Manipulation of Immune Responsiveness after Hematopoietic Cell Transplantation

造血细胞移植后免疫反应的调控

• 批准号: 8656484
• 负责人: JEROME RITZ
• 金额: $ 70万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-08 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656484
• 关键词: Address; Adoptive Transfer; Allogenic; Antibodies; Antigens; Autologous Tumor Cell; CTLA4 gene; Calcineurin inhibitor; Cancer Vaccines; Cell Survival; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Disease; Dose; Double-Blind Method; Granulocyte-Macrophage Colony-Stimulating Factor; Homeostasis; Human; Immune; Immune response; Immunologics; In Vitro; Instruction; Interleukin-2; Laboratories; Lead; Ligands; Link; Malignant - descriptor; Mediating; Monoclonal Antibodies; Myeloproliferative disease; Outcome; Patients; Phase; Placebo Control; Population; Prevention therapy; Progression-Free Survivals; Randomized; Randomized Controlled Trials; Recurrent disease; Refractory; Regulatory T-Lymphocyte; Relapse; Role; Safety; Side; Signal Transduction; Site; Staging; Steroids; T-Lymphocyte; Testing; Therapeutic; Tissues; Transplantation; Vaccination; Vaccines; attenuation; base; cancer cell; chronic graft versus host disease; clinical practice; design; disorder later incidence prevention; graft vs host disease; hematopoietic cell transplantation; high risk; immunoregulation; improved; in vivo; innovation; insight; interest; leukemia; neoplastic cell; novel strategies; outcome forecast; prospective; randomized placebo controlled trial; randomized trial; reconstitution; response; success; tumor

Gaining control over immune responsiveness is critical to the success of allogeneic hematopoietic cell transplantation (HCT). Immune responses of donor cells against host antigens lead to both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). Insufficient donor immune response against host malignant cells permits tumor cell survival. Alternatively, immune reactivity against normal host tissues can lead to fatal GVHD. Project 1 is devoted to clinical trials that are designed to manipulate post-transplant immune reactivity either to target malignant leukemia cells or to enhance regulatory T cell activity to suppress GVH. These trials extend our previous laboratory and clinical observations and are intended to help establish the role of these strategies in clinical practice. In Specific Aim 1. we will focus on the prevention of disease recurrence post-HCT in high risk populations with advanced myeloid malignancies. We have, previously demonstrated that GM-CSF based tumor vaccines in a lymphopenic milieu early after allo- HCT can safely induce GVL responses despite concurrent treatment with calcineurin inhibitors. We now plan to more rigorously test the clinical impact of this strategy by performing a prospective double blind randomized study in patients entering transplant with active disease. Induction of immune responses must be sustained in order to maintain anti-tumor surveillance. There are a number of countermeasures which can suppress these immune responses and may limit the therapeutic potency of vaccination. One such mechanism is the attenuation of T cell function by the interaction of negative regulatory molecules, such as CTLA4, with their ligands. Specific Aim 2 will focus on patients who have relapsed after allo-HCT and will investigate the safety and clinical consequences of antibody blockade of CTLA4 with ipilumumab in the post- relapse setting alone and in conjunction with GM-CSF based vaccination. Specific Aim 3 will address the flip side of immune reactivity post-HCT, namely the indiscriminate host directed consequences of chronic GVHD. Regulatory T cells (Treg) downregulate immune responses. Treg deficiency is linked to chronic GVHD. There is considerable clinical interest in restoring Treg number and activity in these patients. Low dose interleukin-2 (IL-2) delivers a proliferative signal to Treg. We have demonstrated that low doses of 1-2 can be safely administered to patients with chronic GVHD (cGVHD) and can selectively expand Treg in vivo. Initial results indicate that this strategy can induce clinically meaningful responses. We plan to formally test the clinical and immunologic response of low dose lL-2 in a phase 2 clinical study in steroid refractory cGVHD patients alone and in combination with adoptive transfer of freshly isolated donor Treg. The integrated strategy in this application will yield important new insights into the immunologic impact and relevance of GM-CSF based vaccination and the role of counter-regulatory forces mediated by Treg and molecules such as CTLA4 in tumor and host direct immune responses in humans. Dr. Ritz and I have collaborated on immune modulation transplantation for over two decades and we anticipate our partnership will continue to be extremely productive. '" RELEVANCE (See instructions): Discovering how to manipulate donor derived immune responses holds the key to improving results of allo- HCT and is the central theme of this R01 submission. The clinical trials proposed in Aims 1 and 2 and are built upon accomplishments in the past 5 years and are designed to rigorously test innovative strategies to induce and sustain anti-tumor reactivity in patients with relapsed disease or at high risk for relapse. The trials planned for Aim 3 will assess novel approaches to GVH therapy and prevention by expanding regulatory T cells in vivo. Successful modulation of immune responses will have a profound impact on outcome of transplantation and could have implications in other disease settings. PROJECT/PERFORMANGE SITE(S) (if additional space is needed, use Project/Perfonnance Site Fonnat Page)

控制免疫反应对于同种异体造血细胞的成功至关重要 移植（HCT）。供体细胞针对宿主抗原的免疫反应导致移植物抗宿主 疾病（GVHD）和移植物抗白血病（GVL）。供体对宿主的免疫反应不足 恶性细胞允许肿瘤细胞存活。或者，针对正常宿主组织的免疫反应可以 导致致命的GVHD。项目 1 致力于旨在操纵移植后的临床试验 免疫反应要么针对恶性白血病细胞，要么增强调节性 T 细胞活性 抑制GVH。这些试验扩展了我们之前的实验室和临床观察，旨在 帮助确立这些策略在临床实践中的作用。在具体目标 1 中，我们将重点关注 预防晚期骨髓恶性肿瘤高危人群 HCT 后疾病复发。我们 之前已经证明，基于 GM-CSF 的肿瘤疫苗在淋巴细胞减少环境中很早就出现了 尽管同时使用钙调神经磷酸酶抑制剂进行治疗，HCT 仍可以安全地诱导 GVL 反应。我们现在计划 通过进行前瞻性双盲更严格地测试该策略的临床影响 针对患有活动性疾病进行移植的患者的随机研究。诱导免疫反应必须 持续进行，以维持抗肿瘤监测。有很多对策 可以抑制这些免疫反应，并可能限制疫苗接种的治疗效力。这样的一位 机制是通过负调控分子的相互作用减弱 T 细胞功能，例如 CTLA4 及其配体。具体目标 2 将重点关注异基因 HCT 后复发的患者，并将 研究使用 ipilumumab 进行 CTLA4 抗体阻断的安全性和临床后果 单独或与基于 GM-CSF 的疫苗接种联合治疗复发。具体目标 3 将解决翻转问题 HCT 后免疫反应性的一面，即慢性感染的不加区别的宿主直接后果 移植物抗宿主病。调节性 T 细胞 (Treg) 下调免疫反应。 Treg 缺乏与慢性 移植物抗宿主病。临床上对恢复这些患者的 Treg 数量和活性非常感兴趣。低的 剂量白介素 2 (IL-2) 向 Treg 传递增殖信号。我们已经证明，1-2 的低剂量 可以安全地给予患有慢性GVHD（cGVHD）的患者，并且可以在体内选择性地扩增Treg。 初步结果表明，该策略可以引起具有临床意义的反应。我们计划正式测试 低剂量 lL-2 在类固醇难治性 2 期临床研究中的临床和免疫反应 单独的 cGVHD 患者以及与新鲜分离的供体 Treg 的过继转移相结合。这 该应用中的综合策略将对免疫学影响和免疫学影响产生重要的新见解 基于 GM-CSF 的疫苗接种的相关性以及 Treg 和 Treg 介导的反监管力量的作用 肿瘤中的 CTLA4 等分子和人类的直接免疫反应。里兹博士和我 我们在免疫调节移植方面合作了二十多年，我们期待我们的合作伙伴关系 将继续保持极高的生产力。 ’” 相关性（参见说明）： 发现如何操纵供体来源的免疫反应是改善同种异体结果的关键 HCT 是本次 R01 提交的中心主题。目标 1 和 2 中提出的临床试验是 建立在过去 5 年的成就之上，旨在严格测试创新战略 在疾病复发或复发高风险患者中诱导和维持抗肿瘤反应性。试验 计划的目标 3 将通过扩大监管范围来评估 GVH 治疗和预防的新方法 体内的细胞。免疫反应的成功调节将对免疫反应的结果产生深远的影响 移植并可能对其他疾病产生影响。 项目/绩效网站（如果需要额外空间，请使用项目/绩效网站字体页面）