Modulating the PD-1/PD-L1 checkpoint to promote antitumor activity of HER2 CAR T cells in patients with sarcoma

调节PD-1/PD-L1检查点促进肉瘤患者HER2 CAR T细胞的抗肿瘤活性

• 批准号: 10562836
• 负责人: Meenakshi G Hegde
• 金额: $ 66.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-07 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562836
• 关键词: Address; Adoptive Transfer; Adult; Antigen Targeting; Antigens; Antitumor Response; Autologous; Biology; CAR T cell therapy; CD19 gene; CD8B1 gene; Cell Line; Cell Separation; Cell Therapy; Cells; Chemotherapy-Oncologic Procedure; Child; Clinic; Clinical; Clinical Research; Clinical Trials; Combination immunotherapy; Cyclophosphamide; Data; Development; Disease; Dose; Down-Regulation; ERBB2 gene; Engineering; Event; Functional disorder; Future; Goals; Hematologic Neoplasms; Immune; Immune checkpoint inhibitor; Immune signaling; Immunologic Markers; Immunotherapy; In complete remission; Infusion procedures; Intervention; Investigational Drugs; Investigational New Drug Application; Kinetics; Knowledge; Literature; Malignant Neoplasms; Observational Study; Outcome; PD-1 blockade; PD-1/PD-L1; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Predisposition; Property; Public Health; ROR1 gene; Recurrence; Recurrent disease; Refractory; Relapse; Reporting; Research; Research Personnel; Rhabdomyosarcoma; Safety; Serum; Signal Transduction; Solid Neoplasm; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Transgenes; Treatment outcome; Tumor Antigens; Tumor Escape; Tumor Promotion; Tumor Tissue; Up-Regulation; anti-PD1 antibodies; antitumor effect; biomarker identification; cell mediated immune response; checkpoint inhibition; chemotherapy; childhood sarcoma; chimeric antigen receptor T cells; clinical efficacy; clinical predictors; cohort; design; fludarabine; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; improved; innovation; novel strategies; peripheral blood; phase 1 study; phase I trial; preclinical study; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; prospective; rational design; receptor; research clinical testing; response; sarcoma; success; treatment response; tumor; tumor microenvironment; years of life lost; young adult

PROJECT SUMMARY/ABSTRACT Immunotherapy has shown limited efficacy against pediatric sarcoma. In our recently completed phase I study, infusion of HER2-targeted chimeric antigen receptor T cells (CAR-T) was safe and showed encouraging indicators of antitumor activity, including three durable complete responses. The key observations from this study are: (1) lymphodepletion promotes CAR-T expansion but only marginally improves persistence, (2) adoptively transferred CAR-T are susceptible to immune inhibition, and (3) antigen downregulation/loss is associated with disease relapse. While the literature is lacking on immune inhibitory mechanisms and tumor adaptations in sarcoma, our findings are in line with observations made by others in early clinical and pre-clinical studies of cellular therapy for solid tumors. Our long-term goal is to develop new approaches that capitalize on expected tumor defenses which may be key to unleashing the potential of CAR-T against sarcomas and other solid tumors. Therapeutic approaches that integrate strategies to address these compensatory mechanisms up front may mitigate downstream tumor escape and relapse. The objective of this project is to conduct prospective clinical testing of HER2 CAR-T in combination with PD-1/PD-L1 checkpoint disruption strategies in a disease-specific cohort. The central hypothesis is that the combination immunotherapy will promote immune infiltration, remodel the tumor microenvironment, alleviate CAR-T dysfunction, and thereby improve antitumor responses. Our specific aims will test the following hypotheses: (Aim 1) The combination of anti-PD-1 antibody and HER2 CAR- T administered after lymphodepletion is safe in patients with sarcoma, will improve CAR-T kinetics, and will elicit antitumor responses; (Aim 2) Cellular and serum-based studies in treated patients will help identify biomarkers of toxicity and response; and (Aim 3) Engineering CAR-T to positively transform the PD-1/PD-L1 interaction in the tumor microenvironment will potentiate antitumor effects of the cellular product while incorporating design attributes to enhance its safety . We will evaluate Aims 1 and 2 through implementation of a phase I study of autologous HER2 CAR-T and anti-PD-1 antibody after cyclophosphamide and fludarabine lymphodepletion in patients with sarcoma (HEROS 3.0 clinical trial). In Aim 3, we will develop an investigational new drug (IND) for HER2 CAR-T co-expressing a PD-1 checkpoint reversal receptor (CPR). At the conclusion of the project, we will understand if CAR-T can be safely administered with immune checkpoint inhibition to improve treatment outcomes for children and young adults with sarcoma. The significance of these contributions are: (1) establishing the clinical utility of combination immunotherapy for sarcoma, (2) potentially identifying “modifiable” patient- and treatment-related factors to guide future improvements to CAR-T therapy, and (3) enabling clinical testing of an innovative CAR-T platform. This knowledge is critical to advancing the field, as recurrent or refractory sarcomas remain largely incurable.

项目概要/摘要 免疫疗法对儿童肉瘤的疗效有限。在我们最近完成的第一阶段研究中， 输注 HER2 靶向嵌合抗原受体 T 细胞 (CAR-T) 是安全的，令人鼓舞 抗肿瘤活性指标，包括三个持久的完全反应。这项研究的主要观察结果 是：(1) 淋巴细胞清除促进 CAR-T 扩增，但仅略微提高持久性，(2) 过继性 转移的 CAR-T 容易受到免疫抑制，并且 (3) 抗原下调/丢失与 疾病复发。虽然缺乏关于免疫抑制机制和肿瘤适应的文献 肉瘤，我们的发现与其他人在早期临床和临床前研究中的观察结果一致 实体瘤的细胞疗法。我们的长期目标是开发利用预期的新方法 肿瘤防御，这可能是释放 CAR-T 对抗肉瘤和其他实体瘤潜力的关键。 整合策略来预先解决这些补偿机制的治疗方法可能会 减轻下游肿瘤逃逸和复发。该项目的目标是进行前瞻性临床 在特定疾病中结合 PD-1/PD-L1 检查点破坏策略测试 HER2 CAR-T 队列。中心假设是联合免疫疗法将促进免疫浸润、重塑 改善肿瘤微环境，缓解 CAR-T 功能障碍，从而提高抗肿瘤反应。我们的 具体目标将检验以下假设：（目标1）抗PD-1抗体与HER2 CAR的组合 淋巴细胞清除后给予 T 对于肉瘤患者是安全的，将改善 CAR-T 动力学，并引发 抗肿瘤反应； （目标 2）对接受治疗的患者进行基于细胞和血清的研究将有助于识别生物标志物 毒性和反应； （目标 3）工程化 CAR-T 以积极改变 PD-1/PD-L1 相互作用 肿瘤微环境将增强细胞产品的抗肿瘤作用，同时融入设计 属性以增强其安全性。我们将通过实施第一阶段研究来评估目标 1 和 2 环磷酰胺和氟达拉滨淋巴细胞清除后的自体 HER2 CAR-T 和抗 PD-1 抗体 肉瘤患者（HEROS 3.0 临床试验）。在目标 3 中，我们将开发一种研究性新药 (IND) HER2 CAR-T 共表达 PD-1 检查点逆转受体 (CPR)。在项目结束时，我们将 了解 CAR-T 是否可以安全地与免疫检查点抑制一起给药以改善治疗 患有肉瘤的儿童和年轻人的结果。这些贡献的意义在于：（1） 建立肉瘤联合免疫疗法的临床效用，(2) 潜在地识别“可修改的” 患者和治疗相关因素，以指导未来 CAR-T 疗法的改进，以及 (3) 实现临床 测试创新的 CAR-T 平台。这些知识对于推进该领域至关重要，作为经常性或 难治性肉瘤在很大程度上仍然无法治愈。