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: 8698358
• 负责人: JEROME RITZ
• 金额: $ 92.4万
• 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/8698358
• 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)

获得对免疫反应的控制对于同种异体造血细胞的成功至关重要 移植（HCT）。供体细胞对宿主抗原的免疫反应导致两个移植物与宿主 疾病（GVHD）和移植物与白血病（GVL）。对宿主的供体免疫反应不足 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性可以 导致致命的GVHD。项目1致力于旨在操纵移植后的临床试验 免疫反应性要么靶向恶性白血病细胞或增强调节性T细胞活性 抑制GVH。这些试验扩展了我们以前的实验室和临床观察结果，旨在 帮助确定这些策略在临床实践中的作用。在特定目标1中。我们将专注于 在高风险种群中预防患有晚期髓样恶性肿瘤的HCT后HCT疾病复发。我们 以前证明，在同一个淋巴细胞减少环境中基于GM-CSF的肿瘤疫苗 尽管与钙调蛋白抑制剂同时治疗，HCT可以安全地诱导GVL反应。我们现在计划 通过执行前瞻性双盲来更严格地测试该策略的临床影响 进入患有活性疾病移植的患者的随机研究。免疫反应的诱导必须 为了维持抗肿瘤监视而维持。有许多对策 可以抑制这些免疫反应，并可能限制疫苗接种的治疗效力。一个这样的 机理是通过负调节分子的相互作用（例如 CTLA4，带有配体。具体目标2将专注于在Allo-HCT之后复发的患者，并将 研究后，研究CTLA4抗体阻断的安全性和临床后果 仅复发设置并与基于GM-CSF的疫苗接种。特定的目标3将解决翻转 HCT后免疫反应性的一面，即慢性宿主的遗传宿主的导向后果 GVHD。调节性T细胞（Treg）下调免疫反应。 Treg缺乏症与慢性有关 GVHD。在这些患者中恢复Treg的数量和活动方面具有很大的临床兴趣。低的 剂量白介素-2（IL-2）向Treg传达了增生信号。我们已经证明了1-2的低剂量 可以安全地给患有慢性GVHD（CGVHD）的患者使用，并可以在体内有选择地扩展Treg。 初始结果表明，该策略可以引起临床意义的反应。我们计划正式测试 在类固醇难治性的2期临床研究中，低剂量LL-2的临床和免疫反应 CGVHD患者单独并与新鲜分离的供体Treg的过继转移结合使用。这 本应用程序中的综合策略将对免疫学影响和 基于GM-CSF的疫苗接种以及Treg和 肿瘤中的CTLA4等分子和人类中的直接免疫反应。丽思博士和我有 合作进行了二十年以上的免疫调节移植，我们预计我们的合作伙伴关系 将继续非常有生产力。 '” 相关性（请参阅说明）： 发现如何操纵供体衍生的免疫反应是改善同种结果的关键 HCT，是此R01提交的中心主题。目标1和2提出的临床试验是 基于过去5年的成就，旨在严格测试创新策略 在复发性疾病或高复发风险的患者中诱导和维持抗肿瘤反应性。试验 AIM 3计划将通过扩大调节性T来评估GVH疗法和预防的新方法 细胞体内。成功调节免疫反应将对结果产生深远影响 移植，可能在其他疾病环境中产生影响。 项目/绩效网站（如果需要其他空间，请使用项目/perfonnance网站fonnat页面）