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: 10091312
• 负责人: CHRISTINE BROWN
• 金额: $ 66.58万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091312
• 关键词: Address; Advanced Malignant Neoplasm; Animals; Antigen Targeting; Antigens; Biology; CAR T cell therapy; CXCL10 gene; Cells; Cerebrospinal Fluid; Characteristics; Cities; Clinical; Clinical Trials; Combined Modality Therapy; Disease; Effectiveness; Environment; Generations; Glioblastoma; Glioma; Goals; Hematologic Neoplasms; Immune; Immunocompetent; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapy; In complete remission; Interleukin-13; 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; TimeLine; Translating; Treatment Efficacy; Vertebral column; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-cancer; anti-tumor immune response; base; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical candidate; cohort; design; experience; experimental study; immune checkpoint blockade; improved; improved outcome; innovation; insight; mouse model; phase I trial; pre-clinical; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; programs; receptor; recruit; research clinical testing; response; safety and feasibility; standard of care; success; therapeutic development; therapy resistant; 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.

项目摘要 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，可能会提供 尽管汽车T细胞具有 表现出对血液系统恶性肿瘤的显着临床反应，对实体瘤的成功 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 为了达到治疗效率，必须克服的治疗障碍。希望之城是第一个 临床翻译CAR T细胞以治疗MG，而Lead Car计划则针对神经胶质瘤 - 相关的抗原IL13受体α2（IL13Rα2）。初步发现表明治疗良好 耐受并显示抗肿瘤活性的证据。一名复发性多灶性胶质母细胞瘤的患者（包括 具有发炎的TME特征的脊柱转移病变，达到了完全反应（CR） 那是耐用的7个月以上。重要的是，这种情况提供了证据表明汽车T细胞可以介导 对最致命和治疗的实体瘤之一的深刻抗肿瘤活性，还提供 有关肿瘤景观如何调节对CAR T细胞免疫疗法的反应的关键信息。 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 限制汽车T细胞对Mg的微环境。 PD-1/PD-L1途径已成为关键 在包括毫克在内的实体瘤中免疫抑制的驱动器。我们假设检查点封锁将 与CAR T细胞协同创造更有利的免疫疗法的肿瘤景观。 我们建议在临床上评估IL13Rα2-CAR T细胞疗法与抗PD1（Nivolumab）在 IL13Rα2+复发型MG患者（特定目标1）。询问该临床试验中的相关样本， 我们将评估T细胞治疗后有或没有Nivolumab的肿瘤和TME变化，以及 与对治疗的反应和/或抗性相关的分子途径（特定目标2）。 此外，我们将在免疫能力的小鼠中进行彻底评估，这是发炎与非爆发的影响 TME关于联合疗法的效率。这些临床前研究将有助于阐明 两种免疫景观的反应和抗性（特定目标3）。 该项目建立在我们先前使用IL13Rα2-CAR T细胞疗法的临床前和临床经验的基础上 我们对PD-1/PDL-1生物学及其对免疫疗法的影响。我们预计这些实验 将为改进的MG疗法提供见解，这也可能适用于其他高级癌症。