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.

血液学恶性肿瘤的造血细胞移植（HCT）的目的是持续消除疾病。虽然高剂量的化学/放射疗法可能导致肿瘤破坏，但从临床前模型和临床研究中可以明显看出，免疫介导的同种异体作用，称为GRAFT-VS-白血病（GVL）作用，是同种异体HCT的治疗效应的核心。通过供体淋巴细胞输注（DLI）和 非毛囊干细胞移植（NST）的有前途的报道已转移了同种异体造血细胞移植（HCT）的治疗焦点，从高剂量化学/放射疗法和供体免疫系统介导的抗肿瘤作用转移了。首先尝试增加NST后这种移植物VS-Leukemia（GVL）活性，包括早期撤回免疫抑制或早期施用未分离的供体淋巴细胞 输注。这些策略的成功受到了GVHD的加速发展的限制。如果可以诱导白血病特定的反应而不是广泛的同种异反应性，那么在没有GVHD的情况下，有可能促进GVL。该项目提出的研究将研究旨在在同种异体移植后尽早诱导和增强抗白血病免疫力的策略，而不必刺激广泛的同种反应反应。基于鼠模型和人类试验，这些模型和人类试验确定了GM-CSF的可行性，安全性和免疫活性，我们将在同种异体移植设置中使用该策略进行一系列临床试验。我们假设受辐照/改良的白血病细胞对GM-CSF的旁分泌分泌应吸引专业的抗原表现细胞（APC），例如树突状细胞，以吸引白血病 细胞，并刺激这些APC，以呈现白血病抗原对供体淋巴细胞，从而触发白血病特定的同种免疫作用。我们希望从这些试验中建立最佳的免疫环境，以在移植后尽早促进免疫。我们将将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相关联，特别注意调节性T细胞的作用。对T和B细胞对疫苗接种的反应的检查将有望导致发现可以作为随后疫苗接种方案的靶标的基因。通过CTLA-4抗体阻断的肿瘤特异性免疫进一步增强，将在同种异体移植设置中探索患有或以前尚未用基于GM-CSF的疫苗免疫的患者。