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

项目3旨在解决非霍奇金滤泡性淋巴瘤(FL)的高复发率问题 免疫细胞因子(ICK)联合利妥昔单抗和单次分割放射治疗。我们已经开发出 并生产了由去免疫的抗CD20小鼠组成的临床试用级免疫细胞因子 单抗(Leu16)与两个IL2分子融合。DI-Leu16-IL2(IND100885)已被 对两名B细胞NHL患者使用，毒性低，免疫活性好。这 该项目提出了三个具体目标来评估DI-Leu16-IL2治疗的有效性和安全性。 具体目标1：进行DI-Leu16-IL2联合利妥昔单抗和Single的中试阶段研究 受累部位--滤泡性非霍奇金淋巴瘤的野放射治疗。试验的主要目的是 选择DI-Leu16-IL2的治疗方案和剂量。与利妥昔单抗和单组分联合给药时 放射治疗(XRT)，在保持安全性的同时，产生更有利的免疫反应。这个 次要目标是描述其安全性、耐受性。和DI-Leu16-IL2的毒性分布，在 联合利妥昔单抗和XRT。 具体目标2：进行DI-Leu16-IL2联合利妥昔单抗和Single的II期研究 受累部位--滤泡性非霍奇金淋巴瘤的野放射治疗。在这个目标上。我们将进行两个中心的 第二阶段试验针对至少一种先前方案后复发或进展的FL患者。这个 主要目的是确定DI-Leu16-IL2与利妥昔单抗联合应用时的抗肿瘤活性。 以总有效率(CR+PR)评价单次放射治疗。 具体目标3：利用标记的DI-Leu16-IL2评价DI-Leu16-IL2的生物分布。这个 本研究的主要目标是评估DI-Leu16-IL2在DL-Leu16-IL2中的生物分布。 次要目标是获得初步数据，探索DI-Leu16-IL2之间可能的联系 摄取和FDG图像(治疗前和治疗后)和肿瘤反应。 意义：这种基于ICK的非移植疗法，如果能够改善患者的反应持续时间 滤泡性淋巴瘤，由于这种疾病的患病率增加，将对临床产生重大影响 疾病。联合治疗的低毒性特征将对老年患者特别有益。 创新：我们通过DL-Leu16-1L2靶向根除滤泡性淋巴瘤的方法 免疫细胞因子与单组分局部照射相结合，在设计和实现上都是新颖的。 我们已经制造了自己的DI-Leu16-IL2，获得了FDA的批准，并开始了初步测试 这种很有希望的试剂。在这种免疫疗法中加入低剂量辐射的假设是 增强对DI-Leu16-IL2治疗的免疫应答，而没有明显的额外毒性。

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.