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最常见的惰性淋巴瘤的组织学亚型。除了罕见的局部肿瘤外，FL被认为不能用标准的治疗方法治愈；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。传统的标准治疗方法依赖于联合化疗，但这带有明显的毒性。最近，人们对非化疗方法的发展越来越感兴趣。放射免疫疗法（RIT）涉及将放射性核素与单克隆抗体结合，不像外部放射治疗那样基于淋巴瘤的位置，而是基于RIT靶向的细胞表面蛋白的表达来进行放射治疗。目前批准用于复发性惰性B细胞NHL的RIT药物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放射剂量的限制。最近的研究强调了一个概念，即针对同一抗原的未标记抗体和放射性标记抗体可能导致次优辐射靶向（由于竞争结合）。该研究将探索一种新的RIT方法，通过使用针对不同抗原（分别为CD20和CD22）的未标记和放射性标记药物来优化肿瘤的辐射剂量递送，并通过追求以下具体目标来最小化免疫原性（通过人源化）：1)确定放射标记epratuzumab治疗的生物分布，肿瘤定位和药代动力学，并确定由于使用veltuzumab预处理而导致的靶向变化。2)确定分离90Y-epratuzumab四合坦（抗cd22）与veltuzumab（抗CD20）联合用于先前未治疗，中或高风险FL患者的安全性和有效性。我们预计我们的方法将提供高效，可耐受的不使用化疗的治疗，即使是高危患者。本提案中探索的RIT的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。

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.