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)。一些患者对这种类型的治疗可能会有显著的有益反应，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，或与其他类型的抗癌治疗相结合，如化疗、放射治疗或靶向治疗。有效免疫治疗的主要障碍之一似乎是肿瘤内免疫抑制免疫细胞和抗肿瘤免疫细胞的存在。在头颈部癌症中，未成熟的髓系细胞和调节性T细胞是抗肿瘤免疫的有效抑制因子。我们的实验室研究了如何使用靶向药物来阻断免疫抑制的髓系细胞进入肿瘤的能力，使抗肿瘤免疫细胞在被免疫治疗激活后更有效地工作。根据我们实验室的最新研究，阻止髓系细胞募集到肿瘤中的药物正在NIH临床中心进行首例人类临床试验。 让PD-1 ICB免疫疗法更好发挥作用的另一种方法是改变治疗的时间。我们实验室最近的工作表明，与手术后给予治疗相比，手术前给予PD-1 ICB可以使免疫系统更好地看到肿瘤细胞。当免疫系统更好地检测到肿瘤细胞并对其做出反应时，它就可以更好地防止肿瘤复发。这项工作促进了NIH临床中心两项新的创新临床试验的发展，这两项试验涉及在手术切除HPV阴性和HPV阳性肿瘤之前进行免疫治疗。 另一种思路表明，T细胞可能在一些癌症患者身上不起作用，因为肿瘤细胞的潜在突变使它们无法被检测到。T细胞是一种免疫细胞类型，因其检测和杀死癌细胞的能力而受到最多研究。在这种情况下，另一种名为NK细胞的免疫细胞可能仍然能够检测并杀死肿瘤细胞。我们的实验室与国家癌症研究所的其他研究人员密切合作，研究了新开发的基于NK细胞的免疫疗法，这些疗法在治疗那些无法通过旨在激活T细胞的免疫疗法有效治疗的癌症方面是有效的。这项实验室工作正在进行中，预期将在NIH临床中心进行使用这些NK细胞疗法的首例人类临床试验。 我们的实验室还研究一种罕见的疾病，称为复发性呼吸道乳头状瘤病。由HPV引起的RRP患者会在喉咙、声箱、气管和喉咙发生乳头状瘤瘤，从而导致严重的嗓音障碍或呼吸道阻塞。传统的治疗方法包括重复手术，这会导致高复发率。我们正在研究如何用免疫疗法治疗这些肿瘤，并进行了第一次临床试验，证实了PD-1 ICB对RRP患者的安全性和临床活性。在国家癌症研究所的一位同事的合作下，我们获得了癌症登月奖，以进一步发现和开发新的免疫疗法，这些疗法有朝一日不仅可以用于治疗RRP，还可以用于治疗其他由病毒驱动的癌前疾病。 我们很高兴能继续我们的工作，研究新的免疫疗法，最终目标是将每种有希望的治疗方法都转移到NIH和其他学术医学中心的早期临床试验中。

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. 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. This laboratory work is ongoing with anticipated first-in-human clinical trials at the NIH Clinical Center using these NK cellular therapies. 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 lings 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. 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. We are excited to continue our work investigating new immunotherapies, with the ultimate goal of moving each promising treatment into early phase clinical trials at the NIH and other academic medical centers.