Fractionated, Dual-targeted radioimmunotherapy for follicular lymphoma

描述(申请人提供)：滤泡性非霍奇金淋巴瘤是最常见的惰性组织学淋巴瘤亚型。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，但复发是常态，许多患者最终会死于淋巴瘤。标准的治疗方法传统上依赖于联合化疗，但这带来了显著的毒性。最近，人们对非化疗方法治疗FL的兴趣与日俱增。放射免疫治疗(RIT)包括将放射性核素与单抗结合，允许不像外照射那样根据淋巴瘤的位置进行放射治疗，而是根据RIT靶向的细胞表面蛋白的表达进行放射治疗。目前被批准用于复发性惰性B细胞NHL的RIT制剂的应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辐射剂量的限制。最近的研究强调了这样一个概念，即以同一抗原为靶点的未标记和放射性标记抗体可以导致次佳的辐射靶向(由于竞争结合)。这项拟议的研究将探索一种新的RIT方法，它可以优化肿瘤的辐射剂量传递(通过使用分别针对不同抗原CD20和CD22的未标记和放射性标记药物)，并通过追求以下特定目标将免疫原性降至最低：1)确定放射性标记epratuzumab治疗的生物分布、肿瘤定位和药代动力学，并确定由于veltuzumab预处理而导致的靶向变化；2)建立90Y-epratuzumab Tetxetan(anti-CD22)与veltuzumab(anti-CD20)联合应用于先前未治疗的、中危或高危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、可耐受的治疗，而无需使用化疗，即使是在高危患者中也是如此。本提案中探讨的RIT的修改可能会在更广泛的背景下影响类似的方法，包括其他淋巴瘤的组织学以及正在研究RIT的其他恶性肿瘤。 公共卫生相关性：尽管有多种治疗方法和对初始治疗的高应答率，但大多数滤泡性淋巴瘤(FL)患者会发展为复发或难治性疾病，许多人最终将死于淋巴瘤相关并发症。我们建议研究一种非化疗方法来进行FL的初始治疗，包括一种新的放射免疫治疗(RIT)策略，该策略解决了辐射剂量传递和免疫原性的问题，这些问题限制了以前的RIT策略的应用。这一新的方法对其他癌症的类似方法的优化具有借鉴意义。

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.