Biology and Therapy of T Cell Depletion

麦考尔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，开发出在淋巴细胞减少期增强抗肿瘤免疫的疗法，淋巴细胞减少期几乎发生在所有接受化疗的儿童癌症患者身上。通过利用淋巴细胞减少引起的T细胞稳态改变所导致的肿瘤负荷低和诱导对肿瘤抗原反应的能力增强的结合，我们寻求使用肿瘤定向免疫疗法来巩固儿童癌症患者的缓解。研究对象包括用于模拟淋巴细胞减少期间发生的免疫生理变化的小鼠，以及在儿科肿瘤科进行的经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本。这项工作的主要成果可以用三份已发表的报告来概括。#1) （Melchionda等人，J clininvest 2005）我们首次证明了il - 7治疗可以在短期和长期内有效地增强免疫应答，因此，当il - 7治疗同时进行免疫接种时，免疫应答的改善在细胞因子停止后持续很长时间。这些研究是在小鼠身上进行的，也证明了与不含il - 7的疫苗相比，含有il - 7的肿瘤疫苗能够更好地保护肿瘤免受后续的攻击。我们还发现，同时使用il - 15治疗的疫苗应答也有类似的增加，而使用il - 2治疗的疫苗应答没有类似的增加。这些结果提供了确凿的证据，表明il - 7应被考虑作为肿瘤疫苗的临床使用。#2) （Zhang等人，Nature Medicine, 2005）通过仔细研究在化疗后输注自体T细胞和肿瘤疫苗治疗的儿童和年轻人的免疫重建，有或没有il - 2，我们发现T细胞的一个特定抑制亚群（所谓的CD4+CD25+ Tregs）在淋巴细胞减少的反应中显着增加。此外，当il - 2治疗被认为是一种可以在淋巴细胞减少时改善免疫功能的药物时，我们发现在这种情况下，il - 2治疗可以有效地扩大T细胞的抑制性亚群。这一观察结果是范式的改变，因为它证明了il - 2，一种以前被认为是免疫激活的药物，也通过特异性CD4+CD25+亚群调节具有强大的免疫抑制作用。#3) （Rosenberg et al., J of Immunoth, 2006）在与NCI外科分会的合作研究中，完成了rhIL7在人体中的首次临床试验，并提供了该药物显著调节人体T细胞稳态的原理证明。此外，该研究表明，与IL2增加抑制性T细胞不同，IL7增加CD4+ T细胞数量而不优先扩大抑制性亚群。这项早期试验提供了第一个证据，证明il - 7可能是一种有效而安全的人体调节T细胞稳态的药物。

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.