Biology and Therapy of T Cell Depletion

T 细胞耗竭的生物学和治疗

• 批准号: 7594808
• 负责人: CRYSTAL L MACKALL
• 金额: $ 98.46万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594808
• 关键词: Adolescent; Adoptive Immunotherapy; Adult; Age; American Society of Hematology; Animals; Apoptosis; Ascaridil; Autologous Stem Cell Transplantation; B-Lymphocytes; Biology; Blood; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cancer Patient; Cancer Vaccines; Cell Count; Cell Cycle; Cells; Chemotherapy-Oncologic Procedure; Child; Childhood; Clinical; Clinical Trials; Competence; Cytotoxic Chemotherapy; Dendritic Cell Vaccine; Development; Disease; Disease remission; Dose; Effectiveness; Elderly; Enrollment; Evaluation; Event; Ewings sarcoma; Family; Glean; Goals; Growth; HIV Infections; Highly Active Antiretroviral Therapy; Homeostasis; Human; IL2 gene; IL7 gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Immunosuppression; Immunotherapy; Infection prevention; Interleukin 7 Receptor; Interleukin-2; Interleukin-7; Laboratories; Life; Lymphocyte; Lymphocyte Depletion; Lymphopenia; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Medicine; Metastatic Osteosarcoma; Metastatic/Recurrent; Microscopic; Modeling; Mus; Nature; Neoplasm Metastasis; Neuroblastoma; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physiology; Population; Primary Neoplasm; Process; Protocols documentation; Publications; Publishing; Recovery; Recurrence; Refractory; Regulation; Reporting; Research Ethics Committees; Research Subjects; Rhabdomyosarcoma; Series; Solid; Suppressor-Effector T-Lymphocytes; T-Cell Depletion; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Time; Tissues; Toxic effect; Transplantation; Tumor Antigens; Tumor Burden; United States Food and Drug Administration; United States National Institutes of Health; Viral; Woman; Work; age effect; anti aging; base; chemotherapy; follow-up; improved; insight; malignant breast neoplasm; mouse model; normal aging; osteosarcoma; pre-clinical; prevent; reconstitution; response; sarcoma; success; tumor; young adult

Building upon our expertise in the biology of T cell homeostasis, we seek to develop therapies that will enhance antitumor immunity during the phase of lymphopenia, which occurs in nearly all patients who 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 remission in patients with pediatric cancer. Research subjects include mice, used to model the changes in immune physiology which occur during lymphopenia, and children, young adults and adults with lymphopenia as a result of cancer chemotherapy or HIV infection, treated on IRB approved clinical trials in the NIH Clinical Center. Recent major accomplishments of this project prior to 2006 can be summarized by two reports: #1) In Melchionda et al, J Clin Invest 2005, we demonstrated for the first time that IL7 therapy can potently augment responses to immunization, thus providing solid evidence that IL7 should be considered as agent for clinical use in the context of tumor vaccines. #2) In Zhang et al, Nature Medicine, 2005, we demonstrated that a specific suppressive subset of T cells (so-called CD4+CD25+ Tregs) increase in response to lymphopenia and administration of IL2 in this setting further expanded the suppressive subset of T cells. This observation was paradigm changing since it demonstrated that IL2, an agent previously assumed to be immune activating, had potent immunosuppressive effects. As a result of this work, we have focused our efforts of specifically manipulating Treg populations in lymphopenic hosts as a way of augmenting the effectiveness of immunotherapy in this setting. During the past year, two major accomplishments were the completion of the first two clinical trials of rhIL7. Results from the first completed trial were published as part of a collaborative study with the NCI Surgery Branch (Rosenberg et al., J of Immunoth, 2006). It provided proof-of-principle that IL-7 dramatically modulates T cell homeostasis in humans and demonstrated that, unlike IL2, which augments suppressive T cells, IL7 increases CD4+ T cell numbers without preferentially expanding the suppressive subset. However, because this study did not provide significant insight into the mechanisms by IL-7 exerts its effects, we also undertook a second Phase I trial in patients with refractory cancer. This study incorporated extensive biologic studies that provided remarkable insight into the basis for the dramatic changes in T cell homeostasis induced by IL-7. Most notably, we observed that IL-7 causes a broad repertoire of T cells to undergo cell cycling and to resist programmed cell death, resulting in rapid, significant expansion of both blood and tissue T cells. The expansion is tightly regulated by dynamic regulation of the IL7 receptor, thus preventing dangerous increases in lymphocyte with IL7 therapy. Because IL7 selectively expands the youngest or most nave T cell populations, T cells in IL7 treated patients resembled T cells normally present at young ages. Thus, IL7 has an anti-aging effect on the immune system. This capacity to expand a broad pool of nave cells is predicted to be very important for immune competence, especially in the context of T cell depletion. Most importantly, we saw little to no evidence of toxicity with IL-7, providing a solid basis for Phase II trials of this agent in combination with directed immunotherapy. This work has been submitted for publication. A third major accomplishment was completion of a series of studies demonstrating the successes and limitation of immune reconstitution in children in a variety of clinical settings by conducting detailed immunologic evaluation of varied clinical populations, and therefore represented collaborative projects. They build on previous work by our group published in the 1990s demonstrating profound lymphopenia in children and young adults treated with chemotherapy for cancer and a recent collaborative study (Hakim, J Clin Invest 2005) demonstrating that adult women treated for breast cancer with autologous stem cell transplantation show prolonged incomplete recovery of CD4+ T cell populations. In the first study, we studied adolescents and young adults 4-30 years after completion of dose intensive therapy for pediatric sarcomas. Remarkably, all successfully restored lymphocyte homeostasis (Br J Haematol. 2006 Oct;135(2):270-1). This is in direct contrast to studies in older adults, where prolonged follow-up did not show evidence of full immune reconstitution in substantial percentages of patients over age 40 at the time of lymphocyte depletion. Together, this work provides further evidence that age is the central factor determining the extent of immune reconstitution that occurs in human beings, even with prolonged follow-up. We also published a collaborative study in children undergoing HAART for HIV infection, which also demonstrated remarkably good capacity to restore immune responses: (Viral Immunol. 2007 Spring;20(1):131-41). Finally, we studied immune reconstitution in children and young adults treated with a non-myeloablative bone marrow transplantation and observed remarkably early thymic-dependent immune reconstitution, which was more rapid and complete that observed following myeloablative transplants and following adult patients treated on a similar study. This study, which has been presented at the American Society of Hematology meeting in December 2006, is currently being prepared for publication. In studies aimed at applying the principles gleaned regarding immune reconstitution to antitumor imunotherapy, we published the first evidence that immune reconstitution can prevent metastatic recurrence of osteosarcoma. This was performed using a mouse model wherine differential effects of the immune system on bulky primary tumors could be distinguished from effects on microscopic disease. Remarkably, while a fully recovered immune system did not impact growth of primary tumors, rapid immune reconstitution dramatically reduced the development of metastatic osteosarcoma (Merchant, 2006, Cancer Immunol Immunoth). This observation serves as the basis for ongoing development of multiple new tumor models in our laboratory which more accurately reflect the process of spontaneous metastases and will allow us to evaluate and optimize immunotherapies based upon their effects on metastatic disease, which is most highly relevant to the clinical setting. Finally, during the past year we completed the arduous process of developing a new clinical trial of immunotherapy for pediatric sarcomas. This required extensive reviews multiple committees at the NCI as well as the approval of an Institutional New Drug Application at the FDA. This protocol has already enrolled its first patient and will directly apply the principles gleaned from our animal studies to determine whether combining immune reconstitution, depletion of suppressor T cells and the administration of dendritic cell vaccines will improve outcomes for patients with metastatic and recurrent Ewings sarcoma family of tumors, rhabdomyosarcoma and neuroblastoma

基于我们在 T 细胞稳态生物学方面的专业知识，我们寻求开发能够增强淋巴细胞减少症阶段抗肿瘤免疫力的疗法，这种情况几乎发生在所有接受儿童癌症化疗的患者身上。通过利用低肿瘤负荷和因淋巴细胞减少引起的 T 细胞稳态变化而增强的诱导肿瘤抗原反应的能力，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。研究对象包括用于模拟淋巴细胞减少期间发生的免疫生理学变化的小鼠，以及因癌症化疗或 HIV 感染而导致淋巴细胞减少的儿童、年轻人和成人，并在 NIH 临床中心接受 IRB 批准的临床试验治疗。该项目在 2006 年之前的最新主要成就可以通过两份报告来总结：#1) 在 Melchionda 等人的 J Clin Invest 2005 中，我们首次证明 IL7 疗法可以有效增强免疫反应，从而提供了坚实的证据，表明 IL7 应被视为肿瘤疫苗临床应用的制剂。 #2) 在Zhang等人的《自然医学》，2005年中，我们证明了T细胞的特定抑制亚群（所谓的CD4+CD25+ Tregs）响应淋巴细胞减少而增加，并且在这种情况下施用IL2进一步扩大了T细胞的抑制亚群。这一观察结果改变了范式，因为它证明了 IL2（一种以前被认为具有免疫激活作用的药物）具有强大的免疫抑制作用。作为这项工作的结果，我们集中精力专门操纵淋巴细胞减少宿主中的 Treg 群体，作为增强这种情况下免疫疗法有效性的一种方法。在过去的一年里，两项重大成就是完成了rhIL7的前两项临床试验。第一个已完成试验的结果作为与 NCI 外科分部合作研究的一部分发表（Rosenberg 等人，J of Immunoth，2006 年）。它提供了原理证明，即 IL-7 可以显着调节人类 T 细胞稳态，并证明与增强抑制性 T 细胞的 IL2 不同，IL7 会增加 CD4+ T 细胞数量，而不会优先扩大抑制性子集。然而，由于这项研究没有对 IL-7 发挥作用的机制提供重要的见解，我们还在难治性癌症患者中进行了第二项 I 期试验。这项研究结合了广泛的生物学研究，为 IL-7 诱导 T 细胞稳态发生巨大变化的基础提供了深刻的见解。最值得注意的是，我们观察到 IL-7 导致广泛的 T 细胞进行细胞循环并抵抗程序性细胞死亡，从而导致血液和组织 T 细胞快速、显着扩增。这种扩增受到 IL7 受体动态调节的严格调节，从而防止 IL7 治疗导致淋巴细胞出现危险的增加。由于 IL7 选择性地扩增最年轻或最原始的 T 细胞群，因此接受 IL7 治疗的患者中的 T 细胞类似于年轻时通常存在的 T 细胞。因此，IL7对免疫系统具有抗衰老作用。预计这种扩大天然细胞库的能力对于免疫能力非常重要，特别是在 T 细胞耗竭的情况下。最重要的是，我们几乎没有看到 IL-7 毒性的证据，这为该药物与定向免疫疗法相结合的 II 期试验提供了坚实的基础。该作品已提交出版。第三个主要成就是完成了一系列研究，通过对不同临床人群进行详细的免疫学评估，证明了儿童在各种临床环境中免疫重建的成功和局限性，因此代表了合作项目。它们建立在我们小组于 20 世纪 90 年代发表的先前工作的基础上，该研究表明接受癌症化疗的儿童和年轻人会出现严重的淋巴细胞减少症，最近的一项合作研究（Hakim，J Clin Invest 2005）表明，通过自体干细胞移植治疗乳腺癌的成年女性表现出 CD4+ T 细胞群长期不完全恢复。在第一项研究中，我们研究了儿童肉瘤剂量强化治疗完成后 4-30 年的青少年和年轻人。值得注意的是，所有这些都成功恢复了淋巴细胞稳态（Br J Haematol. 2006 Oct；135(2):270-1）。这与针对老年人的研究形成鲜明对比，在老年人中进行的长期随访并未显示出大量 40 岁以上患者在淋巴细胞耗竭时完全免疫重建的证据。总之，这项工作提供了进一步的证据，表明年龄是决定人类免疫重建程度的核心因素，即使是长期随访也是如此。我们还发表了一项针对接受 HAART 治疗 HIV 感染的儿童的合作研究，该研究也证明了其恢复免疫反应的良好能力：（Viral Immunol. 2007 Spring；20(1):131-41）。最后，我们研究了接受非清髓性骨髓移植治疗的儿童和年轻人的免疫重建，并观察到明显早期的胸腺依赖性免疫重建，这比清髓性移植后和接受类似研究的成年患者观察到的更快、更完整。这项研究已于 2006 年 12 月在美国血液学会会议上发表，目前正在准备出版。在旨在将免疫重建的原则应用于抗肿瘤免疫治疗的研究中，我们发表了第一个证据表明免疫重建可以预防骨肉瘤的转移性复发。这是使用小鼠模型进行的，其中免疫系统对大块原发性肿瘤的不同影响可以与对微观疾病的影响区分开来。值得注意的是，虽然完全恢复的免疫系统不会影响原发性肿瘤的生长，但快速免疫重建显着减少了转移性骨肉瘤的发展（Merchant，2006，CancerImmunolImmunoth）。这一观察结果是我们实验室持续开发多种新肿瘤模型的基础，这些模型更准确地反映自发转移的过程，并使我们能够根据免疫疗法对转移性疾病的影响来评估和优化免疫疗法，这与临床环境高度相关。最后，在过去的一年里，我们完成了开发儿童肉瘤免疫疗法新临床试验的艰巨过程。这需要 NCI 多个委员会的广泛审查以及 FDA 机构新药申请的批准。该方案已经招募了第一位患者，并将直接应用从我们的动物研究中收集到的原理，以确定免疫重建、抑制性 T 细胞耗竭和树突状细胞疫苗的施用相结合是否会改善转移性和复发性尤文氏肉瘤家族肿瘤、横纹肌肉瘤和神经母细胞瘤患者的预后

项目成果

Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8+ memory cell pool.

• DOI: 10.1172/jci23134
• 发表时间: 2005-05
• 期刊: The Journal of clinical investigation
• 作者: F. Melchionda;T. Fry;Matthew Milliron;Melissa A McKirdy;Y. Tagaya;C. Mackall

Thymic function in HIV infection.

• DOI: 10.1007/s11904-996-0005-2
• 发表时间: 2005-02-01
• 期刊: Current HIV/AIDS reports
• 影响因子: 4.6
• 作者: Hazra, Rohan;Mackall, Crystal
• 通讯作者: Mackall, Crystal

Cancer therapy-induced immune modulation.

癌症治疗诱导的免疫调节。

• 发表时间: 2005
• 期刊: Cancer chemotherapy and biological response modifiers
• 作者: Karl,JessicaC;Mackall,CrystalL
• 通讯作者: Mackall,CrystalL

Highlights of the First International "Immunotherapy in Pediatric Oncology: Progress and Challenges" Meeting.

首届国际“小儿肿瘤免疫治疗：进展与挑战”会议亮点。

• DOI: 10.1097/mph.0b013e31819a5d8d
• 发表时间: 2009
• 期刊: Journal of pediatric hematology/oncology
• 作者: Capitini,ChristianM;Cooper,LaurenceJN;Egeler,RMaarten;Handgretinger,Rupert;Locatelli,Franco;Sondel,PaulM;Mackall,CrystalL
• 通讯作者: Mackall,CrystalL

Prolonged CD4 depletion after sequential autologous peripheral blood progenitor cell infusions in children and young adults.

• DOI: 10.1182/blood.v96.2.754
• 发表时间: 2000-07
• 期刊: Blood
• 影响因子: 20.3
• 作者: C. Mackall;D. Stein;T. Fleisher;Margaret R. Brown;F. Hakim;C. Bare;S. Leitman;E. Read;C. Carter;L. Wexler;R. Gress