Augmenting Antitumor Immunity

增强抗肿瘤免疫力

• 批准号: 8727264
• 负责人: HYAM Isaac LEVITSKY
• 金额: $ 42.95万
• 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/8727264
• 关键词: Acute Myelocytic Leukemia; Address; Adoptive Transfer; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Antigen Targeting; Antigens; Autoimmunity; Autologous; Blood; Bone Marrow Transplantation; Bypass; Cancer Vaccines; Cells; Clinical Trials; Clonal Expansion; Collaborations; Communicable Diseases; Cyclophosphamide; Cytomegalovirus; Cytotoxic Chemotherapy; Data; Development; Dose; Engraftment; Failure; Frequencies; Funding; Graft-Versus-Tumor Induction; Harvest; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Homeostasis; Immune; Immunity; Immunization; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Incidence; Instruction; Link; Lymphocyte; Major Histocompatibility Complex; Mediating; Morbidity - disease rate; Multi-Institutional Clinical Trial; Mus; Myeloid Leukemia; Normal tissue morphology; Opportunistic Infections; Outcome; Output; Patients; Peptides; Principal Investigator; Procedures; Prophylactic treatment; Regimen; Regulatory T-Lymphocyte; Relapse; Relative (related person); Reporting; Research; Residual Cancers; Residual state; Resistance; Risk; Safety; Severities; T cell differentiation; T-Cell Depletion; T-Lymphocyte; Tacrolimus; Testing; Therapeutic; Toxic effect; Transplantation; Umbilical Cord Blood Transplantation; Vaccination; Vaccine Antigen; Vaccines; Work; base; cancer cell; cancer testis antigen; chemotherapy; experience; graft failure; graft vs host disease; human disease; improved; innovation; killings; leukemia; leukemic stem cell; melanoma; mortality; mouse model; novel; programs; reconstitution; response; tumor

Project 4 Program Director/Principal Investigator (Last, First, Middle): JoneS, Rlchard J. Allogeneic BMT (alloBMT) is the treatment of choice for eligible patients with hematologic malignancies that are incurable by chemotherapy. Donor T cell mediated graft-versus-tumor effects have the potential to eradicate residual cancer cells that survive pre-transplant cytotoxic therapies. T cell recognition of alloantigens as well as leukemia-associated antigens (LAAs) has been reported to contribute to this effect. Historically, the beneficial impact of allorecognition on relapse-free survival has been largely offset by the toxicities of graft-versus-host-disease (GVHD) and its treatment, and attempts to diminish the latter by donor T cell depletion or recipient immunosuppression have resulted in increased rates of relapse. The studies pioneered in PROJECT 4 have led to the development of high doses of cyclophosphamide.in the early post- BMT period (PT/Cy) as a strategy for generating bi-directional tolerance. As a result, patients treated with PT/Cy have achieved stable hematopoietic engraftment with low rates of GVHD, even in HLA-haploidentical donor/recipient pairs. With this innovation, relapse rather than GVHD is now the major cause of transplant failure. As demonstrated by mouse studies in PROJECT 2, adoptive transfer of lymphocytes from donors primed with a cancer vaccine significantly reduces relapse rates in syngeneic, tumor-bearing recipients. These results led to clinical trials testing the integration of a therapeutic leukemia vaccine into the setting of autologous BMT, which demonstrated that the response to a vaccine administered pirior to graft harvest correlated significantly with post-BMT relapse-free survival. We now propose to evaluate donor vaccination as a strategy to improve the outcome of alloBMT. However, two impediments in bringing donor vaccination into the alloBMT setting are: 1) the risk of inducing autoimmunity in the healthy donor, and 2) the potential to increase the incidence or severity of GVHD. Accordingly, we have chosen to target an antigen that is not expressed in normal tissues of healthy donors, but is aberrantly expressed in many myeloid leukemias. A collaboration between PROJECT 1 and PROJECT 2 has led to the discovery that PRAME, a cancer testis antigen, is one of the few identified LAAs that is abundantly expressed in leukemic stem cells (LSCs), but is absent from normal hematopoietic stem cells. This proposal seeks to link these three fundamental discoveries in GVHD prophylaxis (Project 4), adoptive transfer of vaccine pnmed immunity (Project 2), and LSC antigen expression (Project 1) to improve the outcome of alloBMT.

项目 4 项目总监/首席研究员（最后、第一、中间）：JoneS、Rlchard J. 同种异体 BMT (alloBMT) 是符合条件的血液恶性肿瘤患者的首选治疗方法， 化疗无法治愈。供体 T 细胞介导的移植物抗肿瘤效应有可能 根除移植前细胞毒疗法中存活下来的残留癌细胞。 T细胞识别 据报道，同种异体抗原以及白血病相关抗原（LAA）有助于这种作用。 从历史上看，同种异体识别对无复发生存的有益影响在很大程度上被 移植物抗宿主病（GVHD）的毒性及其治疗，并尝试通过捐赠者减少后者 T 细胞耗竭或受体免疫抑制导致复发率增加。研究 项目 4 中首创的技术导致了高剂量环磷酰胺的开发。 BMT 周期 (PT/Cy) 作为产生双向耐受性的策略。结果，接受治疗的患者 PT/Cy 已实现稳定的造血移植，GVHD 发生率低，即使在 HLA-半相合的情况下也是如此 捐赠者/接受者对。通过这项创新，复发而不是 GVHD 现在成为移植的主要原因 失败。正如项目 2 中的小鼠研究所证明的那样，来自供体的淋巴细胞的过继转移 接种癌症疫苗可显着降低同基因、携带肿瘤的受者的复发率。 这些结果引发了临床试验，测试将治疗性白血病疫苗整合到 自体 BMT，证明在移植物收获前注射疫苗的反应 与 BMT 后无复发生存率显着相关。我们现在建议评估捐赠者的疫苗接种 作为改善 alloBMT 结果的策略。然而，捐赠者疫苗接种存在两个障碍 alloBMT 设置中的因素包括：1) 在健康供体中诱发自身免疫的风险，以及 2) 潜在的 增加 GVHD 的发生率或严重程度。因此，我们选择的目标抗原不是 在健康捐献者的正常组织中表达，但在许多骨髓性白血病中异常表达。一个 项目 1 和项目 2 之间的合作发现了 PRAME，一种癌症睾丸 抗原，是少数已确定的在白血病干细胞 (LSC) 中大量表达的 LAA 之一，但 正常造血干细胞中不存在。该提案旨在将这三个基本要素联系起来 GVHD 预防（项目 4）、疫苗调节免疫的过继转移（项目 2）以及 LSC 抗原表达（项目 1）可改善 alloBMT 的结果。