Manipulation of Immune Responsiveness after Hematopoietic Cell Transplantation

控制免疫反应是异基因造血细胞成功的关键 移植(HCT)。供体细胞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)。供者对宿主的免疫反应不足 恶性细胞允许肿瘤细胞存活。或者，对正常宿主组织的免疫反应性可以 导致致命的移植物抗宿主病。项目1致力于设计用于操作移植后的临床试验。 靶向恶性白血病细胞的免疫反应性或增强调节性T细胞的活性 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 帮助确定这些策略在临床实践中的作用。在具体目标1.我们将重点关注 晚期髓系恶性肿瘤高危人群HCT术后疾病复发的预防。我们 以前已经证明，基于GM-CSF的肿瘤疫苗在异基因移植后早期淋巴细胞减少的环境中。 尽管同时使用钙调神经磷酸酶抑制剂，HCT仍可安全地诱导GVL反应。我们现在计划 为了更严格地测试这一策略的临床影响，进行前瞻性双盲试验 活动性疾病患者进入移植的随机研究。免疫反应的诱导必须 以维持对肿瘤的监测。有许多对策可供选择 可能会抑制这些免疫反应，并可能限制疫苗的治疗效力。这样的一个 机制是T细胞功能的减弱由负调节分子的相互作用，如 CTLA4及其配体。特定目标2将侧重于allo-hct后复发的患者 观察伊普鲁单抗阻断CTLA4抗体的安全性和临床效果。 单独设置复发以及与以GM-CSF为基础的疫苗联合接种。具体目标3将解决翻转问题 HCT后免疫反应性的一面，即不分青红皂白的宿主导向的慢性后果 GVHD。调节性T细胞(Treg)下调免疫反应。Treg缺陷与慢性 GVHD。临床上对恢复这些患者的Treg数量和活性有相当大的兴趣。低 剂量白介素2(IL-2)向Treg传递增殖信号。我们已经证明了低剂量的1-2 可以安全地用于慢性移植物抗宿主病(CGVHD)患者，并可以选择性地在体内扩展Treg。 初步结果表明，该策略可以诱导临床上有意义的反应。我们计划正式测试 小剂量IL-2在激素难治性2期临床研究中的临床和免疫学反应 CGVHD患者单独和联合新分离供者Treg的过继转移。这个 这一应用中的综合策略将产生对免疫学影响和 以GM-CSF为基础的疫苗接种与Treg和TREG介导的反调节力量的作用的相关性 肿瘤和宿主中的CTLA4等分子在人类体内直接免疫反应。里茨医生和我 在免疫调节性移植方面合作了20多年，我们期待着我们的合作伙伴关系 将继续保持极高的生产力。‘“ 相关性(请参阅说明)： 发现如何操纵供者来源的免疫反应是改善异基因移植结果的关键。 这是这份R01报告的中心主题。目标1和目标2中提出的临床试验和 建立在过去5年的成就基础上，旨在严格测试创新战略，以 在复发或复发风险高的患者中诱导和维持抗肿瘤反应性。审判 为AIM 3计划的将通过扩展调节T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预后产生深远的影响 并可能在其他疾病环境中产生影响。 项目/绩效网站(S)(如果需要额外空间，请使用项目/绩效网站字体页面)

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)