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)

获得对免疫应答的控制是同种异体造血细胞移植成功的关键。 移植（HCT）。供体细胞对宿主抗原的免疫应答导致移植物抗宿主 疾病（GVHD）和移植物抗白血病（GVL）。供体对宿主的免疫应答不足 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 导致致命GVHD。项目1致力于临床试验，旨在操纵移植后 靶向恶性白血病细胞的免疫反应性或增强调节性T细胞活性， 抑制GVH。这些试验扩展了我们先前的实验室和临床观察， 帮助确定这些策略在临床实践中的作用。具体目标1。重点抓好 预防晚期骨髓恶性肿瘤高危人群HCT后疾病复发。我们 先前已经证明，基于GM-CSF的肿瘤疫苗在异体移植后早期的淋巴细胞减少环境中， 尽管同时使用钙调磷酸酶抑制剂治疗，HCT仍可以安全地诱导GVL应答。我们现在计划 为了更严格地测试这种策略的临床影响， 在患有活动性疾病的患者中进行的随机研究。免疫反应的诱导必须 以维持抗肿瘤监测。有一些对策， 可以抑制这些免疫应答，并可能限制疫苗接种的治疗效力。一个这样 其机制是通过负调节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allo-HCT后复发的患者， 研究在肿瘤术后使用伊匹单抗阻断CTLA 4的安全性和临床结果。 复发设置单独和与基于GM-CSF的疫苗接种联合。具体目标3将解决翻转 HCT后免疫反应性的另一面，即不分青红皂白的宿主定向的慢性炎症的后果。 GVHD。调节性T细胞（Treg）下调免疫应答。Treg缺乏与慢性 GVHD。在这些患者中恢复Treg数量和活性具有相当大的临床兴趣。低 剂量的白细胞介素-2（IL-2）向Treg递送增殖信号。我们已经证明，低剂量的1 - 2 可以安全地给予慢性GVHD（cGVHD）患者，并且可以选择性地在体内扩增Treg。 初步结果表明，这种策略可以诱导临床上有意义的反应。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IL-2的临床和免疫应答 单独的cGVHD患者和与新鲜分离的供体Treg的过继转移组合。的 该应用中的综合策略将产生对免疫学影响的重要新见解， 基于GM-CSF的疫苗接种的相关性和由Treg介导的反调节力的作用， 分子如CTLA4在肿瘤和宿主直接免疫反应在人类。里兹医生和我 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 将继续发挥巨大的作用'" 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移植结果的关键。 HCT是本次R01申报资料的中心主题。目的1和2中提出的临床试验， 建立在过去5年的成就之上，旨在严格测试创新战略， 诱导和维持复发性疾病或复发高风险患者的抗肿瘤反应性。审判 计划的目标3将评估新的方法来GVH的治疗和预防，通过扩大监管T 体内细胞免疫应答的成功调节将对免疫治疗的结果产生深远的影响。 移植，并可能在其他疾病环境中产生影响。 项目/施工现场（如果需要额外空间，请使用项目/施工现场表格页）