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PURPOSE Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC. PATIENTS AND METHODS Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS). RESULTS The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m2. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively. CONCLUSION Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach. more...

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC., Tobacco use is one of the major risk factors for Head and neck squamous cell carcinoma (HNSCC). Here, the authors report an immune-competent syngeneic mouse model that mimics human tobacco-related HNSCC, and develops tumors in the tongue, and report a high response rate to anti-CTLA-4 therapy. more...

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we found that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC. more...

Abstract The incidence of human papillomavirus-associated head and neck squamous cell carcinoma (HPV[ + ] HNSCC) is rapidly increasing. Although clinical management of primary HPV( + ) HNSCC is relatively successful, disease progression, including recurrence and metastasis, is often fatal. Moreover, patients with progressive disease face limited treatment options and significant treatment-associated morbidity. These clinical data highlight the need to identify targetable mechanisms that drive disease progression in HPV( + ) HNSCC to prevent and/or treat progressive disease. Interestingly, β-adrenergic signaling has recently been associated with pro-tumor processes in several disease types. Here we show that an aggressive murine model of recurrent/metastatic HPV( + ) HNSCC upregulates β2-adrenergic receptor (β2AR) expression, concordant with significantly heightened mitochondrial metabolism, as compared with the parental model from which it spontaneously derived. β-Adrenergic blockade effectively inhibits in vitro proliferation and migratory capacity in this model, effects associated with an attenuation of hyperactive mitochondrial respiration. Importantly, propranolol, a clinically available nonselective β-blocker, significantly slows primary tumor growth, inhibits metastatic development, and shows additive benefit alongside standard-of-care modalities in vivo. Further, via CRISPR/Cas9 technology, we show that the hyperactive mitochondrial metabolic profile and aggressive in vivo phenotype of this recurrent/metastatic model are dependent on β2AR expression. These data implicate β2AR as a modulator of mitochondrial metabolism and disease progression in HPV( + ) HNSCC, and warrant further investigation into the use of β-blockers as low cost, relatively tolerable, complementary treatment options in the clinical management of this disease. more...

Oral mucosal wound healing has long been regarded as an ideal system of wound resolution. However, the intrinsic characteristics that mediate optimal healing at mucosal surfaces are poorly understood, particularly in humans. We present a unique comparative analysis between human oral and cutaneous wound healing using paired and sequential biopsies during the repair process. Using molecular profiling, we determined that wound-activated transcriptional networks are present at basal state in the oral mucosa, priming the epithelium for wound repair. We show that oral mucosal wound-related networks control epithelial cell differentiation and regulate inflammatory responses, highlighting fundamental global mechanisms of repair and inflammatory responses in humans. The paired comparative analysis allowed for the identification of differentially expressed SOX2 (sex-determining region Y-box 2) and PITX1 (paired-like homeodomain 1) transcriptional regulators in oral versus skin keratinocytes, conferring a unique identity to oral keratinocytes. We show that SOX2 and PITX1 transcriptional function has the potential to reprogram skin keratinocytes to increase cell migration and improve wound resolution in vivo. Our data provide insights into therapeutic targeting of chronic and nonhealing wounds based on greater understanding of the biology of healing in human mucosal and cutaneous environments. more...

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. There is an urgent need to develop effective therapeutic approaches to prevent and treat HNSCC. Recent deep sequencing of the HNSCC genomic landscape revealed a multiplicity and diversity of genetic alterations in this malignancy. Although a large variety of specific molecules were found altered in each individual tumor, they all participate in only a handful of driver signaling pathways. Among them, the PI3K/mTOR pathway is the most frequently activated, which plays a central role in cancer initiation and progression. In turn, targeting of mTOR may represent a precision therapeutic approach for HNSCC. Indeed, mTOR inhibition exerts potent anti-tumor activity in HNSCC experimental systems, and mTOR targeting clinical trials show encouraging results. However, advanced HNSCC patients may exhibit unpredictable drug resistance, and the analysis of its molecular basis suggests that co-targeting strategies may provide a more effective option. In addition, although counterintuitive, emerging evidence suggests that mTOR inhibition may enhance the anti-tumor immune response. These new findings raise the possibility that the combination of mTOR inhibitors and immune oncology agents may provide novel precision therapeutic options for HNSCC. more...

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we found that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC. Note:This abstract was not presented at the conference. Citation Format: Zhiyong Wang, Victoria H. Wu, Michael M. Allevato, Mara Gilardi, Robert Saddawi-Konefka, Yudou He, Juan Luis Callejas-Valera, Lynn Vitale-Cross, Daniel Martin, Panomwat Amornphimoltham, James Mcdermott, Yusuke Goto, Alfredo A. Molinolo, Andrew B. Sharabi, Ezra E.W. Cohen, Qianming Chen, Guy Lyons, Ludmil B. Alexandrov, J. Silvio Gutkind. Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B51. more...

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The rising incidence of HPV-associated malignancies, especially for head and neck squamous cell carcinoma (HNSCC), has highlighted the urgent need to understand the role of HPV-16 E6/E7 oncogenes in cancer initiation and progression. For that propose we decided to generate a doxycycline inducible E6/E7 transgenic mouse targeting E6/E7 onco-proteins to the basal epithelia layer, including the stem cell compartment, through a doxycycline inducible cytokeratin 5 promoter (cK5-rtTA). This system allows to turn on the expression of HPV genes after birth, minimizing the negative effect that viral E6/E7 expression may have during embryonic development, and mimicking the natural infection process that usually happens in adults after initiation of sexual activities. Interestingly, we found that after doxycycline induction, both E6 and E7 were highly expressed, resulting in a clear increase in the number of proliferative cells even in the suprabasal layers, which results in rapid epidermal hyperplasia. However, in our animal mouse model HPV-16 E6/E7 expression alone was not sufficient to induce spontaneous squamous carcinomas (SCC). Due that we decided to challenge the oncogenic role of HPV using a classical chemical carcinogenesis protocol (DMBA-TPA). These mice develop SCC rapidly after a single exposure to a skin carcinogen, DMBA, which was increased by the prolonged exposure to a tumor promoter, TPA. These data suggest that only few oncogenic hits may be sufficient to induce cancer in humans already infected with HPV-16 E6/E7. Then, we decided to elucidate whether or not a few genomic alterations in combination with HPV-16 expression may be sufficient to induce cancer. One of the most frequent mutations in HNSCC, including HPV-associated cancers, are those affecting the PI3K-mTOR pathway. Based on that, we engineered a genetically defined mouse model combining HPV-16 E6/E7 and PIk3CAH1047R expression under the control of a cytokeratin 14 promoter driven tamoxifen-regulated Cre recombinase (cK14-CreERTM). Surprisingly, we found that upon tamoxifen activation mice develop oral cancer in only few weeks. Furthermore, our HPV-related cancer mouse models exhibited a marker increase of mTOR activation which is a key oncogenic driver in malignant progression to SCC. Remarkably, rapamycin, an mTOR inhibitor, was able to block tumor development, supporting the potential clinical use of direct and indirect mTOR inhibitors as a molecular targeted approach for prevention of HPV-associated malignancies. Citation Format: Juan Luis Callejas-Valera, Ramiro Iglesias-Bartolome, Panomwat Amornphimoltham, Julia Palacios-Garcia, Daniel Martin, Joseph A. Califano, Alfredo A. Molinolo, J.Silvio Gutkind. A next-gen animal model to Study PIK3CA-mTOR driven HPV-related oral malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4800. doi:10.1158/1538-7445.AM2017-4800 more...

mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA- HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy. more...