Developing Immune Based Therapies

该项目的第一个主要成果是出版了一份记录重组人白细胞介素7在人类身上的第二次临床试验的临床结果的出版物(Sportes等人临床癌症研究，2010年1月15日；16(2)：727-35)。我们之前的出版物(2008年，J Exp Medicine)提供了广泛的生物学见解，揭示了IL-7治疗可以增强免疫重建和扩大曲目多样性的基础。这篇手稿提供了同一试验的临床结果，这对进一步的临床开发至关重要。这篇手稿提供了药代动力学参数，证明了重组人白介素7诱导骨髓内早期B细胞前体细胞的可逆扩张，以及外周血淋巴细胞亚群的变化。该项目在2010财年的第二个主要成就是完成了广泛的工作，证明临床级别的主细胞库(KT64.41BBL)能够支持从外周血中扩增NK细胞。CD137L/IL15 NK细胞介导高水平的肿瘤细胞毒作用，且不受KIR信号的明显抑制。我们进一步证明，根据天然细胞毒受体(NKp30、NKp40、NKp44)的表达水平，可以预测CD137L/IL15 NK细胞的杀伤活性。一份总结这项工作的手稿已经提交。此外，这项工作也是人类白细胞抗原相合的造血干细胞移植后用活化的NK细胞过继治疗的临床试验的基础，该试验已经完成了NCI的科学审查，已经由NCI IRB审查，预计很快就会开始。IND已经向FDA提交了申请，正在进行审查。该项目在2010财年的第三个主要成就是继续登记参加临床试验，该试验直接将我们的基础研究转化为针对高危儿科肉瘤患者的基于免疫的治疗试验。这项工作紧随我们的临床前研究(Cui等人，血液2009)，表明Treg耗竭和动态平衡细胞因子的组合是支持基于抗肿瘤的过继细胞治疗的有效组合。NCI 07-c-0206寻求在免疫重建期间通过给予已被耗尽Treg的T细胞(通过CD25选择柱)来诱导Treg耗竭。此外，2009年12月的一项修正案将重组人白细胞介素7纳入该试验。因此，这是第一次对儿童进行重组人白介素7的研究，并使我们能够直接测试我们的假设，即重组人白介素7和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名患者入选，其中26名患者入选，11名患者已开始免疫治疗，其余15名患者仍在接受标准治疗。初步结果显示，与之前的研究相比，在严重的淋巴细胞减少症患者中，无病存活、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.