Developing Immune Based Therapies

该项目的第一个主要成就是记录rhIL-7在人体中的第二次试验的临床结果的出版物（Sportes等Clin Cancer Res.2010 Jan 15;16（2）：727-35）。我们之前的出版物（2008，J Exp Medicine）提供了广泛的生物学见解，通过IL-7治疗可以增强免疫重建并扩大库多样性。该手稿提供了相同试验的临床结果，这些结果对于rhIL 7的进一步临床开发至关重要。该手稿提供了药代动力学参数，证明rhIL 7诱导骨髓内早期B祖细胞的可逆扩增，以及外周血淋巴细胞亚群的变化。2010财年该项目的第二个主要成就是完成了大量工作，证明临床级主细胞库（KT 64. 41 BBL）能够支持外周血NK细胞的扩增。CD 137 L/IL 15 NK细胞介导高水平的肿瘤细胞毒性，并且基本上不受KIR信号传导的抑制。我们进一步证明，可以基于天然细胞毒性受体（NKp 30、NKp 40、NKp 44）的表达水平来预测CD 137 L/IL 15 NK细胞的杀伤活性。已经提交了一份概述这项工作的手稿。此外，这项工作已成为HLA匹配的造血干细胞移植后使用活化NK细胞进行过继治疗的临床试验的基础，该临床试验已完成NCI科学审查，已由NCI IRB审查，预计不久将开放。IND已提交给FDA，正在审查中。该项目在2010财年的第三个主要成就是继续入选临床试验，将我们的基础研究直接转化为针对高危儿童肉瘤患者的免疫治疗试验。这项工作密切遵循我们的临床前研究（Cui等，BLOOD 2009），证明Treg耗竭加稳态细胞因子的组合是支持基于抗肿瘤的过继细胞疗法的有效组合。NCI 07-c-0206试图通过施用已经耗尽TlR的T细胞（经由CD 25选择柱）在免疫重建期间诱导Treg耗尽。此外，2009年12月的一项修正案将rhIL 7纳入了该试验。因此，这是rhIL 7在儿童中的第一项研究，并允许我们直接测试我们的假设，即rhIL 7加Treg耗竭的组合是支持基于免疫的治疗的有效策略。到目前为止，共有25名患者入组，其中26名患者入组，11名患者已开始免疫治疗，而其他15名患者仍在接受标准治疗。初步结果显示，与先前在严重淋巴细胞减少症患者中的研究相比，无病生存期、良好的耐受性和显著的Treg耗竭是有希望的。

The first major accomplishment of this project was a publication documenting the clinical results of the second trial of rhIL-7 in humans (Sportes et al Clin Cancer Res. 2010 Jan 15;16(2):727-35) . Our previous publication (2008, J Exp Medicine) provided extensive biologic insight into the basis through which IL-7 therapy can augment immune reconstitution and broaden repertoire diversity. This manuscript provided the clinical results of the same trial that are essential for further clinical development rhIL7. The manuscript provides pharmacokinetic parameters, the demonstration that rhIL7 induces a reversible expansion in early B cell progenitors within the bone marrow, as well as changes in peripheral blood lymphocyte subsets. A second major accomplishment of this project during FY2010 was the completion of extensive work demonstrating that a clinical grade master cell bank (KT64.41BBL) is able to support expansion of NK cells from peripheral blood. The CD137L/IL15 NK cells mediate high level tumor cytotoxicity and are not inhibited substantial by KIR signaling. We further demonstrated that the killing activity of CD137L/IL15 NK cells can be predicted based upon the level of expression of the natural cytotoxicity receptors (NKp30, NKp40, NKp44). A manuscript summarizing this work has been submitted. Furthermore, this work has served as the basis for a clinical trial of adoptive therapy with activated NK cells following HLA matched hematopoietic stem cell transplantation that has completed NCI Scientific Review, has been reviewed by the NCI IRB and is expected to open shortly. An IND has been filed with the FDA and is under review. A third major accomplishment of this project during FY2010 was continued enrollment onto a clinical trial that directly translates our basic studies into an immune based therapy trial for patients with high-risk pediatric sarcomas. This work follows closely on our preclinical studies (Cui et al, BLOOD 2009) demonstrating that the combination of Treg depletion plus homeostatic cytokines is a potent combination for supporting antitumor based adoptive cell therapy. NCI 07-c-0206 seeks to induce Treg depletion during the period of immune reconstitution by administering T cells that have been depleted of Tregs (via a CD25 selection column). Furthermore, an amendment in December 2009 incorporated rhIL7 into this trial. Thus, this is the first study of rhIL7 in children and allows us to directly test our hypothesis that the combination of rhIL7 plus Treg depletion is a potent maneuver for supporting immune based therapies. Thus far, a total of 25 patients have been enrolled, with 26 patients enrolled and 11 having initiated immunotherapy, whereas the other 15 are still receiving standard therapy. Preliminary results show promising disease free survival, good tolerability and significant Treg depletion compared to previous studies in patients with profound lymphopenia.