Synthetic IL9R signaling to rewire T cells for adoptive cell therapy of cancer

合成 IL9R 信号传导重新连接 T 细胞用于癌症过继细胞治疗

基本信息

批准号：
10504059
负责人：
Anusha Kalbasi
金额：
$ 36.96万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504059
关键词：
ATAC-seq Address Adoptive Cell Transfers Adoptive Transfer Antigens Automobile Driving Binding Biology CTAG1 gene Cells Characteristics Chimera organism Chromatin Chronic Cytokine Receptors Data Epigenetic Process Extracellular Domain Face Functional disorder Gene Expression Profile Genetic Transcription Goals Hematologic Neoplasms Homing Human IL2 gene IL2RA gene IL4R gene IL7R gene IL9 gene Immunotherapy In Vitro Infiltration Interleukin 2 Receptor Interleukin 2 Receptor Gamma Interleukin-2 Maps Memory Modeling Mus Patients Peripheral Phenotype Phosphorylation Positioning Attribute Receptor Cell Receptor Signaling Research Personnel Resistance Role Series Signal Transduction Solid Neoplasm T cell therapy T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Toxic effect Translating Translations antitumor effect base cancer therapy chemotherapy chimeric antigen receptor conditioning cytokine draining lymph node effector T cell engineered T cells exhaustion genetically modified cells improved in vivo interleukin-21 receptor lymph nodes mouse model next generation novel strategies prevent programs rational design receptor safety and feasibility stem cells success synthetic biology transcriptomics tumor

项目摘要

PROJECT SUMMARY Adoptive cell therapy (ACT) using engineered T cells – such as chimeric antigen receptor (CAR) or T cell receptor (TCR) modified T cells – is an effective immunotherapy for hematologic malignancies. Success with ACT has been elusive for solid tumors, which present unique challenges to T cells. ACT also requires conditioning chemotherapy to deplete a patient’s endogenous T cells, which results in significant toxicity. Our goal is to engineer T cells with synthetic functions to overcome hurdles of ACT for solid tumors including the need for conditioning chemotherapy, which would dramatically improve the feasibility and safety of this therapy. In this proposal we use the orthogonal IL2 cytokine-receptor pair developed by our collaborator Dr. Garcia at Stanford. Orthogonal IL2Rβ (o2R) is only activated by the orthogonal IL2 (oIL2) cytokine, and not by wildtype IL2. When activated, o2R signals through the intracellular domain (ICD) of IL2Rβ, which involves cooperation with the native common gamma chain (γc). Leveraging this cooperation, we studied chimeric orthogonal receptors in which the IL2Rβ ICD of o2R is replaced with ICDs of receptors for other γc cytokines, such that oIL2 elicits the corresponding γc signal. Of these chimeras, signaling through the IL9R ICD (o9R) generated a unique STAT phosphorylation profile and differentiation trajectory, prompting further exploration in vivo. Despite a weaker proliferative signal than o2R signaling, o9R signaling resulted in T cells with superior anti-tumor efficacy, an effect pronounced in the absence of lymphodepletion. To translate this finding into a viable treatment for patients with advanced solid tumors will require an understanding of the functional features of o9R signaling T cells that permit their anti-tumor efficacy, especially in the absence of conditioning chemotherapy. Our preliminary data led us to focus on two of these features, which we tackle in Aims 1 and 2. In Aim 1, we focus on the peripheral in vivo effects of o9R signaling that rely on interaction with the host, especially lymph node homing and priming. We hypothesize that the o9R signaling reprograms T cells in the periphery for efficient lymph node homing and spatial positioning that promotes priming that is critical for their anti-tumor effects in vivo. Aim 1 will use both TCR- and CAR- based syngeneic mouse solid tumor models of ACT. In Aim 2, we turn to the cell-intrinsic effects of o9R signaling on effector capacity in the face of chronic antigen stimulation. We hypothesize that o9R signaling interferes with the epigenetic changes that drive T cell dysfunction in the context of chronic antigen stimulation, resulting in superior effector capacity. Aim 2 will primarily use human T cells engineered with a TCR specific for the NY-ESO-1 antigen along with the pmel model. Our complementary aims outline an approach to define the effects of IL9R signaling in T cells that underlie their anti-tumor functions in solid tumors without conditioning chemotherapy. Our findings will set the stage for the therapeutic translation of T cells endowed with IL9R signaling.

项目概要使用工程 T 细胞的过继细胞疗法 (ACT) – 例如嵌合抗原受体 (CAR) 或 T 细胞受体 (TCR) 修饰 T 细胞——是一种治疗血液恶性肿瘤的有效免疫疗法，ACT 已取得成功。实体瘤一直难以捉摸，这对 T 细胞提出了独特的挑战，也需要调节。化疗会消耗患者的内源性 T 细胞，从而导致显着的毒性。设计具有合成功能的 T 细胞，以克服实体瘤 ACT 的障碍，包括需要调理化疗，这将显着提高该疗法的可行性和安全性。在本提案中，我们使用由我们的合作者 Garcia 博士开发的正交 IL2 细胞因子受体对。斯坦福大学。正交 IL2Rβ (o2R) 仅由正交 IL2 (oIL2) 细胞因子激活，而野生型则不激活。 IL2。当激活时，o2R 通过 IL2Rβ 的细胞内结构域 (ICD) 发出信号，这涉及合作。利用这种合作，我们研究了嵌合正交。其中 o2R 的 IL2Rβ ICD 被其他 γc 细胞因子受体的 ICD 取代的受体，使得 oIL2 在这些嵌合体中，通过 IL9R ICD (o9R) 发出的信号产生了独特的信号。 STAT 磷酸化谱和分化轨迹，促使体内进一步探索。增殖信号比o2R信号弱，o9R信号导致T细胞具有优异的抗肿瘤功效，在没有淋巴细胞清除的情况下效果显着。要将这一发现转化为晚期实体瘤患者的可行治疗方法，需要了解 o9R 信号 T 细胞的功能特征，使其具有抗肿瘤功效，尤其是在没有条件化疗的情况下，我们的初步数据使我们关注其中两个特征，我们在目标 1 和 2 中解决这个问题。在目标 1 中，我们重点关注 o9R 信号传导的外周体内效应，该效应依赖于我们捕获了 o9R 信号传导与宿主的相互作用，特别是淋巴结归巢和启动。重新编程周围的 T 细胞，以实现有效的淋巴结归巢和空间定位，从而促进启动这对于它们的体内抗肿瘤作用至关重要，Aim 1 将使用基于 TCR 和 CAR 的同基因小鼠。在 ACT 的实体瘤模型中，我们转向 o9R 信号传导对效应子能力的细胞内在影响。面对慢性抗原刺激，我们勇敢地面对o9R信号传导干扰表观遗传变化。在慢性抗原刺激的情况下驱动 T 细胞功能障碍，从而产生卓越的效应能力。目标 2 将主要使用经过改造的人类 T 细胞，该细胞具有针对 NY-ESO-1 抗原的 TCR 特异性，以及 pmel 模型。我们的补充旨在概述一种方法来定义 T 细胞中 IL9R 信号传导的影响，这是其基础我们的研究结果将为实体瘤的抗肿瘤功能奠定基础，无需进行预处理化疗。赋予 IL9R 信号传导的 T 细胞的治疗性翻译。