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: 10471038
• 负责人: Avinash Desai
• 金额: $ 86.53万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471038
• 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; Generations; Hematologic Neoplasms; 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; Lymphocyte Depletion; 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; Prognosis; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reaction; Recovery; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Reporting; Resistance; Risk; Risk Reduction; Safety; Seizures; Signaling Molecule; Source; Structure; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Transplantation Conditioning; aged; cancer cell; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; cohort; commercialization; 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; participant enrollment; 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.

抽象的 尽管有治疗的进展，但接力或难治（R/R）B细胞急性的成年患者的预后 淋巴细胞白血病（B-all）和R/R弥漫性大B细胞淋巴瘤（DLBCL）仍然很差。自体T- 经过修改以表达CD19靶向的嵌合抗原受体（CAR T细胞）产生持久反应 在这些患者的亚组中，这导致了FDA迄今为止对两种此类疗法的批准；许多其他 CAR T细胞疗法正在研究中，包括带有CD28的CD19靶向汽车T细胞产品 在纪念斯隆·凯特林癌症中心开发的共刺激域（19-28Z）。但是，汽车T细胞 B-All和DLBCL的治疗与严重神经毒性的高风险有关（包括 脑病，癫痫病，癫痫发作和少数脑水肿）和细胞因子释放综合征（CRS）。主持人 单核细胞是在神经系统毒性的背景下观察到的细胞因子升高（IL-1，IL-6）的主要来源。 在进行CAR T细胞输注之前，给予调理或“淋巴结障”化疗，最常见 环磷酰胺和氟达拉滨，似乎将CAR T细胞的膨胀和效率提高了几个 机制。但是，耗尽单核细胞以及淋巴细胞的调节策略可能会减少 在保留抗肿瘤效率的同时，发生严重神经毒性的风险。抗CD45抗体apamistamab 用131-碘（131-I apamistamab）标记为骨髓性调节 III期Sierra试验中的造血细胞移植针对活性，R/R急性髓样患者 白血病。在塞拉利昂，当131-i apamistamab以低点给出时，临床观察到短暂的淋巴结螺旋。 剂量剂量法。另外，在临床前模型中，单个低剂量为131-I-Radiolabeled抗CD45 抗体有效耗尽淋巴细胞，粒细胞衍生的抑制细胞和调节性T细胞，没有 对骨髓造血干细胞的影响。 我们提出了调查低剂量131-I apamistamab，以代替19-28Z汽车之前的调节化疗 R/R B-ALL或R/R DLBCL患者的T细胞疗法，假设这将更有效地复制宿主 单核细胞并降低单核细胞衍生的细胞因子的脑脊液（CSF）水平，从而降低 19-28Z CAR T细胞输注后，严重的神经系统毒性的发生率。该临床试验将是第一个 在进行CAR T细胞治疗之前，测试放射药物调节。 I/II期研究旨在确定 在这种情况下，最大耐受剂量为131-i apamistamab，随后评估 与131-I Apamistamab调节和19-28Z CAR T细胞治疗相关的严重神经毒性 R/R B-ALL或R/R DLBCL以及抗肿瘤效率的患者。相关研究计划将表征 131-I apamistamab对血液和CSF细胞因子谱以及免疫组成的影响 细胞微环境。该试验的结果可以应用于持续的发展和完善 靶向血液学和非血液学恶性肿瘤的汽车T细胞疗法。