In Situ Vaccination for Lymphoma Intratumoral Injection

在这个项目中，我们将在复发的B细胞和T细胞淋巴瘤患者中进行临床试验。它是基于 关于一种新的淋巴瘤治疗性疫苗接种方法，这是我们在小鼠模型中开发的。在老鼠身上， 晚期全身肿瘤可以通过化疗诱导肿瘤细胞死亡来暂时消除。在……里面 相比之下，肿瘤的长期消除是通过化疗后局部病灶内注射实现的。 树突状细胞或CpG寡核苷酸，常驻树突状细胞的激活剂(原位接种)。 无论是单纯的手法、诱导细胞死亡还是瘤内注射，都没有长期效果。这个 联合作用导致树突状细胞摄取和处理肿瘤抗原 诱导全身T细胞免疫反应，能够清除远处的肿瘤。 在临床试验中，将通过低剂量放射治疗诱导局部肿瘤死亡，并将CpG注射到 同样的局部损伤。将监测患者的抗肿瘤免疫反应和肿瘤消退。 在遥远的地点。CpG寡核苷酸对人类肿瘤的直接信号作用将在#年进行研究 在项目2中与诺兰博士合作，并与患者的临床效果相关。我们很幸运 可用于这些研究的临床级CpG化合物已经进行了安全性测试， 它已被证明作为疫苗佐剂在人体内有效，并已初步显示 斯坦福大学皮肤T细胞淋巴瘤患者试验中抗肿瘤疗效的证据。 在这些临床试验的同时，我们将进一步发展动物原位疫苗接种的策略。 通过研究其机制和联合免疫刺激药物优化其抗肿瘤作用来建立模型 效果。从动物模型中学到的经验将转化为未来临床试验的设计。

In this project we will conduct a clinical trial in patients with relapsed B cell and T cell lymphomas. It is based on a new method of therapeutic vaccination for lymphoma, which we developed in murine models. In mice, advanced systemic tumors can be temporarily eliminated by inducing tumor cell death by chemotherapy. In contrast, long-term tumor elimination is achieved by chemotherapy followed by local intralesional injection of either dendritic cells or a CpG oligonucleotide, an activator of resident dentritic cells (in situ vaccination). Either maneuver alone, cell death induction or intralesional injection, has no long-term effect. The combination results in uptake and processing of tumor antigens by the dendritic cells and subsequent induction of a systemic T cell immune response which is capable of eliminating tumor at distant sites. In the clinical trial, local tumor death will be induced by low dose radiotherapy and CpG will be injected into the same local lesion. Patients will be monitored for anti tumor immune responses and for tumor regression at distant sites. Direct signaling effects of CpG oligonucleotides on the human tumors will be studied in collaboration with Dr. Nolan in Project 2, and related to the clinical effects seen in patients. We are fortunate to have available for these studies a clinical grade CpG compound which has already been safety tested, which has proven to be effective in humans as a vaccine adjuvant and which has shown preliminary evidence of anti tumor efficacy in trials at Stanford in patients with cutaneous T cell lymphoma. In parallel with these clinical trials we will further develop the maneuver of in situ vaccination in animal models by studying its mechanism and by combining immunostimulatory agents to optimize their anti tumor effects. Lessons learned from the animal model will be translated into the design of future clinical trials.