Radioimmunotherapy Combinations for B-cell Malignancy

项目总结/摘要 这项研究的目的是最大限度地提高复发性或难治性（R/R）非霍奇金淋巴瘤的治愈率。 通过增强靶向放射性核素疗法的能力， 残留病NHL是美国最常诊断的血液恶性肿瘤， 亚型预示着不良结果，包括所谓的“双重打击”和“三重打击”疾病。此外，惰性 淋巴瘤通常是无法治愈的。虽然CAR T（嵌合抗原受体T细胞疗法） 对于R/R弥漫性大B细胞淋巴瘤，仅30-40%的患者报告了持久的完全缓解率。 患者NHL复发被认为是由于逃避治疗的小肿瘤细胞储备的持续存在。 NHL的显著异质性有助于恶性细胞逃逸，并使治疗NHL的统一方法复杂化。 疗法独立的反应，其他干预措施，然而，几乎所有的NHL是精致的辐射 敏感，使放射性核素为基础的方法具有独特的优势。放射性标记的抗CD 20抗体可 在常规联合化疗失败的淋巴瘤患者中， 清髓剂量的放射免疫疗法（RIT）与干细胞支持一起施用。虽然这些 反应是令人鼓舞的，低肿瘤与非肿瘤吸收辐射，毒性和不可接受的比率 复发率形成了本赠款提案正在进行的工作的基本原理。拟议项目的杠杆作用 在之前的资助期间开发的新型RIT交付方法，并显示出显着改善肿瘤- 正常器官吸收辐射的比率。临床经验表明， 一般最有效的治疗NHL。本提案探讨了三种RIT组合策略， 目标是通过靶向复发的假定原因，在NHL亚型中产生不变的疗效， 隐匿性残留病为实现这一目标，目标1将采用两种目标放射性核素的合理配对， 首先使用β-发射体治疗的较长路径长度和适度的线性能量转移（LET）来安全地减容 NHL肿瘤，其次是极高的LET和短路径长度的α-发射体，以消除残留疾病。 目的2将探索RIT触发肿瘤细胞死亡的能力与促凋亡功效的结合。 紧急BH 3模拟物。目的3将检查RIT与合理选择的免疫检查点抑制剂的组合， 一种新的肿瘤疫苗方法来根除残留疾病。这些拟议的研究共同测试了 假设RIT组合方法将减少有效治疗NHL所需的总辐射剂量， 以便于通过我们的非霍奇金淋巴瘤临床RIT计划快速翻译的方式。

PROJECT SUMMARY/ABSTRACT The objective of this research proposal is to maximize the cure rates of relapsed or refractory (R/R) non-Hodgkin lymphomas (NHL) by enhancing the capacity for targeted radionuclide therapies to comprehensively eliminate residual disease. NHL is the most commonly diagnosed hematologic malignancy in the United States and several subtypes portend poor outcomes, including so called “double hit” and “triple hit” disease. In addition, indolent lymphoma remains generally incurable. While CAR T (chimeric antigen receptor T cell therapy) offers promise for R/R diffuse large B cell lymphoma, durable complete response rates have been reported in only 30-40% of patients. NHL relapse is believed to result from the persistence of small tumor cell reserves that elude treatment. The notable heterogeneity of NHL contributes to malignant cell escape and complicates a uniform approach to therapy. Independent of responsiveness to other interventions however, virtually all NHL is exquisitely radiation sensitive, giving radionuclide based approaches a unique advantage. Radiolabeled anti-CD20 antibodies can achieve remissions in up to 95% of lymphoma patients failing conventional combination chemotherapy when myeloablative doses of the radioimmunotherapy (RIT) are administered with stem cell support. While these responses are encouraging, low tumor-to non-tumor ratios of absorbed radiation, toxicity, and unacceptable rates of relapse form the rationale for the ongoing work of this grant proposal. The proposed projects leverage novel RIT delivery methods developed during prior funding periods and shown to dramatically improve tumor-to- normal organ ratios of absorbed radiation. Clinical experience dictates that multi-agent combinations are generally most effective in the treatment of NHL. This proposal explores three RIT combination strategies with a goal of generating unvarying efficacy across NHL subtypes through targeting the presumptive cause of relapse, occult residual disease. To achieve this goal, Aim 1 will employ the rational pairing of two targeted radionuclides, first using the longer path length and modest linear energy transfer (LET) of β-emitter therapy to safely debulk NHL tumors, followed by an extremely high LET and short path length α-emitter to eliminate residual disease. Aim 2 will explore combining the ability of RIT to trigger tumor cell death with the pro-apoptotic efficacy of emergent BH3 mimetics. Aim 3 will examine RIT combined with rationally selected immune checkpoint inhibitors, in a novel tumor vaccine approach to eradicating residual disease. Collectively these proposed studies test the hypothesis that RIT combination approaches will reduce the total radiation dose required to effectively treat NHL, in a manner that facilitates rapid translation through our non-Hodgkin lymphoma clinical RIT program.