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: 10710036
• 负责人: Anusha Kalbasi
• 金额: $ 35.31万
• 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/10710036
• 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; Endowment; Epigenetic Process; Extracellular Domain; Face; Functional disorder; Gene Expression Profile; Genetic Transcription; Goals; Hematologic Neoplasms; Homing; Human; IL2 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 Signaling; Research Personnel; Resistance; Role; Series; Signal Transduction; Solid Neoplasm; T cell therapy; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Toxic effect; Translating; antitumor effect; 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; translational therapeutics; transmission process; 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 使用工程化T细胞的免疫细胞疗法（ACT）-例如嵌合抗原受体（CAR）或T细胞受体 (TCR)修饰的T细胞-是血液恶性肿瘤的有效免疫疗法。ACT的成功 对于实体肿瘤来说，这是难以捉摸的，它对T细胞提出了独特的挑战。ACT也需要条件反射 化疗消耗患者的内源性T细胞，这导致显著的毒性。我们的目标是 工程化具有合成功能的T细胞，以克服ACT用于实体瘤的障碍，包括需要 条件性化疗，这将显着提高该疗法的可行性和安全性。 在这个提议中，我们使用了由我们的合作者Garcia博士在 斯坦福大学。正交IL 2 R β（o2 R）仅被正交IL 2（oIL 2）细胞因子激活，而不被野生型激活。 IL 2。当被激活时，o2 R通过IL 2 R β的细胞内结构域（ICD）发出信号，这涉及合作 与天然的公共伽马链（γc）。利用这种合作，我们研究了嵌合正交 受体，其中o2 R的IL 2 R β ICD被其他γc细胞因子受体的ICD取代，例如oIL 2 从而得到相应的γc信号。在这些嵌合体中，通过IL 9 R ICD（o 9 R）的信号传导产生了独特的 STAT磷酸化谱和分化轨迹，促进了体内的进一步探索。尽管 增殖信号弱于o 2 R信号，o 9 R信号导致T细胞具有上级抗肿瘤功效， 在没有淋巴细胞耗竭的情况下明显的效果。 要将这一发现转化为晚期实体瘤患者的可行治疗方法， 了解o 9 R信号转导T细胞的功能特征，使其具有抗肿瘤功效，特别是 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的两个特征， 我们在目标1和2中处理了这一问题。在目标1中，我们关注依赖于O 9 R信号传导的外周体内效应。 与宿主的相互作用，特别是淋巴结归巢和启动。我们假设o 9 R信号 重新编程外周的T细胞，以实现有效的淋巴结归巢和空间定位，从而促进引发 这对于它们在体内的抗肿瘤作用至关重要。目标1将使用基于TCR和CAR的同基因小鼠 ACT的实体瘤模型。在目标2中，我们转向o 9 R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。我们假设o 9 R信号干扰了表观遗传变化， 其在慢性抗原刺激的情况下驱动T细胞功能障碍，导致上级效应子能力。 目的2将主要使用用对NY-ESO-1抗原特异性的TCR工程化的人T细胞沿着免疫调节剂。 pmel模型 我们的互补目标概述了一种方法来定义T细胞中IL 9 R信号传导的作用，这些作用是T细胞免疫应答的基础。 在实体瘤中的抗肿瘤功能而无需预处理化疗。我们的发现将为 具有IL 9 R信号传导的T细胞的治疗性翻译。