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

• 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
• 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

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.

项目摘要 使用工程T细胞（例如嵌合抗原受体（CAR）或T细胞受体）的收养细胞疗法（ACT） （TCR）修饰的T细胞 - 是血液学恶性肿瘤的有效免疫疗法。行为的成功已有 对于实体瘤而言是难以捉摸的，这对T细胞提出了独特的挑战。 ACT也需要调理 化学疗法以微妙的患者内源性T细胞，从而导致明显的毒性。我们的目标是 具有合成功能的工程T细胞，以克服实体瘤的ACT障碍，包括需要 调理化疗，这将大大提高该疗法的可行性和安全性。 在此提案中，我们使用合作者Garcia博士在 斯坦福大学。正交IL2Rβ（O2R）仅被正交IL2（油2）细胞因子激活，而不是被野生型激活 IL2。激活时，通过IL2Rβ的细胞内结构域（ICD）信号，涉及协调 与天然普通伽马链（γc）。利用这种合作，我们研究了嵌合正交 O2R的IL2RβICD被其他γC细胞因子的受体取代的受体，以便油2 引起相应的γC信号。在这些嵌合体中，通过IL9R ICD（O9R）发出信号产生了独特的 Stat磷酸化谱和分化轨迹，促使体内进一步探索。尽管有 与O2R信号传导相比，O9R信号的增殖信号较弱，导致T细胞具有较高的抗肿瘤效率， 在没有淋巴结螺旋体的情况下，这种效果发出的效果。 将此发现转化为晚期实体瘤患者的可行治疗 了解允许其抗肿瘤效率的O9R信号T细胞的功能特征，尤其是 在没有调节化疗的情况下。我们的初步数据使我们专注于其中两个功能， 我们在目标1和2中解决的目标。在AIM 1中，我们专注于依赖O9R信号的外围体内效应 与宿主相互作用时，尤其是淋巴结的归因和启动。我们假设O9R信号传导 重新编程在周围的T细胞以促进启动的有效淋巴结的归因和空间定位 这对于它们在体内的抗肿瘤作用至关重要。 AIM 1将同时使用基于TCR和CAR的同性鼠标 实体模型。在AIM 2中，我们转向O9R信号传导对效应能力的细胞中性效应 慢性抗原刺激的脸。我们假设O9R信号传导对表观遗传变化的干扰 在慢性抗原刺激的背景下，驱动T细胞功能障碍，导致效应能力出色。 AIM 2主要使用针对NY-ESO-1抗原特异的TCR设计的人类T细胞以及 PMEL模型。 我们的完整性旨在概述一种定义IL9R信号在T细胞中的影响的方法 抗肿瘤功能在实体瘤中，无需调节化疗。我们的发现将为 具有IL9R信号传导的T细胞的治疗翻译。