineered to express a CD8α:MyD88 (or TCR:MyD88) will amplify TCR signals against a variety of weakly immunogenic or lowly expressed TAgs including neoantigens and reverse the suppressive activity of myeloid cell suppression, resulting in effective and long-lived antitumor responses. Aim 1 is to determine the molecular mechanisms by which MyD88 activation in T cells augments TCR signals. Through in vitro studies of human and mouse cells, we will define the molecular interactions through which MyD88 signaling augments TCR responses to tumor antigens of varying affinities. Aim 2 is determine the fate and antitumor efficacy of each CD8α:MyD88 and TCR:MyD88 T cells in mice with an established subcutaneous or intracranial melanoma tumor. Aim 3 is to ascertain the in vivo significance and define the mechanism(s) through which MyD88 signaling in T cells reverses myeloid cell's suppressive function. These studies are clinically significant as they have the potential to offer mechanistic insights as to how TCR responses can be amplified and, novel strategies for inhibiting and/or reversing MDSC function.

我们的长期目标是开发一种通过增强黑色素瘤治疗的新方法细胞毒性 T 细胞对弱免疫原性和低表达肿瘤抗原 (TAgs) 的反应，包括新抗原，同时赋予 T 细胞对骨髓源性抑制细胞 (MDSC) 的抵抗力 – 在临床试验中，基于 T 细胞的免疫疗法已证明肿瘤消退。然而，尽管有这些令人鼓舞的临床结果，持久的抗肿瘤反应仍然存在。仅在一部分晚期黑色素瘤患者中观察到这种差异，强调需要更多。 T 细胞受体 (TCR) 亲和力低会部分阻碍基于 T 细胞的治疗策略。和/或亲和力以及肿瘤细胞表面TAg的低表达。 MDSC 是产生有效且持久的抗肿瘤 T 细胞反应的主要障碍。已发表的初步研究，通过 Toll 样受体参与激活 T 细胞中的 MyD88 信号传导，通过将 CD8α（细胞外）与 MyD88 融合，增强 T 细胞反应并延长 T 细胞存活时间。（细胞内；CD8α:MyD88）分子或通过将黑色素瘤反应性 TCR 与 MyD88 (TCR:MyD88) 连接，我们得到开发了一个新平台，可以在不依赖于 TLR、严格 TCR 的环境中强烈激活 MyD88 信号传导 T 细胞中 CD8α:MyD88 的表达大大增强了对弱和弱的反应。 TAg 的次优水平和 TCR 依赖性方式，并且在初步研究中已证明将 MDSC 分化为可增强 T 细胞反应的细胞的非凡特性。 CD8α 的使用具有独特的功能，因为它代表了增强 T 细胞的“通用”方法无论患者的 HLA 类型如何，我们的中心假设是 T 细胞被设计为能够产生反应。表达 CD8α:MyD88（或 TCR:MyD88）将放大针对多种弱 TCR 信号免疫原性或低表达的标签，包括新抗原，并逆转抑制骨髓细胞，产生有效且持久的抗肿瘤反应。确定 T 细胞中 MyD88 激活增强 TCR 信号的分子机制。通过对人类和小鼠细胞的体外研究，我们将定义 MyD88 所通过的分子相互作用信号增强 TCR 对不同亲和力的肿瘤抗原的反应目标 2 是确定命运和每种 CD8α:MyD88 和 TCR:MyD88 T 细胞在已建立皮下或目标 3 是确定颅内黑色素瘤的体内意义并确定其机制。 T 细胞中的 MyD88 信号传导可逆转骨髓细胞的抑制功能。具有临床意义，因为它们有可能提供关于 TCR 反应如何发生的机制见解抑制和/或逆转 MDSC 功能的放大和新策略。