Publications by authors named "Sara I Pai"

91 Publications

Myeloid cells are enriched in tonsillar crypts providing insight into the host tropism of HPV.

Am J Pathol 2021 Jul 22. Epub 2021 Jul 22.

Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA. Electronic address:

Viruses are the second leading cause of cancer worldwide, and human papillomavirus (HPV)-associated head and neck cancers are increasing in incidence in the United States. HPV preferentially infects the crypts of the tonsils rather than the surface epithelium. The present study sought to characterize the unique microenvironment within the crypts to better understand the host tropism of HPV to a lymphoid rich organ. Laser-capture microdissection of distinct anatomic areas (crypts, surface epithelium, and germinal centers) of the tonsil coupled with transcriptional analysis and multi-parameter immunofluorescence staining was performed and demonstrated that the tonsillar crypts are enriched with myeloid populations which co-express multiple canonical and non-canonical immune checkpoints, including PD-L1, CTLA-4, HAVCR2 (TIM-3), ADORA2A, IDO1, BTLA, LGALS3, CDH1, CEACAM1, PVR, and C10orf54 (VISTA). The resident monocytes may foster a permissive microenvironment that facilitates HPV infection and persistence. Furthermore, the myeloid populations within HPV-associated tonsil cancers co-express the same immune checkpoints, providing insight into potential novel immunotherapeutic targets for HPV-associated head and neck cancers.
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http://dx.doi.org/10.1016/j.ajpath.2021.06.012DOI Listing
July 2021

Rapid Serial Immunoprofiling of the Tumor Immune Microenvironment by Fine Needle Sampling.

Clin Cancer Res 2021 Jul 7. Epub 2021 Jul 7.

Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts.

Purpose: There is increasing effort to discover and integrate predictive and/or prognostic biomarkers into treatment algorithms. While tissue-based methods can reveal tumor-immune cell compositions at a single time point, we propose that single-cell sampling via fine needle aspiration (FNA) can facilitate serial assessment of the tumor immune microenvironment (TME) with a favorable risk-benefit profile.

Experimental Design: Primary antibodies directed against 20 murine and 25 human markers of interest were chemically modified via a custom linker-bio-orthogonal quencher (FAST) probe. A FAST-FNA cyclic imaging and analysis pipeline were developed to derive quantitative response scores. Single cells were harvested via FNA and characterized phenotypically and functionally both in preclinical and human samples using the newly developed FAST-FNA assay.

Results: FAST-FNA samples analyzed manually versus the newly developed deep learning-assisted pipeline gave highly concordant results. Subsequently, an agreement analysis showed that FAST and flow cytometry of surgically resected tumors were positively correlated with an R = 0.97 in preclinical samples and an R = 0.86 in human samples with the detection of the relevant tumor and immune biomarkers of interest. Finally, the feasibility of applying this minimally invasive approach to analyze the TME during immunotherapy was assessed in patients with cancer revealing local antitumor immune programs.

Conclusions: The FAST-FNA is an innovative technology that combines bio-orthogonal chemistry coupled with a computational analysis pipeline for the comprehensive profiling of single cells obtained through FNA. This is the first demonstration that the complex and rapidly evolving TME during treatment can be accurately and serially measured by simple FNA.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1252DOI Listing
July 2021

Diagnostic challenges and successful organ-preserving therapy in a case of secretory carcinoma of minor salivary glands.

Cancer Rep (Hoboken) 2021 Jul 7:e1491. Epub 2021 Jul 7.

Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Secretory carcinoma is a more recently described subtype of salivary gland carcinoma that may pose diagnostic challenges and frequently harbors NTRK fusions that may successfully be targeted by TRK inhibitors in advanced disease.

Case: We present the case of a female patient with secretory carcinoma arising in the base of tongue with persistent disease after debulking surgery and definitive chemoradiation. As an alternative to salvage surgery, which would have resulted in significant impairment of swallowing and speech function, a targeted therapy with the TRK-inhibitor larotrectinib against an identified ETV6-NTRK3 fusion product was initiated. Larotrectinib treatment has been well tolerated, resulted in durable complete response and the patient maintains good swallowing and speech function.

Conclusion: The presented case underscores the importance of the accurate diagnosis of secretory carcinoma. It further highlights the impact of molecular testing as targeted therapies may play an important role in the management of advanced salivary gland cancers.
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http://dx.doi.org/10.1002/cnr2.1491DOI Listing
July 2021

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Sci Immunol 2021 Jul;6(61)

Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
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http://dx.doi.org/10.1126/sciimmunol.abi7083DOI Listing
July 2021

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

J Immunother Cancer 2020 11;8(2)

Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670953PMC
November 2020

New technology on the horizon: Fast analytical screening technique FNA (FAST-FNA) enables rapid, multiplex biomarker analysis in head and neck cancers.

Cancer Cytopathol 2020 11 25;128(11):782-791. Epub 2020 Aug 25.

Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts.

PD-L1 profiling was recently approved by the US Food and Drug Administration as a companion diagnostic for anti-PD1 treatment in patients with head and neck cancer, ushering in a new era for precision medicine. However, the routine development and implementation of such testing is still limited by current clinical workflows and the lack of better and more comprehensive alternatives. In this review, the authors discuss the real-world challenges of clinically based biomarker testing and highlight the advantages of developing fine-needle aspiration (FNA)-based biomarker testing that would enable frequent and serial tumor sampling. A conceptual and technological innovation is introduced, fast analytical screening technique (FAST)-FNA (FAST chemistry-enabled FNA), which is being developed to inform immunotherapy treatment options in patients with head and neck cancer and to assist with the development of the next generation of predictive biomarkers.
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http://dx.doi.org/10.1002/cncy.22305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276888PMC
November 2020

A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma.

Int J Radiat Oncol Biol Phys 2021 01 8;109(1):134-144. Epub 2020 Aug 8.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address:

Purpose: We evaluated the safety and efficacy of pembrolizumab (pembro) ± radiation therapy (RT) in a phase 2 study among patients with progressive, metastatic adenoid cystic carcinoma (ACC).

Methods And Materials: Eligible patients had metastatic ACC with progression within the last year and ≥1 measurable lesion. Patients were randomized to pembro alone or with RT to 30 Gy in 5 fractions (pembroRT). The primary endpoint was objective response rate outside the RT field. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and local RT responses.

Results: We randomized 20 patients (10 per arm) from 2017 to 2018. We did not observe objective response outside of the radiation treatment field; stable disease (SD) was the best response in 12 (60%) patients and was not different per arm (7 pembro, 5 pembroRT, P = .65). A tumor growth rate decrease (TGR) of >25% was noted among 7 of 12 patients and >75% in 4 patients. There were local responses in the irradiated field among all evaluable pembroRT patients. Median PFS and OS were 4.5/not reached for pembroRT and 6.6 / 27.2 months for pembro patients. One patient developed grade 3 liver enzyme elevation after 27 cycles of therapy. Correlative analyses confirm low levels of programmed death-ligand 1 expression (PD-L1), and CD8 infiltrating T-cells. We identified associations between local response and both MYB/NFIB translocation and PD-L1 expression and between changes in systemic immune populations and RT.

Conclusions: Pembrolizumab and pembroRT were well tolerated. We observed no objective responses, but 60% of patients with PD before the study achieved SD, the majority with decreased TGR and half (n = 10) with clinical benefit (SD >6 months). We observed favorable local responses within the RT field. Additional strategies are needed to further delay progression and effect response.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.018DOI Listing
January 2021

High Expression of Programmed Death Ligand 1 and Programmed Death Ligand 2 in Ophthalmic Sebaceous Carcinoma: The Case for a Clinical Trial of Checkpoint Inhibitors.

Am J Ophthalmol 2020 12 28;220:128-139. Epub 2020 Jul 28.

Division of Head and Neck Pathology, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: To evaluate the expression of programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) in ocular adnexal sebaceous carcinoma (OASC), and to appraise these findings within the context of recent comparable studies.

Designs: Retrospective case series.

Methods: Twenty cases of primary OASC were immunostained for PD-L1, PD-L2 and CD8. PD-L1 and PD-L2 expression were graded with both the combined positive score (CPS) and the tumor proportion score (TPS). Both raw CPS and TPS were reported, as well as positivity with TPS and CPS ≥1. CD8 expression was graded on a 0-3 scale. Charts were reviewed for clinical correlations. The results of the current study were compared with results of similar recent investigations.

Results: For the 20 cases, mean expression of PD-L1 with CPS was 29.7 (range 0-101.5) and with TPS was 12.2 (range 0-95.8); mean expression of PD-L2 with CPS was 7.9 (range 0-37.3) and with TPS was 1.9 (range 0-12.9). PD-L1 CPS ≥1 was detected in 95% of OASC, while PD-L1 TPS ≥1 was found in 75%. PD-L2 CPS ≥1 was present in 60%, while only 20% had PD-L2 TPS ≥1. Immune cells appeared to contribute to a substantial proportion of PD-L1 and PD-L2 positivity, and a conspicuous CD8-positive T-lymphocytic infiltrate was present in most tumors. Significant correlations were identified between tissue expression of PD-L1, PD-L2, and CD8. Tissues with greater levels of PD-L1 tended to express higher levels of PD-L2 and CD8. The degree of PD-L1 and PD-L2 expression was also associated with the area in millimeters squared of the immunostained tumor, suggesting that tumor sampling may influence interpretation of PD-L1 and PD-L2 expression in ocular adnexal tumors.

Conclusions: The current and preceding studies confirm that PD-L1 and PD-L2 are expressed in a high percentage of OASCs. These results support the premise that checkpoint inhibitor drugs hold considerable therapeutic promise for patients with OASC and stimulate the institution of clinical trials.
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http://dx.doi.org/10.1016/j.ajo.2020.07.031DOI Listing
December 2020

The Paradox of Cancer Immune Exclusion: Immune Oncology Next Frontier.

Cancer Treat Res 2020 ;180:173-195

Refuge Biotechnologies, Inc., Menlo Park, CA, USA.

Checkpoint inhibitor therapy (CIT) has revolutionized cancer treatment but it has also reached a standstill when an absent dialog between cancer and immune cells makes it irrelevant. This occurs with high prevalence in the context of "immune silent" and, even perhaps, "immune-excluded" tumors. The latter are characterized by T cells restricted to the periphery of cancer nests. Since in either case T cells do not come in direct contact with most cancer cells, CIT rests immaterial. Adoptive cell therapy (ACT), may also be affected by limited access to antigen-bearing cancer cells. While lack of immunogenicity intuitively explains the immune silent phenotype, immune exclusion is perplexing. The presence of T cells at the periphery suggests that chemo-attraction recruits them and an immunogenic stimulus promotes their persistence. However, what stops the T cells from infiltrating the tumors' nests and reaching the germinal center (GC)? Possibly, a concentric gradient of increased chemo-repulsion or decreased chemo-attraction demarcates an abrupt "do not trespass" warning. Various hypotheses suggest physical or functional barriers but no definitive consensus exists over the weight that each plays in human cancers. On one hand, it could be hypothesized that the intrinsic biology of cancer cells may degenerate from a "cancer stem cell" (CSC)-like phenotype in the GC toward a progressively more immunogenic phenotype prone to immunogenic cell death (ICD) at the periphery. On the other hand, the intrinsic biology of the cancer cells may not change but it is the disorderly architecture of the tumor microenvironment (TME) that alters in a centripetal direction cancer cell metabolism, both directly and indirectly, the function of surrounding stromal cells. In this chapter, we examine whether the paradoxical exclusion of T cells from tumors may serve as a model to understand the requirements for tumor immune infiltration and, correspondingly, we put forth strategies to restore the dialog between immune cells and cancer to enhance the effectiveness of immune oncology (IO) approaches.
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http://dx.doi.org/10.1007/978-3-030-38862-1_6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423459PMC
September 2020

High-dimensional multiplexed immunohistochemical characterization of immune contexture in human cancers.

Methods Enzymol 2020 2;635:1-20. Epub 2019 Jul 2.

Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR, United States; Knight Cancer Research Institute, Oregon Health and Science University, Portland, OR, United States. Electronic address:

Biomarker assessments of tumor specimens is widely used in cancer research to audit tumor cell intrinsic as well as tumor cell extrinsic features including the diversity of immune, stromal, and mesenchymal cells. To comprehensively and quantitatively audit the tumor-immune microenvironment (TiME), we developed a novel multiplex immunohistochemistry (mIHC) platform and computational image processing workflow using a single formalin-fixed paraffin-embedded (FFPE) tissue section. Herein, we validated this platform using nine matched primary newly diagnosed and recurrent head and neck squamous cell carcinoma (HNSCC) sections sequentially subjected to immunodetection with a panel of 29 antibodies identifying malignant tumor cells, and 17 distinct leukocyte lineages and their functional states. Image cytometric analysis was applied to interpret chromogenic signals from digitally scanned and coregistered light microscopy-based images enabling identification and quantification of individual tumor cells, structural features, immune cell phenotypes and their functional state. In agreement with our previous study via a 12-plex imaging mIHC platform, myeloid-inflamed status in newly diagnosed primary tumors associated with significantly short progression free survival, independent of lymphoid-inflamed status. Spatial distribution of tumor and immune cell lineages in TiME was also examined and revealed statistically significant CD8 T cell exclusion from tumor nests, whereas regulatory T cells and myeloid cells, when present in close proximity to tumor cells, highly associated with rapid cancer recurrence. These findings indicate presence of differential immune-spatial profiles in newly diagnosed and recurrent HNSCC, and establish the robustness of the 29-plex mIHC platform and associated analytics for quantitative analysis of single tissue sections revealing longitudinal TiME changes.
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http://dx.doi.org/10.1016/bs.mie.2019.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390987PMC
June 2021

Antibody-mediated delivery of viral epitopes to tumors harnesses CMV-specific T cells for cancer therapy.

Nat Biotechnol 2020 04 10;38(4):420-425. Epub 2020 Feb 10.

Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.

Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8 T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.
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http://dx.doi.org/10.1038/s41587-019-0404-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456461PMC
April 2020

PD-L1 and PD-L2 Expression Levels Are Low in Primary and Secondary Adenoid Cystic Carcinomas of the Orbit: Therapeutic Implications.

Ophthalmic Plast Reconstr Surg 2020 Sep/Oct;36(5):444-450

Division of Head and Neck Pathology, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: To determine if there is a biologic rationale for using checkpoint inhibitor drugs targeting programmed cell death ligand 1 (PD-L1) and PD-L2 in the treatment of adenoid cystic carcinoma of the orbit.

Methods: Twenty-three cases of adenoid cystic carcinoma involving the orbit (13 primary lacrimal gland, 5 secondarily extending into the orbit, and 5 unspecified) were examined histopathologically. Immunohistochemistry for PD-L1, PD-L2, and CD8 was performed. Charts were reviewed for clinical correlations.

Results: Expression of PD-L1 and of PD-L2 was overall low in adenoid cystic carcinoma (mean expression 1.4 ± 0.9 of 5 for PD-L1, mean 0.83 ± 1.1 of 5 for PD-L2), and tumor-infiltrating CD8-positive T-lymphocytes were sparse (mean 1.1 ± 0.51 of 3). Only 13 of the 23 (57%) cases expressed PD-L1 as a combined positive score ≥1 of cells. No associations were found between expression levels of these markers and patient sex, tumor site of origin, Tumor, Node, Metastasis stage, or patient outcome. A significant association was observed between stromal PD-L1 expression and tumor histopathologic subtype (p = 0.05), and between tumor PD-L1 expression and prior exposure to radiation (p = 0.03).

Conclusions: Checkpoint inhibitor drugs may have limited impact in the treatment and clinical course of orbital adenoid cystic carcinoma based on the low frequency of CD8 infiltrate and low expression of PD-L1 and PD-L2. Pretreatment with radiation, however, may improve tumor response to checkpoint inhibitor drugs.
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http://dx.doi.org/10.1097/IOP.0000000000001585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423458PMC
March 2021

Peripheral Circulating CD45RAFOXP3 T Regulatory (T) II Cells Provide a Window into the Activity of Intratumoral T Cells.

Trends Cancer 2020 01 3;6(1):3-6. Epub 2019 Dec 3.

Refuge Biotechnologies, Menlo Park, CA 94025, USA. Electronic address:

The immune landscape of cancer determines its responsiveness to immunotherapy. Tumors infiltrated with CD8 T cells (immune-active tumors) are more likely to respond to immunomodulatory agents. However, immune activation often is counterbalanced by strong immunosuppressive mechanisms that are necessary to maintain homeostasis but consequentially can facilitate the survival of cancer cells in the immunocompetent host, a concept defined as compensatory immune suppression. T cells contribute to compensatory immune suppression, and therapies targeting the immunosuppressive T population are being actively explored. Wang et al. characterize a subset of peripheral circulating CD45FOXP3 T II cells that phenotypically and functionally parallel the activity of their intratumoral counterparts. The findings are paradigm shifting and may provide a potential liquid-based tool to evaluate the immunosuppressive activity of intratumoral T cells; they may also allow temporal assessment of whether the fine balance between immune rejection versus tolerance is achieved with various applied therapies.
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http://dx.doi.org/10.1016/j.trecan.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390988PMC
January 2020

SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

J Transl Med 2019 12 26;17(1):429. Epub 2019 Dec 26.

AstraZeneca, Gaithersburg, MD, USA.

Background: Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy.

Methods: This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC.

Results: 412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively).

Conclusions: PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015.
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http://dx.doi.org/10.1186/s12967-019-02182-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933901PMC
December 2019

Intratumoral delivery of an HPV vaccine elicits a broad anti-tumor immune response that translates into a potent anti-tumor effect in a preclinical murine HPV model.

Cancer Immunol Immunother 2019 Aug 26;68(8):1273-1286. Epub 2019 Jun 26.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1 TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8 T cells. Overall, the CD8/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).
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http://dx.doi.org/10.1007/s00262-019-02357-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684362PMC
August 2019

Comparative analysis of the phase III clinical trials of anti-PD1 monotherapy in head and neck squamous cell carcinoma patients (CheckMate 141 and KEYNOTE 040).

J Immunother Cancer 2019 04 3;7(1):96. Epub 2019 Apr 3.

Département Hématologie-oncologie, Centre hospitalier de l'Université de Montréal, Montréal, Canada.

Two phase III clinical trials (CheckMate 141 and KEYNOTE 040) have independently demonstrated that overall survival (OS) in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients, who have failed platinum-based therapy, can be improved with anti-PD1 monotherapy. Treatment with nivolumab or pembrolizumab in R/M HNSCC patients led to an improved OS with a hazards ratio (HR) of 0.70 (95%CI 0.51-0.96; p = 0.01) and HR of 0.80 (95%CI 0.65-0.98, p = 0.0161), respectively, as compared to standard of care (SOC) chemo monotherapy regimens (specifically, cetuximab, docetaxel, or methotrexate). The gain in OS was similar in both studies, underscoring the role of anti-PD1 drugs in R/M HNSCC patients. One of the striking discrepancies between CheckMate 141 and KEYNOTE 040 was the OS observed in the control SOC arms (6.9 months median in KEYNOTE 040 versus 5.1 months in CheckMate 141), which inadvertently set a higher threshold in the bio-statistical analysis of KEYNOTE 040 so that the clinical outcome of every patient was influential in the analysis. We perform a comparative analysis of the two studies to identify potential factors in the control arm that can impact clinical trial bio-statistical outcomes and which may have implications for future immunotherapy clinical trial designs.
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http://dx.doi.org/10.1186/s40425-019-0578-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446400PMC
April 2019

Programmed Cell Death 1 Ligand 1 and Programmed Cell Death 1 Ligand 2 Are Expressed in Conjunctival Invasive Squamous Cell Carcinoma: Therapeutic Implications.

Am J Ophthalmol 2019 04 8;200:226-241. Epub 2019 Jan 8.

Division of Head and Neck Pathology, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: Novel cancer immunotherapies, called immune checkpoint inhibitors, have demonstrated clinical efficacy in the treatment of squamous cell carcinomas of the head and neck. Tissue expression of programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 ligand 2 (PD-L2) has been shown to predict tumor response to these drugs. We examine the expression of prognostic immune biomarkers, PD-L1 and PD-L2, in invasive ocular surface squamous neoplasia.

Design: Retrospective case series.

Methods: Eighteen cases of ocular surface or ocular adnexal invasive squamous cell carcinomas were identified in pathology case files of the Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary and at the Wills Eye Hospital accessioned between January 1, 2014 and January 1, 2017. Immunohistochemical staining for PD-L1, PD-L2, CD8, and p16 was performed and graded in a standardized fashion.

Results: PD-L1 and PD-L2 were expressed on tumor cells to varying degrees, and also on some stromal cells and endothelial cells. Stromal and endothelial cell expression was also seen in control conjunctival specimens. Tumor expression of PD-L1 and PD-L2 was present on the cell membranes. All 18 (100%) of the tumors expressed PD-L1: 7 (39%) expressed a high level, 3 (17%) expressed a medium level, and 8 (44%) expressed a low level. Only 9 (50%) tumors expressed PD-L2 and it was at a low level. The expression of PD-L1 in tumor cells correlated with the presence of CD8-positive cytotoxic T lymphocytes among tumor cells (P < .01) and with the presence of CD8-positive cells in the surrounding stroma (P = .04).

Conclusions: A subset of ocular invasive conjunctival squamous carcinomas express high levels of PD-L1 and CD8 and therefore may respond therapeutically to immune checkpoint inhibition.
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http://dx.doi.org/10.1016/j.ajo.2018.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456462PMC
April 2019

Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12.

Immunity 2018 12 11;49(6):1148-1161.e7. Epub 2018 Dec 11.

Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA. Electronic address:

Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
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http://dx.doi.org/10.1016/j.immuni.2018.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301092PMC
December 2018

Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer.

Genome Med 2018 07 20;10(1):54. Epub 2018 Jul 20.

Department of Molecular and Cell Biology, Goldman School of Dental Medicine, Boston University School of Medicine, 72 East Concord Street, E4, Boston, MA, 02118, USA.

Background: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease. To date, few targeted therapies are available for HNSCC, and only a small fraction of patients have benefited from these treatments. A frequent feature of HNSCC is the inappropriate activation of β-catenin that has been implicated in cell survival and in the maintenance and expansion of stem cell-like populations, thought to be the underlying cause of tumor recurrence and resistance to treatment. However, the therapeutic value of targeting β-catenin activity in HNSCC has not been explored.

Methods: We utilized a combination of computational and experimental profiling approaches to examine the effects of blocking the interaction between β-catenin and cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We generated and annotated in vitro treatment gene expression signatures of HNSCC cells, derived from human oral squamous cell carcinomas (OSCCs), using microarrays. We validated the anti-tumorigenic activity of ICG-001 in vivo using SCC-derived tumor xenografts in murine models, as well as embryonic zebrafish-based screens of sorted stem cell-like subpopulations. Additionally, ICG-001-inhibition signatures were overlaid with RNA-sequencing data from The Cancer Genome Atlas (TCGA) for human OSCCs to evaluate its association with tumor progression and prognosis.

Results: ICG-001 inhibited HNSCC cell proliferation and tumor growth in cellular and murine models, respectively, while promoting intercellular adhesion and loss of invasive phenotypes. Furthermore, ICG-001 preferentially targeted the ability of subpopulations of stem-like cells to establish metastatic tumors in zebrafish. Significantly, interrogation of the ICG-001 inhibition-associated gene expression signature in the TCGA OSCC human cohort indicated that the targeted β-catenin/CBP transcriptional activity tracked with tumor status, advanced tumor grade, and poor overall patient survival.

Conclusions: Collectively, our results identify β-catenin/CBP interaction as a novel target for anti-HNSCC therapy and provide evidence that derivatives of ICG-001 with enhanced inhibitory activity may serve as an effective strategy to interfere with aggressive features of HNSCC.
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http://dx.doi.org/10.1186/s13073-018-0569-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053793PMC
July 2018

PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma.

Endocr Pathol 2018 Mar;29(1):59-67

Department of Pathology, Massachusetts General Hospital, Warren 219, 55 Fruit Street, Boston, MA, 02114, USA.

Poorly differentiated thyroid carcinoma (PDTC) is an aggressive form of thyroid cancer that currently has limited effective treatment options. Immune checkpoint inhibitors (ICIs) have shown to be an effective treatment for a variety of carcinomas. In this study, we explore whether immune checkpoint pathways, such as programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1), are activated in a cohort of patients with PDTC to determine whether ICIs may be an effective therapy for these patients. PDTC from 28 patients were stained for IDO1, PD-L1, and CD8 using immunohistochemistry. Staining was scored using an H-score, and PD-L1 and IDO1 expression was correlated with clinicopathologic characteristics. Positivity for PD-L1 and IDO1 was set at an H-score cutoff of five. Twenty-five percent (n = 7/28) of the PDTC were positive for PD-L1 expression. Twenty-nine percent (n = 2/7) of the PD-L1 positive PDTCs also co-expressed IDO1. The expression of PD-L1 in PDTC was significantly associated with tumor size and multifocality, with a non-significant trend towards associations with older age, extrathyroidal extension, presence of metastasis, higher stage, increased number of CD8+ T cells, and decreased disease-free and overall survival. PD-L1 expression occurs in a subset of PDTC, and is associated with a subset of clinical features of aggressive thyroid disease. Given the limited effective treatments for this patient population, consideration for ICIs as monotherapy or in combination with an IDO1 inhibitor should be explored as a novel treatment modality for patients with PDTC.
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http://dx.doi.org/10.1007/s12022-018-9514-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500591PMC
March 2018

HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers.

Oral Oncol 2018 02 28;77:92-97. Epub 2017 Dec 28.

Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

Human immunodeficiency virus (HIV)-infected individuals are at increased risk for developing several non-AIDS related malignancies and are often excluded from cancer immunotherapy regimens. To evaluate the immune competence of this cancer patient population, we evaluated HLA class I antigen presenting machinery (APM) component expression and PD-1:PD-L1 pathway upregulation in HIV(+) and HIV(-) head and neck cancers (HNCs). Sixty-two HIV(+) and 44 matched HIV(-) controls diagnosed with HNC between 1991 and 2011 from five tertiary care referral centers in the United States were identified. HLA class I APM component, PD-1, and PD-L1 expression were analyzed by immunohistochemical staining with monoclonal antibodies (mAbs). Clinical data was abstracted from the medical records. There was no significant difference between the cases and controls in LMP2, TAP1, HLA-A and HLA-B/C, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1 within the tumor microenvironment. LMP2, HLA-A and HLA-B/C expression were significantly associated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = .004, p = .026, and p = .006, respectively) but not in the HIV(-) controls. In addition, HLA-A expression was significantly associated with PD-L1 expression in the HIV(+) HNC cases only (p = .029). HIV-infected individuals diagnosed with HNC do not have any detectable defects in HLA class I APM component expression and in PD-1:PD-L1 pathway activation. Given the current successes of HAART therapy in maintaining immune cell counts, HIV(+) patients diagnosed with cancer may benefit from the recently FDA-approved immune checkpoint blockade therapy.
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http://dx.doi.org/10.1016/j.oraloncology.2017.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786382PMC
February 2018

Checkpoint cluster: biomarkers of response.

Emerg Top Life Sci 2017 Dec;1(5):501-508

Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, U.S.A.

Current clinical knowledge surrounding one of the most promising immune checkpoint pathways, namely programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2, is reviewed in the context of head and neck squamous cell carcinoma. The results of two phase III clinical trials (KEYNOTE 040 and CheckMate 141) are critically examined. The utility of predictive biomarkers of response to immune checkpoint blockade, such as PD-L1/PD-L2 protein expression, interferon-gamma gene expression signatures, and mutational and neoantigen load, is discussed. Finally, we project future directions in the immuno-oncology field by discussing other promising predictive biomarkers as well as areas where the next advances are likely to take place, such as in the implementation of immune checkpoint inhibitors earlier in the course of cancer treatment and/or in combination therapies.
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http://dx.doi.org/10.1042/ETLS20170077DOI Listing
December 2017

Distinct pattern of TP53 mutations in human immunodeficiency virus-related head and neck squamous cell carcinoma.

Cancer 2018 Jan 20;124(1):84-94. Epub 2017 Oct 20.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Human immunodeficiency virus-infected individuals (HIVIIs) have a higher incidence of head and neck squamous cell carcinoma (HNSCC), and clinical and histopathological differences have been observed in their tumors in comparison with those of HNSCC patients without a human immunodeficiency virus (HIV) infection. The reasons for these differences are not clear, and molecular differences between HIV-related HNSCC and non-HIV-related HNSCC may exist. This study compared the mutational patterns of HIV-related HNSCC and non-HIV-related HNSCC.

Methods: The DNA of 20 samples of HIV-related HNSCCs and 32 samples of non-HIV-related HNSCCs was sequenced. DNA libraries covering exons of 18 genes frequently mutated in HNSCC (AJUBA, CASP8, CCND1, CDKN2A, EGFR, FAT1, FBXW7, HLA-A, HRAS, KEAP1, NFE2L2, NOTCH1, NOTCH2, NSD1, PIK3CA, TGFBR2, TP53, and TP63) were prepared and sequenced on an Ion Personal Genome Machine sequencer. DNA sequencing data were analyzed with Ion Reporter software. The human papillomavirus (HPV) status of the tumor samples was assessed with in situ hybridization, the MassARRAY HPV multiplex polymerase chain reaction assay, and p16 immunostaining. Mutation calls were compared among the studied groups.

Results: HIV-related HNSCC revealed a distinct pattern of mutations in comparison with non-HIV-related HNSCC. TP53 mutation frequencies were significantly lower in HIV-related HNSCC. Mutations in HIV+ patients tended to be TpC>T nucleotide changes for all mutated genes but especially for TP53.

Conclusions: HNSCC in HIVIIs presents a distinct pattern of genetic mutations, particularly in the TP53 gene. HIV-related HNSCC may have a distinct biology, and an effect of the HIV virus on the pathogenesis of these tumors should not be ruled out. Cancer 2018;124:84-94. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785080PMC
January 2018

PD-1 Expression in Head and Neck Squamous Cell Carcinomas Derives Primarily from Functionally Anergic CD4 TILs in the Presence of PD-L1 TAMs.

Cancer Res 2017 11 25;77(22):6365-6374. Epub 2017 Sep 25.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of programmed cell death protein (PD-1)-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8, CD4, and FoxP3 tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-1 ligand (PD-L1) to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4 and CD8 TILs. We found that CD4 TILs were present in equal or greater frequencies than CD8 TILs in 94% of OTSCC and that CD4FOXP3neg TILs were colocalized with PD-1/PD-L1/CD68 more frequently than CD8 TILs. Both CD4PD1 and CD8PD1 TILs were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4 TILs as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-3453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690870PMC
November 2017

Prognostic biomarkers in patients with human immunodeficiency virus-positive disease with head and neck squamous cell carcinoma.

Head Neck 2017 12 25;39(12):2433-2443. Epub 2017 Sep 25.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.

Background: We examined the prognostic value of a panel of biomarkers in patients with squamous cell carcinoma of the head and neck (SCCHN) who were human immunodeficiency virus (HIV) positive (HIV-positive head and neck cancer) and HIV negative (HIV-negative head and neck cancer).

Methods: Tissue microarrays (TMAs) were constructed using tumors from 41 disease site-matched and age-matched HIV-positive head and neck cancer cases and 44 HIV-negative head and neck cancer controls. Expression of tumor biomarkers was assessed by immunohistochemistry (IHC) and correlations examined with clinical variables.

Results: Expression levels of the studied oncogenic and inflammatory tumor biomarkers were not differentially regulated by HIV status. Among patients with HIV-positive head and neck cancer, laryngeal disease site (P = .003) and Clavien-Dindo classification IV (CD4) counts <200 cells/μL (P = .01) were associated with poor prognosis. Multivariate analysis showed that p16 positivity was associated with improved overall survival (OS; P < .001) whereas increased expression of transforming growth factor-beta (TGF-β) was associated with poor clinical outcome (P = .001).

Conclusion: Disease site has significant effect on the expression of biomarkers. Expression of tumor TGF-β could be a valuable addition to the conventional risk stratification equation for improving head and neck cancer disease management strategies.
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http://dx.doi.org/10.1002/hed.24911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808949PMC
December 2017

Programmed cell death ligand 1 as a biomarker in head and neck cancer.

Cancer Cytopathol 2017 07 4;125(7):529-533. Epub 2017 May 4.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/cncy.21872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690557PMC
July 2017

Adjuvant radiotherapy is not supported in patients with verrucous carcinoma of the oral cavity.

Laryngoscope 2017 06 1;127(6):1334-1338. Epub 2017 Feb 1.

Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.

Objective: To analyze the impact of adjuvant radiation therapy (RT) on overall survival (OS) and disease-specific survival (DSS) in patients with verrucous carcinoma (VC) as compared to squamous cell carcinoma (SCC) of the oral cavity.

Study Design: Cross-sectional population analysis.

Methods: Cases of nonmetastatic VC/SCC of the oral cavity were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (1988-2013). Kaplan-Meier survivals, stratified according to T stage, were compared between VC and SCC for treatment with or without adjuvant RT.

Results: A total of 18,819 VC/SCC cases were identified. There were 581 (3.1%) VC (mean age 69.6 years, 48.9% female) versus 18,238 (97.0%) SCC (mean age, 65.3, 37.1% female) patients. Verrucous carcinoma patients receiving surgery alone (N = 539) demonstrated a trend toward improved OS versus VC patients receiving surgery and RT (N = 40) (117.0 vs. 71.4 months, respectively, P = 0.119). There was a statistically significant improvement in DSS in VC patients receiving surgery alone (217.2 vs. 110.9 months, P = 0.05). Verrucous carcinoma patients treated with adjuvant RT demonstrated a trend toward a worse OS (71.4 vs. 93.0 months, P = 0.992) and DSS (110.9 vs. 162.3 months, P = 0.275) compared to SCC treated with adjuvant RT, suggesting a different biology and radiosensitivity between VC and SCC.

Conclusion: Verrucous carcinoma treated with adjuvant RT had a worse OS and DSS compared to both VC treated with surgery alone and SCC treated with surgery and adjuvant RT. Consideration should be given to surgical re-section rather than adjuvant RT in patients with positive margins or local recurrence.

Level Of Evidence: 2C. Laryngoscope, 127:1334-1338, 2017.
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http://dx.doi.org/10.1002/lary.26443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388729PMC
June 2017

High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV.

Mol Cancer Res 2017 02 29;15(2):179-188. Epub 2016 Nov 29.

Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positive cases and 41 HIV-negative controls. Tumors from 11 of 40 (28%) cases, and 10 of 41 (24%) controls contained hrHPV. p16 expression, indicative of E7 oncogene activity, was present in 10 of 11 HPV-positive cases and 7 of 10 HPV-positive controls. Low p16 and high TP53 expression in some HPV-positive tumors suggested HPV-independent tumorigenesis. Survival did not differ in cases and controls. RB expression was significantly associated with poor survival (P = 0.01). High TP53 expression exhibited a trend for poorer survival (P = 0.12), but among cases, association with poor survival reached statistical significance (P = 0.04). The proportion of HPV-positive tumors was similar, but the heterogeneity of HPV types was higher in the HIV-positive cases than in HIV-negative controls. High RB expression predicted poor survival, and high TP53 expression was associated with poorer survival in the HIV-positive cases but not HIV-negative controls.

Implications: HIV infection did not increase risk of death from HNSCC, and HPV-positive tumors continued to be associated with a significantly improved survival, independent of HIV status. Mol Cancer Res; 15(2); 179-88. ©2016 AACR.
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http://dx.doi.org/10.1158/1541-7786.MCR-16-0255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290187PMC
February 2017

The role of antagonists of the PD-1:PD-L1/PD-L2 axis in head and neck cancer treatment.

Oral Oncol 2016 10 5;61:152-8. Epub 2016 Aug 5.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, United States; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States.

We review the current clinical knowledge surrounding one of the most promising immune checkpoint pathways currently investigated in head and neck squamous cell carcinoma patients, programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2). We review ongoing clinical trials and associated clinical responses observed with targeting the receptor, PD-1, and its ligand, PD-L1. A recent phase III clinical trial (Checkmate 141) demonstrated an improved overall survival in head and neck cancer patients treated with anti-PD-1 monotherapy as compared to standard of care for recurrent and/or metastatic disease, which raises questions on how best to incorporate immunotherapy in the context of standard of care. We discuss biomarkers of response to this class of novel drugs, which is an area of active investigation. Lastly, we project future directions in the field wherein understanding how the Fc portions of the various monoclonal antibodies may impact their clinical efficacy as well as discuss areas where our next advances may take place, such as combination strategies.
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http://dx.doi.org/10.1016/j.oraloncology.2016.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690560PMC
October 2016

Eurogin Roadmap 2015: How has HPV knowledge changed our practice: Vaccines.

Int J Cancer 2016 08 22;139(3):510-7. Epub 2016 Mar 22.

International Agency for Research on Cancer, 69372 Lyon cedex 08, France.

This review is one of two complementary reviews that have been prepared in the framework of the Eurogin Roadmap 2015 to evaluate how knowledge about HPV is changing practices in HPV infection and disease control through vaccination and screening. In this review of HPV vaccine knowledge, we present the most significant findings of the past year which have contributed to our knowledge of the two HPV prophylactic vaccines currently in widespread use and about the recently licensed nonavalent HPV vaccine. Whereas anal cancer is dealt with in the companion mini-review on screening, we also review here the rapidly evolving evidence regarding HPV-associated head and neck cancer and priority research areas.
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http://dx.doi.org/10.1002/ijc.30063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388730PMC
August 2016
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