Induction of Anti-Tumor Immunity after HC Transplant

HC移植后抗肿瘤免疫的诱导

• 批准号: 6922269
• 负责人: Robert Jon Soiffer
• 金额: $ 17.21万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922269
• 关键词: antigen presenting cell; blood /lymphatic neoplasm; clinical research; clinical trials; colony stimulating factor; graft versus host disease; hematopoietic tissue transplantation; homologous transplantation; host neoplasm interaction; human subject; human therapy evaluation; leukocyte transfusion; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; stem cell transplantation; transplantation immunology; tumor antigens

The goal of hematopoietic cell transplantation (HCT) for hematologic malignancies is sustained eradication of disease. While high dose chemo/radiotherapy can contribute to tumor destruction, it is clear from pre-clinical models and clinical studies that immune mediated allogeneic effects, termed graft-vs-leukemia (GVL) effects, are central to the therapeutic effect of allogeneic HCT. Successful trials of adoptive immunotherapy with donor lymphocytes infusions (DLI) and promising reports of non-myeloablative stem cell transplants (NST) have shifted the therapeutic focus of allogeneic hematopoietic cell transplantation (HCT) away from high dose chemo/radiotherapy and toward anti-tumor effects mediated by the donor's immune system. Initial attempts to augment this graft-vs-leukemia (GVL) activity after NST have included early withdrawal of immune suppression or early administration of unfractionated donor lymphocyte infusions. The success of these strategies has been limited by the accelerated development of GVHD. If leukemia specific responses rather than broad allogeneic reactivity could be induced, then it might be possible to promote GVL in the absence of GVHD. The studies proposed in this Project will examine strategies aimed at inducing and augmenting anti-leukemic immunity early after allogeneic transplantation without necessarily stimulating broad allo-reactive responses. Based upon murine models and human trials that have established the feasibility, safety, and immunologic activity of GM-CSF secreting autologous tumor vaccines, we will initiate a series of clinical trials utilizing this strategy in the allogeneic transplant setting. We hypothesize that paracrine secretion of GM-CSF by the irradiated/modified leukemia cells should attract professional antigen presentation cells (APCs), such as dendritic cells, to the leukemia cells, and stimulate these APCs to present leukemia antigens to donor lymphocytes, thereby triggering a leukemia specific allo-immune effect. We hope from these trials to establish the optimal immunologic milieu to promote immunization early after transplantation. We will correlate functional and phenotypic parameters of immune reconstitution with vaccine mediated induction of tumor specific immunity, paying particular attention to the role of regulatory T cells. Examination of T and B cell responses to vaccination will hopefully lead to discovery of genes that could serve as targets for subsequent vaccination protocols. Further augmentation of tumor specific immunity through CTLA-4 antibody blockade will be explored in the allogeneic transplant setting in patients who have or have not been previously immunized with GM-CSF based vaccines.

造血细胞移植(HCT)治疗恶性血液病的目的是持续根除疾病。虽然大剂量化疗/放射治疗可以促进肿瘤的破坏，但从临床前模型和临床研究中可以清楚地看到，免疫介导的同种异体效应，即移植物抗白血病(GVL)效应，是异基因HCT治疗效果的核心。供者淋巴细胞输注(DLI)过继免疫治疗的成功试验 有关非清髓性干细胞移植(NST)的报道使异基因造血细胞移植(HCT)的治疗重点从大剂量化疗/放射治疗转向由供者免疫系统介导的抗肿瘤作用。NST后增强移植物抗白血病(GVL)活性的初步尝试包括早期取消免疫抑制或早期给予未分离的供者淋巴细胞 输液。这些战略的成功受到全球艾滋病毒/艾滋病加速发展的限制。如果可以诱导白血病特异性反应而不是广泛的同种异体反应，那么在没有移植物抗宿主病的情况下促进移植物抗宿主病是可能的。本项目中提出的研究将审查旨在诱导和增强异基因移植后早期抗白血病免疫而不一定刺激广泛的同种异体反应的策略。在小鼠模型和已确定GM-CSF分泌自体肿瘤疫苗的可行性、安全性和免疫活性的人体试验的基础上，我们将在异基因移植环境中利用这一策略启动一系列临床试验。我们推测，受照射/修饰的白血病细胞的GM-CSF旁分泌应该会吸引专业抗原提呈细胞(APC)，如树突状细胞，进入白血病。 细胞，并刺激这些APC将白血病抗原呈递给供者淋巴细胞，从而触发白血病特异性同种免疫效应。我们希望通过这些试验建立最佳的免疫环境，以促进移植后早期免疫。我们将把免疫重建的功能和表型参数与疫苗介导的肿瘤特异性免疫诱导联系起来，特别关注调节性T细胞的作用。检查T和B细胞对疫苗的反应将有望发现可以作为后续疫苗接种方案目标的基因。通过阻断CTLA-4抗体进一步增强肿瘤特异性免疫力将在同种异体移植环境中探索，这些患者以前已经或没有接种过基于GM-CSF的疫苗。