Induction of Anti-Tumor Immunity after HC Transplant

造血细胞移植（HCT）治疗恶性血液病的目的是持续根除疾病。虽然高剂量化疗/放疗可能有助于肿瘤破坏，但临床前模型和临床研究清楚地表明，免疫介导的同种异体效应（称为移植物抗白血病（GVL）效应）对于同种异体HCT的治疗效果至关重要。供体淋巴细胞输注（DLI）过继免疫治疗的成功试验， 非清髓性干细胞移植（NST）的有希望的报道已经将同种异体造血细胞移植（HCT）的治疗焦点从高剂量化疗/放疗转移到由供体免疫系统介导的抗肿瘤作用。NST后增加移植物抗白血病（GVL）活性的最初尝试包括早期取消免疫抑制或早期给予未分级供体淋巴细胞 输液这些策略的成功受到GVHD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性，那么在没有GVHD的情况下促进GVL是可能的。本项目中提出的研究将检查旨在诱导和增强抗白血病免疫的策略，在异基因移植后早期，不一定刺激广泛的同种异体反应。基于小鼠模型和人体试验，已经建立的可行性，安全性和GM-CSF分泌自体肿瘤疫苗的免疫活性，我们将启动一系列的临床试验，利用这种策略在同种异体移植设置。我们假设，由辐射/修饰的白血病细胞旁分泌GM-CSF应该吸引专职抗原呈递细胞（APC），如树突状细胞，到白血病细胞。 细胞，并刺激这些APC将白血病抗原呈递给供体淋巴细胞，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，特别注意调节性T细胞的作用。T和B细胞对疫苗接种的反应的检查将有望发现可作为后续疫苗接种方案的靶点的基因。通过CTLA-4抗体阻断进一步增强肿瘤特异性免疫将在同种异体移植环境中在先前已经或尚未用基于GM-CSF的疫苗免疫的患者中进行探索。

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.