Radioimmunotherapy Combinations for B-cell Malignancy

项目摘要/摘要 本研究建议的目标是最大化复发或难治性(R/R)非霍奇金患者的治愈率 淋巴瘤(NHL)通过增强靶向放射性核素治疗的能力来全面消除 残留病。非霍奇金淋巴瘤是美国最常见的血液系统恶性肿瘤，有几种 亚型预示着不良结局，包括所谓的“二重打击”和“三重打击”疾病。此外，懒惰 淋巴瘤通常仍是无法治愈的。而CAR T(嵌合抗原受体T细胞疗法)提供了希望 对于R/R弥漫性大B细胞淋巴瘤，报告的持久完全应答率仅为30%-40% 病人。NHL复发被认为是由于小肿瘤细胞储备持续存在而逃脱治疗所致。 NHL的显著异质性有助于恶性细胞逃逸，并使统一的治疗方法复杂化。 心理治疗。然而，与对其他干预措施的反应性无关，几乎所有的非霍奇金淋巴瘤都具有微妙的辐射性。 灵敏，使基于放射性核素的方法具有独特的优势。放射性标记的抗CD20抗体可以 在以下情况下，传统联合化疗失败的淋巴瘤患者可获得高达95%的缓解 清髓剂量的放射免疫疗法(RIT)是在干细胞支持下进行的。而这些 反应令人鼓舞，肿瘤与非肿瘤吸收辐射的比率低，毒性和不可接受。 复发率构成了这项赠款提案正在进行的工作的理由。拟议的项目具有杠杆作用 在之前的资金时期开发的新的RIT交付方法，并被证明显著改善了肿瘤到肿瘤的比率 吸收辐射的器官比率正常。临床经验表明，多药联合是 通常在治疗非霍奇金淋巴瘤方面最有效。本提案探讨了三种RIT组合策略，其中包括 目标是通过针对复发的推定原因在NHL各亚型之间产生不同的疗效， 隐匿性残留病。为了实现这一目标，目标1将使用两个靶向放射性核素的合理配对， 首次使用β发射体疗法较长的路径长度和适度的线性能量转移(LET)来安全地清除 NHL肿瘤，然后是极高的LET和短路径长度的α发射体，以消除残留疾病。 目标2将探索将RIT触发肿瘤细胞死亡的能力与RIT的促凋亡作用相结合 新出现的BH3模拟。AIM 3将检查RIT与合理选择的免疫检查点抑制剂的组合， 在一种新的肿瘤疫苗方法中根除残留疾病。总而言之，这些拟议的研究测试了 假设RIT联合疗法将减少有效治疗NHL所需的总辐射剂量， 以通过我们的非霍奇金淋巴瘤临床RIT计划促进快速翻译的方式。

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.