Characterization and Enhancement of Anti-Tumor Immune Responses in Head and Neck Cancer

程序性死亡-1免疫检查点阻断（PD-1 ICB）现已被fda批准用于治疗复发/转移性头颈部鳞状细胞癌（HNSCC）。一些患者对这种治疗有显著的有益反应，但大多数患者没有反应。我们的目标是增加对这些治疗有反应的患者数量。一种方法是将不同的免疫疗法相互结合，或与化疗、放疗或靶向治疗等其他类型的抗癌治疗相结合。有效免疫治疗的主要障碍之一似乎是肿瘤内存在免疫抑制免疫细胞和抗肿瘤免疫细胞。在头颈部癌症中，未成熟骨髓细胞和调节性t细胞是抗肿瘤免疫的有效抑制因子。我们的实验室已经研究了如何使用靶向药物来阻断免疫抑制性骨髓细胞进入肿瘤的能力，使抗肿瘤免疫细胞在被免疫疗法激活后更有效地工作。根据我们实验室的新研究，阻断骨髓细胞进入肿瘤的药物正在NIH临床中心进行首次人体临床试验。

Programmed death-1 immune checkpoint blockade (PD-1 ICB) is now FDA-approved for the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Some patients can have dramatic beneficial responses to this type of treatment, but the majority of patients do not respond. We aim to enhance the number of patients that responses to these treatments. One approach is to combine different immunotherapies with each other or with other types of anti-cancer treatment like chemotherapy, radiation, or targeted therapies. One of the major barriers to effective immunotherapy seems to be the presence of immunosuppressive immune cells alongside the anti-tumor immune cells within the tumor. In head and neck cancers, immature myeloid cells and regulatory T-cells are potent suppressors of anti-tumor immunity. Our laboratory has investigated how to use targeted drugs that block the ability of immunosuppressive myeloid cells into the tumor to allow the anti-tumor immune cells to work more effectively after they have been activated by immunotherapy. Based on new investigation from our laboratory, drugs that block the recruitment of myeloid cells into tumors are being investigated in first-in-human clinical trials at the NIH clinical center. A different approach to allowing PD-1 ICB immunotherapy to work better is to alter the timing of treatment. Recent work from our laboratory has demonstrated that giving PD-1 ICB before surgery allows the immune system to see the tumor cells better than if the treatment is given after surgery. When the immune system detects and reacts against tumor cells better, it can better prevent the tumor from coming back. This work has contributed to the development of two new innovative clinical trials at the NIH Clinical Center that involve the administration of immunotherapy before surgical excision of both HPV-negative and HPV-positive tumors. These clinical trials are underway. Another line of thinking suggests that T cells, the immune cell type most studied for their ability to detect and kill cancer cells, may not work in some patients with cancer because of underlying mutations in the tumor cells that make them undetectable. In this case, another type of immune cell called NK cells may still be able to detect and kill the tumor cells. Working closely with other investigators in the National Cancer Institute, our laboratory has studied newly developed immunotherapies based on NK cells that be effective in treating cancers that cannot be effectively treated by immunotherapies designed to activate T cells. First in human clinical trials designed to study the safety and activity of these new NK cell immunotherapies are currently being reviewed for approval. Our laboratory also studies a rare disorder called recurrent respiratory papillomatosis. Patients with RRP, caused by HPV, develop papilloma tumors in their throat, voicebox, windpipe and lungs that can lead to severe voice disturbance or airway obstruction. Traditional treatment involves repeated surgery that leads to high recurrent rates. We are studying how to treat these tumors with immunotherapy and have performed the first clinical trial that has established the safety and clinical activity of PD-1 ICB in patients with RRP. WE also have developed a novel therapeutic vaccine, in collaboration with Precigen, Inc., designed to help activate new anti-HPV immune responses. This is currently being studies in a first-in-human phase I clinical trial at the NIH. In collaboration a colleague in the National Cancer Institute, we have received a Cancer Moonshot Award to further discover and develop new immunotherapies that someday could be used to treat not only RRP but other virally driven pre-cancerous disorders. These new immunotherapies include new therapeutic vaccines, and the ability to engineer someones immune system to be specific for HPV. We are excited to continue our work investigating new immunotherapies, with the ultimate goal of studying each new promising treatment in clinical trials at the NIH Clinical Center.