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基于免疫的治疗方法。这种方法建立在我们在T细胞稳态生物学方面的专业知识的基础上，开发出在淋巴细胞减少阶段增强抗肿瘤免疫的治疗方法，淋巴细胞减少阶段几乎所有接受儿童癌症化疗的患者都会发生这种情况。通过利用低肿瘤负荷和由于淋巴细胞减少引起的T细胞稳态变化而增强的对肿瘤抗原的反应的组合，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。研究对象包括用来模拟淋巴细胞减少期间发生的免疫生理变化的小鼠，以及在儿科肿瘤科通过IRB批准的临床试验治疗侵袭性肿瘤的儿童和年轻人的血液样本。这项工作的主要成就可以用三份已发表的报告来概括。#1)(Melchionda等人，J Clin Invest 2005)我们首次证明了IL7疗法可以在短期和长期内有效地增强免疫反应，因此，当免疫与IL7疗法同时进行时，所发生的改善的免疫反应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，也证明了注射了IL7的肿瘤疫苗比不注射IL7的疫苗能够更好地预防后续的肿瘤攻击。我们也看到同时使用IL15治疗的疫苗应答率有类似的增加，但IL2治疗没有。这些结果提供了确凿的证据，表明IL7应该被考虑作为肿瘤疫苗的临床使用试剂。#2)(Zhang等，自然医学，2005)通过仔细研究化疗后注射自体T细胞和肿瘤疫苗的儿童和年轻人的免疫重建，无论有没有IL2，我们发现T细胞的一个特定抑制亚群(所谓的CD4CD25Tregs)显著增加，以应对淋巴细胞减少。此外，在IL2治疗被认为是一种可以改善淋巴细胞减少期间免疫功能的药物的情况下，我们发现在这种情况下使用IL2可以有效地扩大T细胞的抑制亚群。这一观察结果是一种范式改变，因为它表明IL2，一种以前被认为是免疫激活的药物，也通过特定的CD4CD25亚群调节而具有强大的免疫抑制作用。#3)(Rosenberg等人，免疫学杂志，2006年)在与NCI外科分部的一项合作研究中，重组人白细胞介素7在人类身上的第一次临床试验已经完成，并提供了该药显著调节人类T细胞动态平衡的原理证据。此外，研究表明，与增强抑制性T细胞的IL2不同，IL7增加了CD4T细胞的数量，而不优先扩大抑制性亚群。这一早期试验提供了第一个证据，IL7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.