Iomab-ACT: A phase I/II study of 131-I apamistamab targeted lymphodepletion followed by CD19-targeted CAR T-cell therapy for patients with relapsed or refractory B-ALL or DLBCL

Iomab-ACT：针对复发或难治性 B-ALL 或 DLBCL 患者进行 131-I apamistamab 靶向淋巴细胞清除随后进行 CD19 靶向 CAR T 细胞治疗的 I/II 期研究

• 批准号: 10081925
• 负责人: Mark S Berger
• 金额: $ 37.84万
• 依托单位: ACTINIUM PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081925
• 关键词: Actinium; Acute Myelocytic Leukemia; Address; Adopted; Adoptive Cell Transfers; Adult; Antibodies; Antibody-drug conjugates; Autologous; B-Cell Acute Lymphoblastic Leukemia; Behavior Therapy; Biodistribution; Blood; Bone Marrow; CD19 Antigens; CD19 gene; CD28 gene; Cells; Cerebral Edema; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Combination Drug Therapy; Correlative Study; Cyclophosphamide; Development; Dose; Dysphasia; Effector Cell; Encephalopathies; Enrollment; Generations; Hematology; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; I131 isotope; Immune; Immunotherapy; In complete remission; Incidence; Inflammatory; Infusion procedures; Interleukin-1; Interleukin-6; Investigation; Kinetics; Label; Lead; Leukocytes; Link; Lymphocyte; Lymphocyte Count; Lymphoma cell; Maximum Tolerated Dose; Memorial Sloan-Kettering Cancer Center; Myeloid-derived suppressor cells; Myelosuppression; Neurologic; Neurotoxicity Syndromes; Non-Hematologic Malignancy; PTPRC gene; Patients; Peripheral; Phase; Pre-Clinical Model; Prior Chemotherapy; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reaction; Recovery; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Reporting; Resistance; Risk; Safety; Seizures; Signaling Molecule; Source; Structure; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Transplantation Conditioning; aged; cancer cell; chemotherapy; chimeric antigen receptor; cohort; conditioning; cytokine; cytokine release syndrome; design; dosimetry; experience; fludarabine; hematopoietic cell transplantation; high risk; immunoregulation; improved; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; monocyte; multimodality; novel strategies; outcome forecast; patient population; patient subsets; peripheral blood; preclinical study; preservation; response; safety and feasibility; side effect; targeted treatment; tumor

ABSTRACT Despite treatment advances, the prognosis of adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and R/R diffuse large B-cell lymphoma (DLBCL) remains poor. Autologous T- cells modified to express a CD19-targeted chimeric antigen receptor (CAR T-cells) produce durable responses in subgroups of these patients, which has led to FDA approval of two such therapies to date; numerous other CAR T-cell therapies are under investigation, including a CD19-targeted CAR T-cell product bearing a CD28 costimulatory domain (19-28z) developed at Memorial Sloan Kettering Cancer Center. However, CAR T-cell therapy for B-ALL and DLBCL is associated with high risk of severe neurologic toxicity (including encephalopathy, dysphasia, seizures, and rarely, cerebral edema) and cytokine release syndrome (CRS). Host monocytes are the major source of elevated cytokines (IL-1, IL-6) observed in the context of neurologic toxicity. Administration of conditioning or “lymphodepleting” chemotherapy prior to CAR T-cell infusion, most commonly cyclophosphamide and fludarabine, appears to improve CAR T-cell expansion and efficacy by several mechanisms. However, a conditioning strategy that depletes monocytes as well as lymphocytes may reduce the risk of severe neurologic toxicity while preserving antitumor efficacy. The anti-CD45 antibody apamistamab labeled with 131-iodine (131-I apamistamab) is being investigated as myeloablative conditioning prior to hematopoietic cell transplantation in the Phase III SIERRA trial for patients with active, R/R acute myeloid leukemia. In SIERRA, transient lymphodepletion is observed clinically when 131-I apamistamab is given at low doses for dosimetry. Additionally, in preclinical models, a single low dose of 131-I-radiolabeled anti-CD45 antibody efficiently depletes lymphocytes, myeloid-derived suppressor cells, and regulatory T-cells, without impact on bone marrow hematopoietic stem cells. We propose investigating low-dose 131-I apamistamab in lieu of conditioning chemotherapy prior to 19-28z CAR T-cell therapy in patients with R/R B-ALL or R/R DLBCL, hypothesizing this will more effectively deplete host monocytes and reduce cerebrospinal fluid (CSF) levels of monocyte-derived cytokines, and thereby lower the incidence of severe neurologic toxicity following 19-28z CAR T-cell infusion. This clinical trial will be the first to test radiopharmaceutical conditioning prior to CAR T-cell therapy. The phase I/II study is designed to determine the maximum tolerated dose of 131-I apamistamab in this setting and subsequently to assess the incidence of severe neurologic toxicity associated with 131-I apamistamab conditioning and 19-28z CAR T-cell therapy in patients with R/R B-ALL or R/R DLBCL, as well as antitumor efficacy. A correlative study plan will characterize the effects of 131-I apamistamab on cytokine profiles in blood and CSF, and on the composition of the immune cellular microenvironment. Results of this trial can be applied toward ongoing development and refinement of CAR T-cell therapies targeting hematologic and non-hematologic malignancies.

摘要 尽管治疗取得了进展，但复发性或难治性（R/R）B细胞急性白血病成人患者的预后仍不乐观。 淋巴母细胞性白血病（B-ALL）和R/R弥漫性大B细胞淋巴瘤（DLBCL）仍然较差。自动化- 经修饰以表达CD 19靶向嵌合抗原受体的细胞（CAR T细胞）产生持久应答 在这些患者的亚组中，这导致FDA批准了迄今为止的两种此类疗法;许多其他疗法 CAR T细胞疗法正在研究中，包括携带CD 28的CD 19靶向CAR T细胞产品。 共刺激结构域（19- 28 z），由Memorial Sloan Kettering癌症中心开发。然而，CAR T细胞 B-ALL和DLBCL的治疗与严重神经系统毒性（包括 脑病、言语障碍、癫痫发作，以及罕见的脑水肿）和细胞因子释放综合征（CRS）。主机 单核细胞是在神经毒性的情况下观察到的升高的细胞因子（IL-1，IL-6）的主要来源。 在CAR T细胞输注前给予预处理或“淋巴细胞清除”化疗，最常见的是 环磷酰胺和氟达拉滨似乎改善了CAR T细胞的扩增和功效。 机制等然而，消耗单核细胞和淋巴细胞的调节策略可能会减少细胞的增殖。 严重神经毒性的风险，同时保留抗肿瘤疗效。抗CD 45抗体apamistamab 标记有131-碘（131-I apamistamab）的药物正在研究作为清髓性预处理， 造血细胞移植在活动性R/R急性髓系白血病患者中的III期SIERRA试验 白血病在SIERRA中，当131-I apamistamab以低剂量给药时，临床上观察到一过性淋巴细胞耗竭。 用于剂量测定的剂量。此外，在临床前模型中，单次低剂量的131-I-放射性标记的抗CD 45 抗体有效地消耗淋巴细胞，骨髓源性抑制细胞和调节性T细胞，而不 影响骨髓造血干细胞。 我们建议在19- 28 z CAR之前研究低剂量131-I apamistamab代替预处理化疗 R/R B-ALL或R/R DLBCL患者的T细胞治疗，假设这将更有效地消耗宿主 单核细胞和降低脑脊液（CSF）水平的单核细胞衍生的细胞因子，从而降低 19- 28 z CAR T细胞输注后严重神经毒性的发生率。这项临床试验将是第一个 在CAR T细胞治疗之前测试放射性药物调节。I/II期研究旨在确定 在这种情况下，131-I apamistamab的最大耐受剂量，随后评估 与131-I apamistamab预处理和19- 28 z CAR T细胞治疗相关的严重神经毒性， R/R B-ALL或R/R DLBCL患者，以及抗肿瘤疗效。相关研究计划将描述 131-I apamistamab对血液和CSF中的细胞因子谱以及对免疫细胞的组成的影响 细胞微环境这项试验的结果可以应用于正在进行的开发和完善， 针对血液学和非血液学恶性肿瘤的CAR T细胞疗法。