Biology and Therapy of T Cell Depletion

Mackall实验室的主要目标是为儿童癌症开发有效的免疫疗法。该方法建立在我们在T细胞稳态生物学方面的专业知识基础上，以开发在淋巴细胞减少症阶段增强抗肿瘤免疫力的疗法，淋巴细胞减少症发生在几乎所有接受化疗的儿童癌症患者中。通过利用低肿瘤负荷和由于淋巴细胞减少症诱导的T细胞稳态变化而诱导对肿瘤抗原的应答的能力提高的组合，我们寻求使用肿瘤定向免疫疗法来巩固儿科癌症患者的缓解。研究受试者包括用于模拟淋巴细胞减少症期间发生的免疫生理学变化的小鼠，以及在儿科肿瘤学分支的IRB批准的临床试验中治疗侵袭性肿瘤的儿童和年轻人的血液样品。这项工作的主要成就可以用三份已发表的报告来概括。#1）（Melchionda等，J Clin Invest 2005）我们首次证明了IL 7疗法可以在短期和长期内有效地增强对免疫的应答，使得当与IL 7疗法同时进行免疫时发生的改善的免疫应答在细胞因子停止后持续很长时间。这些研究在小鼠中进行，并且还证明了与IL 7一起施用的肿瘤疫苗比在没有IL 7的情况下施用的疫苗能够更好地保护免受随后的肿瘤攻击。我们还观察到伴随IL 15治疗而非IL 2治疗的疫苗应答的类似增加。这些结果提供了强有力的证据，表明IL 7应被认为是在肿瘤疫苗的背景下临床使用的试剂。#2）（Zhang等，Nature Medicine，2005）通过仔细研究在化疗后用自体T细胞和肿瘤疫苗的输注（有或没有IL 2）治疗的儿童和年轻人中的免疫重建，我们发现特异性抑制性T细胞亚群（所谓的CD4+CD25+ T细胞亚群）响应于淋巴细胞减少症而显著增加。此外，在IL 2治疗被认为是可以在淋巴细胞减少症期间改善免疫功能的药剂的情况下，我们表明在这种情况下施用IL 2有效地扩增了T细胞的抑制性亚群。这一观察结果改变了范式，因为它证明了IL 2，一种以前被认为是免疫活化的试剂，也通过特异性CD 4 + CD 25+亚群调节具有有效的免疫抑制作用。#3）（Rosenberg等人，J of Immunoth，2006）在与NCI Surgery分支的合作研究中，完成了rhIL 7在人体中的首次临床试验，并提供了该试剂显著调节人体T细胞稳态的原理证明。此外，该研究表明，与增强抑制性T细胞的IL 2不同，IL 7增加CD4+ T细胞数量而不优先扩增抑制性亚群。这项早期试验提供了第一个证据，表明IL 7可能是人类调节T细胞稳态的有效和安全的药物。

The primary goal of the Mackall laboratory is to develop effective immune based therapies for pediatric cancer. The approach builds upon our expertise in the biology of T cell homeostasis to develop therapies that will enhance antitumor immunity during the phase of lymphopenia which occurs in nearly all patients which receive chemotherapy for childhood cancer. By exploiting the combination of low tumor burdens and the heightened capacity to induce responses to tumor antigens as a result of the changes in T cell homeostasis induced by lymphopenia, we seek to use tumor directed immunotherapies to consolidate remissions in patients with pediatric cancer. Research subjects include both mice which are used to model the changes in immune physiology which occur during lymphopenia and blood samples from children and young adults treated for aggressive tumors on IRB approved clinical trials in the Pediatric Oncology Branch. The primary accomplishments of this work can be summarized by three published reports. #1) (Melchionda et al, J Clin Invest 2005) We demonstrated for the first time that IL7 therapy can potently augment responses to immunization both in the short term and the long term, such that the improved immune responses that occur when immunization is undertaken at the same time as IL7 therapy lasts long after the cytokine is discontinued. These studies were performed in mice and also demonstrated that a tumor vaccine administered with IL7 was better able to protect against subsequent tumor challenge than a vaccine administered without IL7. We also saw similar increases in vaccine responses with concomitant IL15 therapy but not with IL2 therapy. These results provide firm evidence that IL7 should be considered as agent for clinical use in the context of tumor vaccines. #2) (Zhang et al, Nature Medicine, 2005) By careful study of immune reconstitution in children and young adults treated with infusions of autologous T cells and tumor vaccines, with or without IL2 following chemotherapy, we discovered that a specific suppressive subset of T cells (so-called CD4+CD25+ Tregs) are substantially increased in response to lymphopenia. Furthermore, where IL2 therapy was considered to be an agent which could improve immune function during lymphopenia, we showed that administration of IL2 in this setting potently expanded the suppressive subset of T cells. This observation is paradigm changing in that it demonstrates that IL2, an agent which was previously assumed to be immune activating, also have potent immunosuppressive effects via the specific CD4+CD25+ subset regulation. #3) (Rosenberg et al., J of Immunoth, 2006) In a collaborative study with the NCI Surgery Branch, the first clinical trial of rhIL7 in humans was completed and provided proof of principle that this agent dramatically modulates T cell homeostasis in humans. Furthermore, the study demonstrated that unlike IL2 which augments suppressive T cells, IL7 increases CD4+ T cell numbers without preferentially expanding the suppressive subset. This early phase trial provides the first evidence the IL7 may be an effective and safe agent in humans to modulate T cell homeostasis.