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

摘要 尽管治疗取得了进展，但复发或难治性(R/R)B细胞急性白血病成人患者的预后 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)仍然很差。自体T- 经修饰表达CD19靶向嵌合抗原受体的细胞(CAR T细胞)可产生持久反应 在这些患者的亚组中，这导致FDA迄今批准了两种这样的疗法；许多其他 CAR T细胞疗法正在研究中，包括一种以CD19为靶标的带有CD28的CAR T细胞产品 共刺激结构域(19-28Z)由纪念斯隆-凯特琳癌症中心开发。然而，CAR T细胞 B-ALL和DLBCL的治疗与严重神经毒性的高风险相关(包括 脑病、言语障碍、癫痫发作，极少出现脑水肿)和细胞因子释放综合征(CRS)。寄主 单核细胞是在神经毒性背景下观察到的升高的细胞因子(IL-1、IL-6)的主要来源。 最常见的是在CAR T细胞输注前进行调理或“淋巴清除”化疗 环磷酰胺和氟达拉滨似乎可以改善CAR T细胞的扩增和疗效 机械装置。然而，消耗单核细胞和淋巴细胞的调节策略可能会降低 在保留抗肿瘤疗效的同时有严重神经毒性的风险。抗CD45抗体apamistamab 用131-I标记的apamistamab(131-I apamistamab)正被研究为在 造血细胞移植在活动性R/R急性髓系患者中的III期塞拉试验 白血病。在塞拉，在低剂量给予131-I apamistamab时，临床上观察到一过性淋巴枯竭。 用于剂量测定的剂量。此外，在临床前模型中，单次小剂量131I标记的抗CD45 抗体有效地耗尽淋巴细胞、髓系来源的抑制细胞和调节性T细胞，而不是 对骨髓造血干细胞的影响。 我们建议在19-28Z CAR前研究小剂量131-I apamistamab替代条件性化疗 T细胞治疗R/R B-ALL或R/R DLBCL患者，假设这将更有效地耗尽宿主 并降低脑脊液(CSF)中单核细胞衍生细胞因子的水平，从而降低 19-28Z 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次 在CAR T细胞治疗前测试放射性药物调理。第一阶段/第二阶段研究旨在确定 在这种情况下，131-I apamistamab的最大耐受量，并随后评估 131-I apamistamab条件化和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的患者，以及抗肿瘤疗效。一项相关的研究计划将成为 131-I apamistamab对血液和脑脊液细胞因子谱及免疫成分的影响 细胞微环境。此试验的结果可应用于持续开发和完善 针对血液系统和非血液系统恶性肿瘤的CAR T细胞治疗。

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.