Fractionated, Dual-targeted radioimmunotherapy for follicular lymphoma

描述（由申请人提供）：滤泡性非霍奇金淋巴瘤是淋巴瘤中最常见的惰性组织学亚型。除了罕见的局部肿瘤外，FL被认为是无法用标准治疗方法治愈的;虽然大多数患者对治疗有反应，但复发是规律，许多患者最终会死于淋巴瘤。标准治疗方法传统上依赖于联合化疗，但这带来了显着的毒性。最近，人们对FL治疗的非化疗方法的发展越来越感兴趣。放射免疫疗法（RIT）涉及放射性核素与单克隆抗体的缀合，允许不基于淋巴瘤的位置（如外部束放射疗法）递送辐射，而是基于RIT所靶向的细胞表面蛋白的表达。目前批准用于复发性惰性B细胞NHL的RIT试剂的效用受到两个主要因素的限制，包括抗体的免疫原性和与治疗方案相关的递送放射剂量的限制。最近的研究强调了这样一个概念，即靶向相同抗原的未标记和放射性标记抗体的施用可能导致次优的辐射靶向（由于竞争性结合）。这项研究将探索一种新的RIT方法，优化肿瘤的辐射剂量输送（通过使用分别靶向不同抗原（CD 20和CD 22）的未标记和放射性标记试剂），并最大限度地降低免疫原性（通过人性化），追求以下具体目标：1）确定生物分布，放射性标记的依帕珠单抗治疗的肿瘤定位和药代动力学，并确定由于用维妥珠单抗预处理引起的靶向的任何变化，和2）确定分级90 Y-依帕珠单抗四聚体的安全性和有效性（抗CD 22）与维妥珠单抗联合给药我们预期我们的方法将提供高度有效、可耐受的治疗，而无需使用化疗，即使是高危患者。本提案中探索的RIT修改可能会在更广泛的背景下影响类似的方法，包括其他淋巴瘤组织学以及正在探索RIT的其他恶性肿瘤。 公共卫生相关性：尽管有多种治疗方式和高反应率的初始治疗，大多数滤泡性淋巴瘤（FL）患者将开发复发性或难治性疾病，许多人最终死于淋巴瘤相关的并发症。我们建议研究一种非化疗的方法，以初步治疗FL涉及一种新的战略，放射免疫治疗（RIT），解决问题的辐射剂量输送和免疫原性，以前的RIT策略的效用有限。这种新方法对其他癌症中类似方法的优化具有意义。

DESCRIPTION (provided by applicant): Follicular non-Hodgkin's lymphoma is the most common indolent histologic subtype of lymphoma. With the exception of rare localized tumors, FL is thought not to be curable with standard therapeutic approaches; while most patients respond to treatment, relapses are the rule, and many patients will eventually die of their lymphoma. Standard treatment approaches have traditionally relied on combination chemotherapy, but this carries with it significant toxicities. Recently, interest has grown in development of non-chemotherapy approaches to FL treatment. Radioimmunotherapy (RIT) involves the conjugation of a radionuclide with a monoclonal antibody, allowing delivery of radiation based not on location of the lymphoma, as with external beam radiotherapy, but on expression of a cell-surface protein against which the RIT is targeted. The utility of RIT agents currently approved for use in recurrent indolent B cell NHL has been limited by two major factors, including immunogenicity of the antibody and limitations of delivered radiation dose related to the treatment protocol. Recent studies have highlighted the concept that administration of unlabeled and radiolabeled antibodies targeting the same antigen can cause suboptimal radiation targeting (due to competitive binding). The proposed study will explore a novel approach to RIT which optimizes radiation dose delivery to tumor (through use of unlabeled and radiolabeled agents targeting different antigens, CD20 and CD22 respectively) and minimizes immunogenicity (through humanization) by pursuing the following Specific Aims: 1) Determine the biodistribution, tumor localization and pharmacokinetics of radiolabeled epratuzumab therapy and determine any changes in targeting due to pretreatment with veltuzumab, and 2) Establish the safety and efficacy of fractionated 90Y-epratuzumab tetraxetan (anti-CD22) given in combination with veltuzumab (anti- CD20) in patients with previously untreated, intermediate or high risk FL. We anticipate that our approach will provide highly effective, tolerable treatment without use of chemotherapy, even in high risk patients. The modifications of RIT explored in this proposal could impact similar approaches in a broader context, including other histologies of lymphoma as well as other malignancies in which RIT is being explored. PUBLIC HEALTH RELEVANCE: Despite the availability of multiple therapeutic modalities and a high response rate to initial therapy, most patients with follicular lymphoma (FL) will develop recurrent or refractory disease and many will ultimately die from lymphoma-related complications. We propose to study a non-chemotherapeutic approach to initial therapy of FL involving a novel strategy of radioimmunotherapy (RIT) which addresses problems of radiation dose delivery and immunogenicity which have limited utility of previous RIT strategies. This novel approach has implications for optimization of similar approaches in other cancers.