Harnessing Alloreactivity

利用同种异体反应

• 批准号: 8065388
• 负责人: FUCHS EPHRAIM
• 金额: $ 35.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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/8065388
• 关键词: Acute Myelocytic Leukemia; Adoptive Immunotherapy; Age; Allogeneic Lymphocyte; Allogenic; American; Antigen-Presenting Cells; Antigens; Autologous Cell Vaccine; Blood; Bone Marrow Transplantation; CD8B1 gene; Cancer Vaccines; Cells; Chimerism; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Clinical; Clinical Trials; Conduct Clinical Trials; Cyclophosphamide; Development; Disease; Disease Resistance; Donor Lymphocyte Infusion; Dose; Dysmyelopoietic Syndromes; Eligibility Determination; Engraftment; Funding; Goals; Gold; Graft-Versus-Tumor Induction; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoietic; Histocompatibility Antigens; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Incidence; Infection; Infusion procedures; Leukocyte Transfusion; Lymphocyte; Lymphoma; Malignant Neoplasms; Marrow; Memory; Methods; Opportunistic Infections; Patients; Pharmaceutical Preparations; Procedures; Prophylactic treatment; Reaction; Regimen; Regulatory T-Lymphocyte; Relapse; Rest; Safety; Staging; Stem cell transplant; Stem cells; T cell response; T-Lymphocyte; Toxic effect; Transplantation; Transplantation Tolerance; Virus; Work; base; cancer therapy; chemotherapy; conditioning; fungus; graft vs host disease; mouse model; novel; prevent; reconstitution; response; success; tumor

Allogeneic blood or marrow transplantation, or alloBMT, is a potentially curative therapy for a wide variety of chemotherapy-incurable hematologic malignancies. However, the overall success of alloBMT remains constrained by procedure-related toxicity, which limits eligibility to relatively young patients with histocompatible donors, and by lack of efficacy, manifested as post-transplantation progression of the underlying disease. In the previous funding period, we had conducted clinical trials of post-transplantation, high dose cyclophosphamide (Cy) to reduce toxicity by promoting bi-directional transplantation tolerance while sparing stem cells and preserving immune responses to infection. A major goal of Aim 1 of the current proposal is to characterize in detail the mechanisms of Cy-induced tolerance and the effect of post- transplantation Cy on regulatory T cells, antigen-presenting cells, and antigen-specific T cells. To increase the anti-tumor efficacy of allogeneic T cell infusions, we will focus on inducing tumor-specific immunity by two distinct approaches. The first approach is to administer cell-based tumor vaccines, with or without donor lymphocyte infusion, after nonmyeloablative allogeneic stem cell transplantation (Aim 2). The second approach will be to treat non-BMT candidates with Cy followed by transiently engrafting allogeneic lymphocytes so as to induce an "allogeneic effect" that breaks tolerance in the patient's tumor-specific T cells (Aim 3). We will also study the capacity of tumor-targeted therapies to augment the effect of administering allogeneic lymphocytes in this context (Aim 4). The ultimate goals of this project are to establish post- transplantation Cy as the gold standard of GVHD prophylaxis and to extend the application of adoptive cellular immunotherapy with allogeneic T cells outside of the context of alloBMT. Cancer is now the leading killer of Americans under the age of 85. Transfusions of white blood cells from a healthy donor can actually make a cancer shrink, but this is a dangerous treatment that doesn't always work. The goal of this project is to find ways to make white blood cell transfusions safer and more effective in the treatment of cancer.

同种异体血液或骨髓移植（alloBMT）是一种潜在的治疗多种疾病的方法 化疗无法治愈的血液系统恶性肿瘤。然而，alloBMT 的总体成功仍然是 受到手术相关毒性的限制，这限制了相对年轻的患者的资格 组织相容性供体，由于缺乏疗效，表现为移植后进展 原发疾病。在之前的资助期间，我们进行了移植后的临床试验， 高剂量环磷酰胺 (Cy) 通过促进双向移植耐受来降低毒性 同时保留干细胞并保留对感染的免疫反应。当前目标1的主要目标 提案的目的是详细描述 Cy 诱导的耐受机制和后处理的影响 将 Cy 移植到调节性 T 细胞、抗原呈递细胞和抗原特异性 T 细胞上。增加 鉴于同种异体T细胞输注的抗肿瘤功效，我们将重点关注通过两种方法诱导肿瘤特异性免疫 不同的方法。第一种方法是在有或没有供体的情况下施用基于细胞的肿瘤疫苗 非清髓性同种异体干细胞移植后淋巴细胞输注（目标 2）。第二个 方法是用 Cy 治疗非 BMT 候选者，然后短暂移植同种异体 淋巴细胞，从而诱导“同种异体效应”，打破患者肿瘤特异性 T 细胞的耐受性 （目标 3）。我们还将研究肿瘤靶向治疗增强给药效果的能力 在这种情况下，同种异体淋巴细胞（目标 4）。该项目的最终目标是建立后 Cy移植作为GVHD预防的金标准并扩大过继的应用 在同种异体 BMT 范围之外使用同种异体 T 细胞进行细胞免疫治疗。 癌症现在是 85 岁以下美国人的头号杀手。 健康的捐赠者实际上可以使癌症缩小，但这是一种危险的治疗方法，并不总是有效。 该项目的目标是找到使白细胞输注更安全、更有效的方法。 癌症的治疗。