Strategies to Enhance Post-Transplant Tumor Vaccination

加强移植后肿瘤疫苗接种的策略

• 批准号: 7728794
• 负责人: Marcel R M van den Brink
• 金额: $ 17.39万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728794
• 关键词: Achievement; Address; Adjuvant; Adjuvant Study; Allogeneic Bone Marrow Transplantation; Allogenic; Antigens; Area; B-Lymphocytes; Cancer Immunology Science; Cancer Vaccines; Clinical; Clinical Research; Collaborations; DNA Vaccines; DNA delivery; Development; Differentiation Antigens; Disease; Genes; Graft-Versus-Tumor Induction; Hematopoietic Stem Cell Transplantation; Human; Immune response; Immune system; Immunity; Immunization; Immunology; Immunotherapy; Infection; Infusion procedures; Interleukin-15; Interleukin-7; Investigation; Laboratories; Lead; Leukocytes; Lymphoma; MS4A1 gene; Malignant - descriptor; Malignant Neoplasms; Measures; Melanoma Vaccine; Memorial Sloan-Kettering Cancer Center; Modeling; Mus; Neoplasm Transplantation; Numbers; Outcome; Patients; Pre-Clinical Model; Prophylactic treatment; Publications; Rate; Relapse; Renal Cell Carcinoma; Research Design; Research Personnel; Risk; Solid Neoplasm; Staging; T-Lymphocyte; Time; Transplantation; Treatment Protocols; Tumor Antigens; Tumor Immunity; Vaccination; Vaccines; Work; anticancer research; base; cancer immunology function; cancer immunotherapy; clinically relevant; conditioning; cytokine; experience; graft vs host disease; immunogenic; leukemia/lymphoma; melanoma; mortality; mouse model; neoplastic cell; novel; novel therapeutics; pre-clinical; preclinical study; prevent; research clinical testing; research study; response; tool; tumor

Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy with curative potential for a variety of malignant diseases, including leukemias, lymphomas and some solid tumors. Despite significant progress in reducing treatment-related mortality, malignant relapse remains a major problem. Studies regarding non-myeloablative HSCT and donor leukocyte infusions have irrefutably demonstrated that the donor immune system can generate a graft-versus-tumor (GVT) effect that can prevent or treat malignant relapse. At the same time advances in tumor vaccines have resulted in promising pre-clinical and clinical results. We hypothesize that immunization of HSCT recipients against specific tumor antigens can decrease the risk of relapse without enhancing graft-versus-host disease (GVHD). We propose to use clinically relevant mouse allogeneic HSCT models and DMA vaccines which encode for specific melanoma and lymphoma differentiation antigens. In our preliminary studies with two different DNA vaccines in HSCT recipients we have found specific anti-tumor T cell responses, significant tumor protection and no evidence of GVHD. In Specific Aim 1 we will analyze the efficacy of post-transplant tumor vaccination of HSCT recipients. We will measure T and B cell responses, assess the effects on tumor protection, GVHD and overall survival, and determine the optimal time point after transplant for tumor vaccination. In Specific Aim 2 we will study adjuvant strategies to enhance the efficacy of post-transplant tumor vaccination with DNA vaccines in HSCT recipients, including the administration of IL-7 and IL-15, the co-delivery of DNA encoding for IL-7 and IL-15, and CTLA-4 blockade. In Specific Aim 3 we will study the efficacy of adoptive therapy with donor T cells in combination with DNA vaccines in HSCT recipients. These studies will lead to a better understanding of the mechanisms involved in post-transplant vaccination with melanoma and lymphoma differentiation antigens, and could result in the development of novel therapeutic strategies by combining allogeneic HSCT, post-transplant tumor vaccination and adoptive T cell therapy.

异基因造血干细胞移植（HSCT）是一种具有治疗潜力的重要治疗方法， 多种恶性疾病，包括白血病、淋巴瘤和一些实体瘤。尽管取得了重大 尽管在降低治疗相关死亡率方面取得了进展，但恶性复发仍然是一个主要问题。研究 关于非清髓性HSCT和供体白细胞输注的研究无可辩驳地证明， 供体免疫系统可以产生移植物抗肿瘤（GVT）效应，其可以预防或治疗恶性肿瘤。 复发与此同时，肿瘤疫苗的进展已经导致有希望的临床前和临床治疗。 结果我们假设HSCT受者对特异性肿瘤抗原的免疫可以减少HSCT受者的免疫反应。 复发的风险，而不增加移植物抗宿主病（GVHD）。我们建议在临床上使用 相关的小鼠同种异体HSCT模型和编码特异性黑素瘤的DMA疫苗， 淋巴瘤分化抗原。在我们对两种不同的DNA疫苗在HSCT中的初步研究中， 我们已经发现了特异性抗肿瘤T细胞反应，显着的肿瘤保护作用，没有证据表明 GVHD。在具体目标1中，我们将分析HSCT移植后肿瘤疫苗接种的有效性。 受惠人士我们将测量T和B细胞反应，评估对肿瘤保护、GVHD和 总存活率，并确定移植后肿瘤疫苗接种的最佳时间点。具体目标2 我们将研究辅助策略，以增强移植后肿瘤DNA疫苗接种的功效。 HSCT受者中的疫苗，包括IL-7和IL-15的施用， 用于IL-7和IL-15以及CTLA-4阻断。在具体目标3中，我们将研究过继治疗的有效性， 供体T细胞与DNA疫苗联合用于HSCT受者。这些研究将导致更好的 了解移植后接种黑色素瘤和淋巴瘤疫苗的机制 分化抗原，并可能导致新的治疗策略的发展， 同种异体HSCT、移植后肿瘤疫苗接种和过继性T细胞治疗。