Strategies to Enhance Post-Transplant Tumor Vaccination

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 各种恶性疾病，包括白血病、淋巴瘤和一些实体瘤。尽管意义重大 尽管在降低与治疗相关的死亡率方面取得了进展，但恶性肿瘤复发仍然是一个主要问题。研究 关于非清髓性造血干细胞移植和供者白细胞输注已无可辩驳地证明 供者免疫系统可以产生移植物抗肿瘤(GVT)效应，可以预防或治疗恶性肿瘤 旧病复发。与此同时，肿瘤疫苗的进步带来了良好的临床前和临床应用前景。 结果。我们假设HSCT受者对特定肿瘤抗原的免疫可以减少 在不加强移植物抗宿主病(GVHD)的情况下复发的风险。我们建议在临床上使用 相关的小鼠异基因HSCT模型和编码特定黑色素瘤和 淋巴瘤分化抗原。在两种不同DNA疫苗用于造血干细胞移植的初步研究中 受者我们发现了特异性的抗肿瘤T细胞反应，显著的肿瘤保护作用，但没有证据 是GVHD的。在特定目标1中，我们将分析移植后肿瘤疫苗接种的效果。 收件人。我们将测量T和B细胞反应，评估对肿瘤保护、GVHD和 并确定移植后接种肿瘤疫苗的最佳时间点。《特定目标2》 我们将研究辅助策略，以提高移植后肿瘤DNA疫苗的效果 造血干细胞移植受者的疫苗，包括IL-7和IL-15的接种，编码DNA的联合传递 用于IL-7、IL-15和CTLA-4的阻断。在具体目标3中，我们将研究过继治疗的疗效 供者T细胞联合DNA疫苗在造血干细胞移植受者中的应用这些研究将导致更好的 对移植后接种黑色素瘤和淋巴瘤疫苗机制的认识 分化抗原，并可能导致通过结合 异基因造血干细胞移植、移植后肿瘤疫苗接种和过继T细胞治疗。

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.