Cisplatin Mediated Immune Modulation of HPV Positive Head and Neck Cancer

顺铂介导的 HPV 阳性头颈癌的免疫调节

• 批准号: 9150013
• 负责人: William Charles Spanos
• 金额: $ 29.24万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9150013
• 关键词: Adenoviruses; Adverse effects; Affect; Aftercare; Antibodies; B-Lymphocytes; CD8B1 gene; Cancer Biology; Cancer Center; Cancer Etiology; Cancer Patient; Cell Communication; Cell surface; Cells; Cisplatin; Clinical; Clinical Treatment; Clustered Regularly Interspaced Short Palindromic Repeats; Combination Drug Therapy; DNA; DNA Intercalation; Data; Deglutition; Dendritic Cells; Dose; Drug usage; Environment; Flow Cytometry; Functional disorder; Goals; Head and Neck Cancer; Head and neck structure; Human; Human Papillomavirus; Human papillomavirus 16; Immune; Immune response; Immune system; Immunotherapy; Incidence; Knowledge; Label; Life; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Mediating; Microscopy; Modality; Modeling; Mus; Neoplasm Metastasis; Population; Proteins; Public Health; Radiation; Signal Transduction; Staging; T cell response; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Technology; Time; Treatment Efficacy; Treatment Protocols; United States; Vaccines; Viral Antigens; Viral Oncogene; Virus; adaptive immunity; cancer cell; cancer site; cancer therapy; cervical and anal cancer; chemotherapy; clinical application; conventional therapy; design; effective therapy; immune clearance; immunoregulation; improved; inhibitor/antagonist; mouse model; neoplastic cell; pre-clinical; prognostic; receptor recycling; response; small hairpin RNA; therapy development; treatment response; tumor

PROJECT SUMMARY While head and neck squamous cell cancer (HNSCC) is only 5% of all cancers in the United States, the incidence of a subset of HNSCC caused by human papilloma virus (HPV) is increasing rapidly. Conventional treatment of these cancers requires chemotherapy (usually Cisplatin) and radiation. While the HPV positive HNSCC have an improved response to treatment, the overall 5 year survival for HNSCC is only 50% and the short and long term side effects from treatment are significant. Modulation of current effective treatment and new less toxic treatments are needed to improve the long term cures as well as limit the side effects in a progressively younger cancer population that may live with these side effects for 30 to 40 years post treatment. We have previously shown a directed adaptive immune response to HPV positive HNSCC in a mouse model and the importance of the immune response to HPV positive HNSCC has been confirmed in correlative human studies as well. While cisplatin has been described as interfering with DNA, we have found some preliminary evidence for a potential immune stimulating mechanism through a cellular protein, CD154. We have found that the CD154-CD40 interaction, classically described in B and T cell interactions, is required for the clearance of tumors in our model. CD154 is present in human and mouse HNSCC lines and increases after cisplatin treatment. Our hypothesis is cisplatin causes an increase of CD154 in the tumor cell that results in immune mediated clearance of HPV positive HNSCC. This project proposes to define the interaction of the tumors cells and the immune system, determine the mechanism that cisplatin uses to increase CD154, and to improve this cisplatin driven immune clearance through off the shelf immune modulating agents. This project is designed to 1) provide more information about the specific components of the immune system in and around the tumor that are affected by this increase in CD154 through Cisplatin treatment 2) understand the mechanism that Cisplatin uses to increase CD154 in HPV positive tumor cells and 3) Combine immune modulation with Cisplatin treatment in our mouse model of HPV positive HNSCC. This immune modulation will utilize off the shelf antibody and vaccine treatments that are already in clinical application or within a few years of clinical implementation in humans. The data from this project will provide a greater understanding of a common chemotherapy agent, Cisplatin, that may prompt use of the drug in doses and timing that could improve the efficacy of treatment and potentially the long term response of HPV positive cancers. The knowledge gained from this study could be potentially applied to other HPV positive cancers (cervical, anal, etc.) as well as perhaps HPV negative cancers responsive to cisplatin. The long term goal of this project is to understand the modulation of the local tumor environment and to use this information to find treatment regimens that cure patients of cancer with limited side effects.

项目摘要 虽然头部和颈部鳞状细胞癌（HNSCC）仅占美国所有癌症的5％，但 由人乳头状瘤病毒（HPV）引起的HNSCC子集的发生率正在迅速增加。传统的 这些癌症的治疗需要化学疗法（通常是顺铂）和辐射。而HPV阳性 HNSCC对治疗的反应有所改善，HNSCC的总体5年生存率仅为50％，而 短期和长期治疗的副作用是显着的。调节当前有效治疗和 需要新的毒性治疗方法来改善长期治疗方法，并限制 逐渐年轻的癌症人群可能会在治疗后30至40年患有这些副作用。 我们以前已经显示了小鼠模型中对HPV阳性HNSCC的定向自适应免疫反应 在相关人类中，已经证实了免疫反应对HPV阳性HNSCC的重要性 也研究。虽然顺铂被描述为干扰DNA，但我们发现了一些初步 通过细胞蛋白CD154具有潜在的免疫刺激机制的证据。我们找到了 CD154-CD40相互作用（在B和T细胞相互作用中经典描述）是必需的 在我们的模型中清除肿瘤。 CD154存在于人和小鼠HNSCC线中，并在 顺铂治疗。我们的假设是顺铂导致肿瘤细胞中CD154的增加 导致HPV阳性HNSCC的免疫介导的清除。该项目建议定义 肿瘤细胞和免疫系统的相互作用，确定顺铂用于 增加CD154，并通过架子免疫来改善顺铂驱动的免疫清除率 调节剂。该项目旨在1）提供有关特定组件的更多信息 肿瘤内外的免疫系统受CD154通过顺铂增加的影响 处理2）了解顺铂用于增加HPV阳性肿瘤细胞中CD154的机制 3）在我们的HPV阳性HNSCC的小鼠模型中将免疫调节与顺铂治疗相结合。 这种免疫调节将利用已经处于临床中的架子抗体和疫苗治疗 应用或在人类临床实施的几年内。该项目的数据将提供 对常见化学疗法剂顺铂的更多了解可能会引起药物的使用 以及可以提高治疗功效以及HPV阳性的长期反应的时间安排 癌症。从这项研究中获得的知识可以可能应用于其他HPV阳性癌症 （宫颈，肛门等）以及对顺铂有反应的HPV阴性癌。长期目标的 该项目是了解当地肿瘤环境的调节，并使用此信息来查找 治疗癌症患者的治疗方案有限。