Clinical evaluation of IL13Ra2-targeted CAR T cell therapy in combination with nivolumab in patients with recurrent malignant glioma

IL13Ra2靶向CAR T细胞疗法联合纳武单抗治疗复发性恶性胶质瘤的临床评价

• 批准号: 10629150
• 负责人: CHRISTINE BROWN
• 金额: $ 46.96万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10629150
• 关键词: Address; Advanced Malignant Neoplasm; Animals; Antigen Targeting; Antigens; Biology; CAR T cell therapy; CXCL10 gene; CXCR3 gene; Cells; Cerebrospinal Fluid; Characteristics; Cities; Clinical; Clinical Trials; Combined Modality Therapy; Disease; Effectiveness; Environment; Generations; Glioblastoma; Glioma; Goals; Hematologic Neoplasms; IL13RA1 gene; Immune; Immunocompetent; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapy; In complete remission; Intraventricular; Lead; Letters; Malignant Glioma; Mediating; Modeling; Molecular; Mus; Neoplasm Metastasis; Nivolumab; PD-1 blockade; PD-1/PD-L1; PDL1 pathway; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Phenotype; Population; Positioning Attribute; Recurrence; Resistance; Role; Safety; Sampling; Solid Neoplasm; T cell response; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; T-cell inflamed; Therapeutic; Translating; Treatment Efficacy; Vertebral column; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-cancer; anti-tumor immune response; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical candidate; cohort; design; experience; experimental study; immune checkpoint blockade; immune resistance; improved; improved outcome; innovation; insight; interleukin-13 receptor; manufacture; mouse model; phase I trial; pre-clinical; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; programs; recruit; research clinical testing; response; safety and feasibility; standard of care; success; synergism; therapeutic development; therapy resistant; timeline; tumor; tumor microenvironment

PROJECT SUMMARY Chimeric antigen receptor (CAR) T cell therapy is emerging as a powerful anti-cancer strategy that may offer new opportunities to improve outcomes for patients with malignant gliomas (MG). Although CAR T cells have demonstrated remarkable clinical responses against hematologic malignancies, success against solid tumors remains an important therapeutic goal. The immunosuppressive solid tumor microenvironment (TME) presents obstacles to therapy that must be overcome in order to achieve therapeutic efficacy. City of Hope was the first to clinically translate CAR T cells for the treatment of MG, and the lead CAR program targets the glioma- associated antigen IL13 receptor alpha 2 (IL13Rα2). Initial findings have demonstrated that the treatment is well tolerated and shows evidence of antitumor activity. One patient with recurrent multifocal glioblastoma (including metastatic lesions in the spine) with characteristics of an inflamed TME, achieved a complete response (CR) that was durable for more than 7 months. Importantly, this case provides evidence that CAR T cells can mediate profound antitumor activity against one of the most lethal and difficult-to-treat solid tumors, and also provides critical information on how the tumor landscape can modulate response to CAR T cell immunotherapy. Our goal is to implement strategies to overcome the underlying causes of immunosuppression within the tumor microenvironment that limit CAR T cell responses to MG. The PD-1/PD-L1 pathway has emerged as a critical driver of immune suppression in solid tumors, including MG. We hypothesize that checkpoint blockade will synergize with CAR T cells to create a tumor landscape more favorable to immunotherapy. We propose to clinically evaluate IL13Rα2-CAR T cell therapy in combination with anti-PD1 (nivolumab) in patients with IL13Rα2+ recurrent MG (Specific Aim 1). Interrogating correlative samples from this clinical trial, we will assess tumor and TME changes that occur post T cell therapy with and without nivolumab, as well as molecular pathways that dominantly correlate with response and/or resistance to therapy (Specific Aim 2). In addition, we will preclinically evaluate in immunocompetent mice, the impact of an inflamed versus non-inflamed TME on the efficacy of the combination therapy. These preclinical studies will aid in elucidating mechanisms of response and resistance in the two immunological landscapes (Specific Aim 3). This project builds upon our prior preclinical and clinical experience with IL13Rα2-CAR T cell therapy, as well as our understanding of PD-1/PDL-1 biology and its impact on immunotherapy. We anticipate these experiments will provide insights for improved MG therapies, which also may apply to other advanced cancers.

项目概要 嵌合抗原受体 (CAR) T 细胞疗法正在成为一种强大的抗癌策略，可以提供 改善恶性胶质瘤（MG）患者预后的新机会。虽然 CAR T 细胞具有 对血液系统恶性肿瘤表现出显着的临床反应，在实体瘤方面取得了成功 仍然是一个重要的治疗目标。免疫抑制实体瘤微环境（TME）呈现 为了达到治疗效果必须克服的治疗障碍。希望之城是第一个 临床转化 CAR T 细胞用于治疗 MG，领先的 CAR 项目针对神经胶质瘤 相关抗原 IL13 受体 α2 (IL13Rα2)。初步结果表明治疗效果良好 耐受并显示出抗肿瘤活性的证据。 1例复发性多灶性胶质母细胞瘤患者（包括 脊柱转移性病变）具有发炎 TME 的特征，实现了完全缓解 (CR) 耐用超过 7 个月。重要的是，这个案例提供了证据表明CAR T细胞可以介导 对最致命和最难治疗的实体瘤之一具有深远的抗肿瘤活性，并且还提供 关于肿瘤景观如何调节 CAR T 细胞免疫疗法反应的关键信息。 我们的目标是实施策略来克服肿瘤内免疫抑制的根本原因 限制 CAR T 细胞对 MG 反应的微环境。 PD-1/PD-L1 通路已成为关键的通路 实体瘤（包括 MG）免疫抑制的驱动因素。我们假设检查站封锁将 与 CAR T 细胞协同作用，创造更有利于免疫治疗的肿瘤环境。 我们建议对 IL13Rα2-CAR T 细胞疗法与抗 PD1（纳武单抗）联合进行临床评估 IL13Rα2+ 复发性 MG 患者（具体目标 1）。询问本次临床试验的相关样本， 我们将评估使用或不使用纳武单抗的 T 细胞治疗后发生的肿瘤和 TME 变化，以及 与治疗反应和/或耐药性主要相关的分子途径（具体目标 2）。在 此外，我们将在免疫功能正常的小鼠中进行临床前评估，炎症与非炎症的影响 TME 对联合疗法疗效的影响。这些临床前研究将有助于阐明其机制 两种免疫学景观中的反应和耐药性（具体目标 3）。 该项目建立在我们之前的 IL13Rα2-CAR T 细胞疗法的临床前和临床经验以及 我们对 PD-1/PDL-1 生物学及其对免疫治疗影响的了解。我们预计这些实验 将为改进 MG 疗法提供见解，这也可能适用于其他晚期癌症。