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

头颈癌抗肿瘤免疫反应的表征和增强

• 批准号: 10687953
• 负责人: Clint Allen
• 金额: $ 321.06万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 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/10687953
• 关键词: Award; Back; Blood specimen; Cells; Chemotherapy and/or radiation; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Development; Disease; Drug Industry; Drug Targeting; Engineering; Excision; FDA approved; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Investigation; Laboratories; Lead; Lung; Malignant Neoplasms; Metastatic/Recurrent; Mutation; Myeloid Cells; Myeloid-derived suppressor cells; National Cancer Institute; Natural Killer Cells; Operative Surgical Procedures; Papilloma; Patients; Pharmaceutical Preparations; Pharyngeal structure; Phase I Clinical Trials; Quality of life; Radiation therapy; Rare Diseases; Recurrence; Recurrent respiratory papillomatosis; Regulatory T-Lymphocyte; Repeat Surgery; Research Personnel; Safety; T-Lymphocyte; Therapeutic; Thinking; Tissue Sample; Trachea; Translational Research; Tumor Immunity; Tumor-infiltrating immune cells; United States National Institutes of Health; Viral; Voice Disturbances; Work; airway obstruction; anti-tumor immune response; anticancer treatment; base; cancer cell; cell type; clinical center; design; early phase clinical trial; first-in-human; immune checkpoint blockade; improved; innovation; neoplastic cell; novel therapeutics; patient response; pre-clinical; premalignant; prevent; programmed cell death protein 1; programs; recruit; response; safety study; targeted treatment; therapeutic vaccine; treatment response; tumor

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.

程序性死亡-1免疫检查点阻断（PD-1 ICB）现已获得FDA批准用于治疗复发性/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。一种方法是将联合收割机不同的免疫疗法相互结合或与其他类型的抗癌治疗如化疗，放疗或靶向治疗相结合。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性免疫细胞以及抗肿瘤免疫细胞。在头颈部癌症中，未成熟的骨髓细胞和调节性T细胞是抗肿瘤免疫的有效抑制剂。我们的实验室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，以使抗肿瘤免疫细胞在被免疫疗法激活后更有效地发挥作用。根据我们实验室的新研究，NIH临床中心正在进行首次人体临床试验，研究阻止骨髓细胞招募到肿瘤中的药物。 让PD-1 ICB免疫疗法更好地发挥作用的另一种方法是改变治疗时机。我们实验室最近的工作表明，手术前给予PD-1 ICB可以让免疫系统比手术后给予治疗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，它可以更好地防止肿瘤复发。这项工作为NIH临床中心两项新的创新临床试验的开发做出了贡献，这些试验涉及在HPV阴性和HPV阳性肿瘤的手术切除前进行免疫治疗。这些临床试验正在进行中。 另一种思路表明，T细胞是一种因其检测和杀死癌细胞的能力而被研究得最多的免疫细胞类型，可能在一些癌症患者中不起作用，因为肿瘤细胞中的潜在突变使它们无法检测到。在这种情况下，另一种称为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，这些免疫疗法可有效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。第一个人体临床试验旨在研究这些新的NK细胞免疫疗法的安全性和活性，目前正在审查批准。 我们的实验室还研究了一种罕见的疾病，称为复发性呼吸道乳头状瘤病。由HPV引起的RRP患者在咽喉、喉腔、气管和肺部发生乳头状瘤，可导致严重的声音障碍或气道阻塞。传统的治疗方法包括重复手术，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，并进行了第一项临床试验，确定了PD-1 ICB在RRP患者中的安全性和临床活性。我们还与Precigen公司合作开发了一种新型治疗性疫苗，旨在帮助激活新的抗HPV免疫反应。这是目前正在研究的第一次在人体I期临床试验在美国国立卫生研究院。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，有朝一日不仅可以用于治疗RRP，还可以用于治疗其他病毒驱动的癌前疾病。这些新的免疫疗法包括新的治疗性疫苗，以及将某人的免疫系统设计成对HPV特异性的能力。 我们很高兴能继续研究新的免疫疗法，最终目标是在NIH临床中心的临床试验中研究每一种新的有希望的治疗方法。

项目成果

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types.

• DOI: 10.1080/2162402x.2018.1466018
• 发表时间: 2018
• 期刊: Oncoimmunology
• 影响因子: 7.2
• 作者: Hicks KC;Fantini M;Donahue RN;Schwab A;Knudson KM;Tritsch SR;Jochems C;Clavijo PE;Allen CT;Hodge JW;Tsang KY;Schlom J;Gameiro SR
• 通讯作者: Gameiro SR

Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma.

• DOI: 10.1158/2326-6066.cir-17-0235
• 发表时间: 2017-12
• 期刊: Cancer immunology research
• 影响因子: 10.1
• 作者: Tran L;Allen CT;Xiao R;Moore E;Davis R;Park SJ;Spielbauer K;Van Waes C;Schmitt NC
• 通讯作者: Schmitt NC

Biologics for the Treatment of Recurrent Respiratory Papillomatosis.

• DOI: 10.1016/j.otc.2021.05.002
• 发表时间: 2021-08
• 期刊: Otolaryngologic clinics of North America
• 影响因子: 1.7
• 作者: Allen CT

Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells.

• DOI: 10.1136/jitc-2020-002128
• 发表时间: 2021-03
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Lee MY;Robbins Y;Sievers C;Friedman J;Abdul Sater H;Clavijo PE;Judd N;Tsong E;Silvin C;Soon-Shiong P;Padget MR;Schlom J;Hodge J;Hinrichs C;Allen C
• 通讯作者: Allen C

Preclinical study of a novel therapeutic vaccine for recurrent respiratory papillomatosis.

• DOI: 10.1038/s41541-021-00348-x
• 发表时间: 2021-06-18
• 期刊: NPJ vaccines
• 影响因子: 9.2
• 作者: Lee MY;Metenou S;Brough DE;Sabzevari H;Bai K;Jochems C;Schlom J;Allen CT
• 通讯作者: Allen CT