Humanized Anti-CD20-IL2 for the Treatment of CD20 Positive Lymphomas

项目3旨在解决高复发率的非霍奇金滤泡性淋巴瘤（FL）使用 免疫细胞因子（ICK）治疗与利妥昔单抗和单次放疗的组合。我们已经开发 制备了一种临床试验级的免疫细胞因子， 单克隆抗体（Leu 16）与两个IL 2分子融合。DI-Leu 16-IL 2（IND 100885）已 向两名患有B细胞NHL的患者施用，并表现出低毒性和良好的免疫活化。这 该项目提出了三个具体目标来评估DI-Leu 16-IL 2治疗的有效性和安全性。 具体目的1：进行DI-Leu 16-IL 2联合利妥昔单抗和单用 分次累及野放射治疗滤泡性NHL。试验的主要目的是 选择DI-Leu 16-IL 2的给药方案和剂量。当与利妥昔单抗和单一组分联合给药时 辐射（XRT），产生更有利的免疫反应，同时保持安全性。的 次要目的是描述安全性、耐受性。DI-Leu 16-IL 2的毒性特征， 利妥昔单抗和XRT的组合。 具体目标2：进行DI-Leu 16-IL 2联合利妥昔单抗和单用利妥昔单抗的II期研究 分次累及野放射治疗滤泡性NHL。在这个目标。我们将进行一次双中心的 在至少一种既往治疗方案后复发或进展的FL患者中进行的II期试验。的 主要目的是确定DI-Leu 16-IL 2与利妥昔单抗联合时的抗肿瘤活性， 单次放疗，根据总体缓解率（CR+PR）评估。 具体目的3：使用111 In标记的DI-Leu 16-IL 2评价DI-Leu 16-IL 2的生物分布。的 本研究的主要目的是在D1-Leu 16-IL 2中使用“^”来评估D1-Leu 16-IL 2的生物分布。的 第二个目标是获得初步数据，探索DI-Leu 16-IL 2之间可能的关联， 摄取和FDG图像（治疗前和治疗后）和肿瘤反应。 意义：这种基于非移植的IK治疗，如果能够改善患者的缓解持续时间 与滤泡性淋巴瘤，将有一个显着的临床影响，由于日益增加的患病率，这 疾病联合治疗的低毒性特征在老年患者中尤其有益。 创新：我们的方法通过Dl-Leu 16 - 1 L2靶向根除滤泡性淋巴瘤 免疫细胞因子协同单次局部照射在其设计和实施上都是新颖。 我们已经生产了自己的DI-Leu 16-IL 2，获得FDA批准并开始初步测试 这个有前途的试剂。假设在这种免疫疗法中加入低剂量照射， 增强对DI-Leu 16-IL 2治疗的免疫应答，而没有显著的额外毒性。

Project 3 seeks to address the high relapse rate of non-Hodgkin follicular lymphoma (FL) using immunocytokine (ICK) therapy combined with rituximab and single fraction radiation. We have developed and produced a clinical-trial grade immunocytokine composed of de-immunized anti-CD20 mouse monoclonal antibody (Leu16) fused with two IL2 molecules. DI-Leu16-IL2 (IND100885) has been administered to two patients with B-cell NHL and exhibits low toxicity with good immune activation. This project proposes three specific aims to assess the effectiveness and safety of DI-Leu16-IL2 therapy. Specific Aim 1: Perform a Pilot-Phase I study of DI-Leu16-IL2 combined with rituximab and single fraction involved-field radiation for treatment of follicular NHL. The primary objective of the trial is to select the schedule and dose of DI-Leu16-IL2. when given in combination with rituximab and single fraction radiation (XRT) that yields the more favorable immunologic response while maintaining safety. The secondary objective is to describe the safety, tolerability. and toxicity profile of DI-Leu16-IL2, given in combination with rituximab and XRT. Specific Aim 2: Perform a Phase II study of DI-Leu16-IL2 combined with rituximab and single fraction involved-field radiation for treatment of follicular NHL. In this aim. we will conduct a two-center Phase II trial of patients with FL who have relapsed or progressed after at least one prior regimen. The primary objective is to determine the anti-tumor activity of DI-Leu16-IL2 when combined with rituximab and single fraction radiation as assessed by overall response rate (CR+PR). Specific Aim 3: Evaluate the Biodistribution of DI-Leu16-IL2 using ^^^In labeled DI-Leu16-IL2. The primary goal of this study is to assess the biodistribution of DI-Leu16-IL2 using '^''in Dl-Leu16-IL2. The secondary goal is to obtain preliminary data that explores the possible association between DI-Leu16-IL2 uptake and FDG images (pre- and post- therapy) and tumor response. Significance: This non-transplant ICK-based therapy, if able to improve response duration for patients with follicular lymphoma, would have a significant clinical impact due to the increasing prevalence of this disease. The low toxicity profile of the combined treatment would be especially beneficial in older patients. Innovation: Our approach to targeted eradication of follicular lymphoma via the Dl-Leu16-1L2 immunocytokine in concert with single fraction local irradiation is novel in both its design and implementation. We have manufactured our own DI-Leu16-IL2, obtained FDA approval and commenced preliminary testing of this promising reagent. The addition of low-dose irradiation to this immunotherapy is hypothesized to enhance the immunologic response to DI-Leu16-IL2 treatment without significant additional toxicity.