Melanoma immunotherapy targeting sentinel lymph nodes

项目摘要 黑色素瘤是一种皮肤癌，仅占病例的4%，但占死亡人数的80%;仅在2014年， 在美国造成了大约一万人死亡。抗肿瘤的自发发展 免疫与改善的临床结果相关，表明免疫治疗的潜力， 提高黑素瘤患者存活率。抗肿瘤免疫应答是在肿瘤细胞内启动和调节的。 前哨（肿瘤引流）淋巴结（TDLN），但由于局部免疫反应， 抑制信号因此，TDLN介导的肿瘤免疫抑制是一个关键障碍 有效的黑色素瘤免疫疗法。因此，存在显著且未满足的需求， 增加免疫调节剂向TDLN驻留免疫细胞的递送的技术 改善黑色素瘤的治疗本R 01项目的目标是开发和验证 前哨淋巴结给药技术提高免疫抑制剂内药物生物活性 黑色素瘤TDLN。这将在严格的BRAF突变的临床前诱导模型中进行测试。 黑色素瘤，其发生在50%的人类黑色素瘤中。提出了三个目标： 目的1：测量TDLN中药物蓄积相对于由LN-1引起的全身组织的特异性 与非靶向免疫疗法相比。 目的2：描述LN-与非靶向免疫治疗在 BRAFv 600 E黑素瘤模型。 目的3：评价LN-与非靶向免疫疗法单独与联合治疗的治疗效果。 与BRAFv 600 E组合抑制BRAFv 600 E中的疾病进展和动物存活 黑素瘤模型。 预计该项目将产生若干成果。首先，这些研究将确定参数， 通过LN药物靶向增强黑色素瘤免疫治疗的功效。第二，潜力 TDLN靶向免疫疗法以改善BRAFv 600 E抑制在治疗急性白血病中的功效 将形成晚期黑素瘤。已经在人体临床试验中的治疗剂或 将在这项工作中研究批准用于人类的药物，以确保快速临床应用的最大潜力。 翻译.

PROJECT SUMMARY Melanoma is a skin cancer that accounts for only 4% of cases but 80% of deaths; in 2014 alone it resulted in approximately 10,000 deaths in the United States. Spontaneous development of anti-tumor immunity is associated with improved clinical outcome, indicating the potential for immunotherapy to increase melanoma patient survival. Anti-tumor immune responses are initiated and regulated within sentinel (tumor-draining) lymph nodes (TDLN), but are often inefficient as the result of local immune suppressive signaling. TDLN-directed tumor immune suppression therefore represents a critical hurdle in effective melanoma immunotherapy. Therefore, there is a significant and unmet need for technologies that increase the delivery of immunomodulatory agents to TDLN-resident immune cells improve the treatment of melanoma. The objective of this R01 project is to develop and validate a sentinel lymph node drug delivery technology to improve immunotherapeutic drug bioactivity within melanoma TDLN. This will be tested in a rigorous preclinical inducible model of BRAF mutated melanoma, which occurs in 50% of human melanomas. Three aims are proposed: Aim 1: Measure specificity of drug accumulation in TDLN versus systemic tissues resulting from LN- versus non-targeted immunotherapy. Aim 2: Delineate the immune modulatory effect of LN- versus non-targeted immunotherapy in the BRAFv600E melanoma model. Aim 3: Evaluate the therapeutic efficacy of LN- versus non-targeted immunotherapy alone versus in combination with BRAFv600E inhibition on disease progression and animal survival in the BRAFv600E melanoma model. This project is expected to yield several outcomes. First, these studies will define parameters for enhancing the efficacy of melanoma immunotherapy via LN drug targeting. Second, the potential for TDLN-targeted immunotherapy to improve the efficacy of BRAFv600E inhibition in the treatment of advanced melanomas will be established. Therapeutic agents already in human clinical testing or approved for human use will be investigated in this work to ensure the highest potential for rapid clinical translation.