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545 results on '"Cohen, Ezra E."'

1. Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma

Author

Flanagan, Kevin C., Earls, Jon, Schillebeeckx, Ian, Hiken, Jeffrey, Wellinghoff, Rachel L., LaFranzo, Natalie A., Bradley, Zachary S., Babbitt, Joey, Westra, William H., Hsu, Raymond, Nadauld, Lincoln, Mcleod, Howard, Firth, Sean D., Sharp, Brittany, Fuller, Josh, Vavinskaya, Vera, Sutton, Leisa, Deichaite, Ida, Bailey, Samuel D., Sandulache, Vlad C., Rendo, Matthew J., Macdonald, Orlan K., Welaya, Karim, Wade, III, James L., Pippas, Andrew W., Slim, Jennifer, Bank, Bruce, Saccaro, Steven J., Sui, Xingwei, Akhtar, Adil, Balaraman, Savitha, Kossman, Steven E., Sonnier, Scott A., Shenkenberg, Todd D., Alexander, Warren L., Price, Katherine A., Bane, Charles L., Ley, Jessica, Messina, David N., Glasscock, Jarret I., Cohen, Ezra E. W., Adkins, Douglas R., and Duncavage, Eric J.

Published
2023
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3. Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC

Author

Saddawi-Konefka, Robert, O’Farrell, Aoife, Faraji, Farhoud, Clubb, Lauren, Allevato, Michael M., Jensen, Shawn M., Yung, Bryan S., Wang, Zhiyong, Wu, Victoria H., Anang, Nana-Ama, Msari, Riyam Al, Schokrpur, Shiruyeh, Pietryga, Ida Franiak, Molinolo, Alfredo A., Mesirov, Jill P., Simon, Aaron B., Fox, Bernard A., Bui, Jack D., Sharabi, Andrew, Cohen, Ezra E. W., Califano, Joseph A., and Gutkind, J. Silvio

Published
2022
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7. A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer

Author

Miller, Aaron M., primary, Koşaloğlu-Yalçın, Zeynep, additional, Westernberg, Luise, additional, Montero, Leslie, additional, Bahmanof, Milad, additional, Frentzen, Angela, additional, Lanka, Manasa, additional, Logandha Ramamoorthy Premlal, Ashmitaa, additional, Seumois, Gregory, additional, Greenbaum, Jason, additional, Brightman, Spencer E., additional, Soria Zavala, Karla, additional, Thota, Rukman R., additional, Naradikian, Martin S., additional, Makani, Samir S., additional, Lippman, Scott M., additional, Sette, Alessandro, additional, Cohen, Ezra E. W., additional, Peters, Bjoern, additional, and Schoenberger, Stephen P., additional

Published
2024
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8. Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial

Author

Sacco, Assuntina G, Chen, Ruifeng, Worden, Francis P, Wong, Deborah J L, Adkins, Douglas, Swiecicki, Paul, Chai-Ho, Wanxing, Oppelt, Peter, Ghosh, Debanjali, Bykowski, Julie, Molinolo, Alfredo, Pittman, Emily, Estrada, M Valeria, Gold, Kathryn, Daniels, Gregory, Lippman, Scott M, Natsuhara, Amanda, Messer, Karen, and Cohen, Ezra E W

Published
2021
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10. A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA + oral cancers

Author

Yamaguchi, Kosuke, Iglesias-Bartolomé, Ramiro, Wang, Zhiyong, Callejas-Valera, Juan Luis, Amornphimoltham, Panomwat, Molinolo, Alfredo A, Cohen, Ezra E, Califano, Joseph A, Lippman, Scott M, Luo, Ji, and Gutkind, J Silvio

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Biotechnology, Dental/Oral and Craniofacial Disease, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases, Drug Synergism, Female, Heterografts, Humans, MAP Kinase Signaling System, Mice, Mice, Nude, Molecular Targeted Therapy, Mouth Neoplasms, Pyridones, Pyrimidinones, RNA Interference, Sirolimus, TOR Serine-Threonine Kinases, synthetic lethality screen, shRNA library, rapamycin, trametinib, co-targeting therapy, Oncology and carcinogenesis
Abstract

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.

Published
2016

11. A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers.

Author

Yamaguchi, Kosuke, Iglesias-Bartolomé, Ramiro, Wang, Zhiyong, Callejas-Valera, Juan Luis, Amornphimoltham, Panomwat, Molinolo, Alfredo A, Cohen, Ezra E, Califano, Joseph A, Lippman, Scott M, Luo, Ji, and Gutkind, J Silvio

Subjects
Cell Line, Tumor, Animals, Humans, Mice, Mice, Nude, Mouth Neoplasms, Sirolimus, Pyridones, Pyrimidinones, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, MAP Kinase Signaling System, RNA Interference, Drug Synergism, Female, Class I Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Molecular Targeted Therapy, Heterografts, co-targeting therapy, rapamycin, shRNA library, synthetic lethality screen, trametinib, Cell Line, Tumor, Nude, Oncology and Carcinogenesis
Abstract

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.

Published
2016

12. Nivolumab for Patients With High-Risk Oral Leukoplakia

Author

Hanna, Glenn J., primary, Villa, Alessandro, additional, Nandi, Shuvro P., additional, Shi, Ruichao, additional, ONeill, Anne, additional, Liu, Mofei, additional, Quinn, Charles T., additional, Treister, Nathaniel S., additional, Sroussi, Herve Y., additional, Vacharotayangul, Piamkamon, additional, Goguen, Laura A., additional, Annino, Donald J., additional, Rettig, Eleni M., additional, Jo, Vickie Y., additional, Wong, Kristine S., additional, Lizotte, Patrick, additional, Paweletz, Cloud P., additional, Uppaluri, Ravindra, additional, Haddad, Robert I., additional, Cohen, Ezra E. W., additional, Alexandrov, Ludmil B., additional, William, William N., additional, Lippman, Scott M., additional, and Woo, Sook-bin, additional

Published
2023
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14. Combined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma

Author

Raju, Sharat C, Hauff, Samantha J, Lemieux, Aaron J, Orosco, Ryan K, Gross, Andrew M, Nguyen, Linda T, Savariar, Elamprakash, Moss, William, Whitney, Michael, Cohen, Ezra E, Lippman, Scott M, Tsien, Roger Y, Ideker, Trey, Advani, Sunil J, and Nguyen, Quyen T

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Genetics, Dental/Oral and Craniofacial Disease, Acid Anhydride Hydrolases, Carcinoma, Squamous Cell, Cell Line, Tumor, Chromosome Deletion, Chromosomes, Human, Pair 3, Genes, p53, Head and Neck Neoplasms, Humans, Matrix Metalloproteinases, Mutation, Neoplasm Proteins, Radiation Tolerance, Head and neck cancer, TP53 mutation, 3p Deletion, FHIT, Matrix metalloproteinases, "double-hit'', "single-hit'', Double-stranded DNA breaks, RNA interference, Radiosensitivity, “double-hit”, “single-hit”, Dentistry, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

ObjectivePatients with head and neck squamous cell carcinoma (HNSCC) containing TP53 mutation and 3p deletion ("double-hit") have poorer prognosis compared to patients with either event alone ("single-hit"). The etiology for worse clinical outcomes in patients with "double-hit" cancers is unclear. We compared radiosensitivity of cell lines containing both TP53 mutations and deletion of Fragile Histidine Triad (FHIT, the gene most commonly associated with 3p deletion) to "single-hit" lines with only TP53 mutation. We compared radiosensitivity in a "single-hit" cell line with TP53 mutation converted to "double-hit" using RNA interference targeting FHIT. Finally, we compared matrixmetalloproteinase-2/9 (MMP-2/9) activity, a previously-established biomarker for tumor aggressiveness, in xenograft tumors derived from these cell lines.Materials/methodsTP53 mutation and FHIT deletion profiles of HNSCC lines were established using Cancer Cell Line Encyclopedia (CCLE). We used RNA-interference to convert a "single-hit" cell line (SCC4) to "double-hit". Cultured cells were examined for radiosensitivity and cisplatin sensitivity. MMP-2/9 activity was evaluated in "double-hit" versus "single-hit" tumors using ratiometric activatable cell-penetrating peptide (RACPP) in tongue (n=17) and flank xenografts (n=4).ResultsRadiotherapy caused greater double-stranded DNA breaks in "single-hit" vs naturally occurring and engineered "double-hit" cells. In-vivo, "double-hit" xenografts demonstrated higher MMP-2/9 activity compared to "single-hit" xenografts (p

Published
2015

15. Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss

Author

Gross, Andrew M, Orosco, Ryan K, Shen, John P, Egloff, Ann Marie, Carter, Hannah, Hofree, Matan, Choueiri, Michel, Coffey, Charles S, Lippman, Scott M, Hayes, D Neil, Cohen, Ezra E, Grandis, Jennifer R, Nguyen, Quyen T, and Ideker, Trey

Subjects
Biological Sciences, Genetics, Human Genome, Cancer, Rare Diseases, Dental/Oral and Craniofacial Disease, Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 3, Genes, p53, Genomics, Head and Neck Neoplasms, Humans, Infant, Infant, Newborn, Middle Aged, Mutation, Prognosis, Squamous Cell Carcinoma of Head and Neck, Tumor Suppressor Protein p53, Young Adult, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p and validates in HNSCC and pan-cancer cohorts. In human papillomavirus (HPV)-positive tumors, in which HPV inactivates TP53, 3p deletion is also common and is associated with poor outcomes. The TP53-3p event is modified by mir-548k expression, which decreases survival further, and is mutually exclusive with mutations affecting RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease.

Published
2014

17. Abstract PO-003: Lenvatinib with or without pembrolizumab versus chemotherapy for treatment of recurrent or metastatic head and neck squamous cell carcinoma that progressed on platinum therapy and immunotherapy: Phase 2 LEAP-009

Author

Harrington, Kevin J., primary, Kim, Hye Ryun, additional, Salas, Sebastien, additional, Oliva, Marc, additional, Metcalf, Robert, additional, Bernsdorf, Mogens, additional, Kim, Ji-Won, additional, Cohen, Ezra E. W., additional, Siu, Lillian, additional, Rischin, Danny, additional, Licitra, Lisa, additional, Vermorken, Jan, additional, Le, Quynh, additional, Tahara, Makoto, additional, Machiels, Jean-Pascal, additional, O'Hara, Karen, additional, Pathiraja, Kumudu, additional, Gumuscu, Burak, additional, Bidadi, Behzad, additional, and Burtness, Barbara, additional

Published
2023
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18. Abstract PO-002: Pembrolizumab as neoadjuvant and adjuvant therapy in combination with standard of care in resectable, locally advanced head and neck squamous cell carcinoma: Phase 3 KEYNOTE-689

Author

Klochikhin, Arkadiy, primary, Haddad, Robert I., additional, Meirovitz, Amichay, additional, Safina, Sufia, additional, Brana, Irene, additional, Tourneau, Christophe Le, additional, Uppaluri, Ravindra, additional, Lee, Nancy Y., additional, Cohen, Ezra E. W., additional, Chernock, Rebecca, additional, Westra, William, additional, Liu, Hong, additional, Gumuscu, Burak, additional, Benjamin, Kimberly, additional, and Adkins, Douglas, additional

Published
2023
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19. Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression

Author

Dolina, Joseph S., primary, Lee, Joey, additional, Brightman, Spencer E., additional, McArdle, Sara, additional, Hall, Samantha M., additional, Thota, Rukman R., additional, Zavala, Karla S., additional, Lanka, Manasa, additional, Ramamoorthy Premlal, Ashmitaa Logandha, additional, Greenbaum, Jason A., additional, Cohen, Ezra E. W., additional, Peters, Bjoern, additional, and Schoenberger, Stephen P., additional

Published
2023
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20. Author Correction: Neoantigen-specific stem cell memory-like CD4+ T cells mediate CD8+ T cell-dependent immunotherapy of MHC class II-negative solid tumors

Author

Brightman, Spencer E., primary, Becker, Angelica, additional, Thota, Rukman R., additional, Naradikian, Martin S., additional, Chihab, Leila, additional, Zavala, Karla Soria, additional, Ramamoorthy Premlal, Ashmitaa Logandha, additional, Griswold, Ryan Q., additional, Dolina, Joseph S., additional, Cohen, Ezra E. W., additional, Miller, Aaron M., additional, Peters, Bjoern, additional, and Schoenberger, Stephen P., additional

Published
2023
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21. Method for estimation of apoptotic cell fraction of cytotherapy using in vivo fluorine-19 magnetic resonance: pilot study in a patient with head and neck carcinoma receiving tumor-infiltrating lymphocytes labeled with perfluorocarbon nanoemulsion

Author

Ahrens, Eric T, primary, Helfer, Brooke M, additional, O’Hanlon, Charles F, additional, Lister, Deanne R, additional, Bykowski, Julie L, additional, Messer, Karen, additional, Leach, Benjamin I, additional, Chen, Jiawen, additional, Xu, Hongyan, additional, Daniels, Gregory A, additional, and Cohen, Ezra E W, additional

Published
2023
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23. 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

Author

Pai, Sara I., Cohen, Ezra E. W., Lin, Derrick, Fountzilas, George, Kim, Edward S., Mehlhorn, Holger, Baste, Neus, Clayburgh, Daniel, Lipworth, Loren, Resteghini, Carlo, Shara, Nawar, Fujii, Takashi, Zhang, Jun, Stokes, Michael, Wang, Huifen, Twumasi-Ankrah, Philip, Wildsmith, Sophie, Khaliq, Asud, Melillo, Giovanni, and Shire, Norah

Published
2019
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24. Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4

Author

Wang, Zhiyong, Wu, Victoria H., Allevato, Michael M., Gilardi, Mara, He, Yudou, Luis Callejas-Valera, Juan, Vitale-Cross, Lynn, Martin, Daniel, Amornphimoltham, Panomwat, Mcdermott, James, Yung, Bryan S., Goto, Yusuke, Molinolo, Alfredo A., Sharabi, Andrew B., Cohen, Ezra E. W., Chen, Qianming, Lyons, J. Guy, Alexandrov, Ludmil B., and Gutkind, J. Silvio

Published
2019
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26. Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial.

Author

Hanna, Glenn J., Villa, Alessandro, Nandi, Shuvro P., Shi, Ruichao, ONeill, Anne, Liu, Mofei, Quinn, Charles T., Treister, Nathaniel S., Sroussi, Herve Y., Vacharotayangul, Piamkamon, Goguen, Laura A., Annino Jr, Donald J., Rettig, Eleni M., Jo, Vickie Y., Wong, Kristine S., Lizotte, Patrick, Paweletz, Cloud P., Uppaluri, Ravindra, Haddad, Robert I., and Cohen, Ezra E. W.

Published
2024
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28. Abstract CT012: Clinical activity of MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell cancer (HNSCC)

Author

Cohen, Ezra E., primary, Fayette, Jérôme, additional, Daste, Amaury, additional, Even, Caroline, additional, Tourneau, Christophe Le, additional, Brana, Irene, additional, Saada, Esma, additional, Fontana, Elisa, additional, Iglesias, Lara, additional, Kato, Shumei, additional, Garcia-Carbonero, Rocio, additional, Tabernero, Josep, additional, Argilés, Guillem, additional, Magin, Marina, additional, Shen, Yu-Ming, additional, de Leeuw, Renée, additional, Bekradda, Mohamed, additional, Pennella, Eduardo, additional, Wasserman, Ernesto, additional, Stalbovskaya, Viktoriya, additional, van Bueren, Jeroen Lammerts, additional, Jain, Lokesh, additional, Joe, Andrew, additional, and Hollebecque, Antoine, additional

Published
2023
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30. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC)

Author

Cohen, Ezra E. W., Bell, R. Bryan, Bifulco, Carlo B., Burtness, Barbara, Gillison, Maura L., Harrington, Kevin J., Le, Quynh-Thu, Lee, Nancy Y., Leidner, Rom, Lewis, Rebecca L., Licitra, Lisa, Mehanna, Hisham, Mell, Loren K., Raben, Adam, Sikora, Andrew G., Uppaluri, Ravindra, Whitworth, Fernanda, Zandberg, Dan P., and Ferris, Robert L.

Published
2019
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32. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial

Author

Machiels, Jean-Pascal H, Haddad, Robert I, Fayette, Jérôme, Licitra, Lisa F, Tahara, Makoto, Vermorken, Jan B, Clement, Paul M, Gauler, Thomas, Cupissol, Didier, Grau, Juan José, Guigay, Joël, Caponigro, Francesco, de Castro, Gilberto, Jr, de Souza Viana, Luciano, Keilholz, Ulrich, del Campo, Joseph M, Cong, Xiuyu Julie, Ehrnrooth, Eva, and Cohen, Ezra E W

Published
2015
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33. Somatic 9p24.1 alterations in HPV – head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity

Author

Zhao, Xin, primary, Cohen, Ezra E. W., additional, William, William N., additional, Bianchi, Joy J., additional, Abraham, Jim P., additional, Magee, Daniel, additional, Spetzler, David B., additional, Gutkind, J. Silvio, additional, Alexandrov, Ludmil B., additional, Cavenee, Webster K., additional, Lippman, Scott M., additional, and Davoli, Teresa, additional

Published
2022
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34. PI3K is a molecular switch that controls immune suppression

Author

Kaneda, Megan M., Messer, Karen S., Ralainirina, Natacha, Li, Hongying, Leem, Christopher J., Gorjestani, Sara, Woo, Gyunghwi, Nguyen, Abraham V., Figueiredo, Camila C., Foubert, Philippe, Schmid, Michael C., Pink, Melissa, Winkler, David G., Rausch, Matthew, Palombella, Vito J., Kutok, Jeffery, McGovern, Karen, Frazer, Kelly A., Wu, Xuefeng, Karin, Michael, Sasik, Roman, Cohen, Ezra E. W., and Varner, Judith A.

Subjects
Macrophages -- Health aspects, Molecular motors (Biochemistry) -- Health aspects, Immune response -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Megan M. Kaneda [1]; Karen S. Messer [1, 2]; Natacha Ralainirina [1]; Hongying Li [1, 2]; Christopher J. Leem [1]; Sara Gorjestani [1]; Gyunghwi Woo [1]; Abraham V. Nguyen [...]

Published
2016
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38. Neoantigen-specific stem cell memory-like CD4+T cells mediate CD8+T cell-dependent immunotherapy of MHC class II-negative solid tumors

Author

Brightman, Spencer E., Becker, Angelica, Thota, Rukman R., Naradikian, Martin S., Chihab, Leila, Zavala, Karla Soria, Ramamoorthy Premlal, Ashmitaa Logandha, Griswold, Ryan Q., Dolina, Joseph S., Cohen, Ezra E. W., Miller, Aaron M., Peters, Bjoern, and Schoenberger, Stephen P.

Abstract

CD4+T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8+T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8+T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4+T cells is less well understood. We have characterized the murine CD4+T cell response against a validated NeoAg (CLTCH129>Q) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTCH129>Q-specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4+T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8+T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4+T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (TSCM)-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with TSCM-like CD4+T cells results in lower PD-1 expression by CD8+T cells in the tumor microenvironment and an increased frequency of PD-1+CD8+T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4+T cells in mediating antitumor immunity via providing help to CD8+T cells and highlight their therapeutic potential in ACT.

Published
2023
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41. Corrigendum: PI3Kγ is a molecular switch that controls immune suppression

Author

Kaneda, Megan M., Messer, Karen S., Ralainirina, Natacha, Li, Hongying, Leem, Christopher J., Gorjestani, Sara, Woo, Gyunghwi, Nguyen, Abraham V., Figueiredo, Camila C., Foubert, Philippe, Schmid, Michael C., Pink, Melissa, Winkler, David G., Rausch, Matthew, Palombella, Vito J., Kutok, Jeffery, McGovern, Karen, Frazer, Kelly A., Wu, Xuefeng, Karin, Michael, Sasik, Roman, Cohen, Ezra E. W., and Varner, Judith A.

Published
2017
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43. Lymphatic-Preserving Treatment Sequencing with Immune Checkpoint Inhibition Unleashes cDC1-Dependent Antitumor Immunity in HNSCC

Author

Saddawi-Konefka, Robert, primary, O’Farrell, Aoife, additional, Faraji, Farhoud, additional, Clubb, Lauren, additional, Allevato, Michael M., additional, Anang, Nana-Ama A. S., additional, Jensen, Shawn M., additional, Wang, Zhiyong, additional, Wu, Victoria H., additional, Yung, Bryan S., additional, Msari, Riyam Al, additional, Pietryga, Ida Franiak, additional, Molinolo, Alfredo A., additional, Mesirov, Jill P., additional, Simon, Aaron B., additional, Fox, Bernard A., additional, Bui, Jack D., additional, Sharabi, Andrew, additional, Cohen, Ezra E. W., additional, Califano, Joseph A., additional, and Silvio Gutkind, J., additional

Published
2022
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47. Erlotinib and the Risk of Oral Cancer: The Erlotinib Prevention of Oral Cancer (EPOC) Randomized Clinical Trial

Author

William, William N., Jr, Papadimitrakopoulou, Vassiliki, Lee, J. Jack, Mao, Li, Cohen, Ezra E. W., Lin, Heather Y., Gillenwater, Ann M., Martin, Jack W., Lingen, Mark W., Boyle, Jay O., Shin, Dong M., Vigneswaran, Nadarajah, Shinn, Nancy, Heymach, John V., Wistuba, Ignacio I., Tang, Ximing, Kim, Edward S., Saintigny, Pierre, Blair, Elizabeth A., Meiller, Timothy, Gutkind, J. Silvio, Myers, Jeffrey, El-Naggar, Adel, and Lippman, Scott M.

Published
2016
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48. Somatic 9p24.1 alterations in HPV– head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity.

Author

Xin Zhao, Cohen, Ezra E. W., William Jr., William N., Bianchi, Joy J., Abraham, Jim P., Magee, Daniel, Spetzler, David B., Gutkind, J. Silvio, Alexandrov, Ludmil B., Cavenee, Webster K., Lippman, Scott M., and Davoli, Teresa

Subjects
*HEAD & neck cancer, *IMMUNE checkpoint proteins, *SURVIVAL rate, *CHROMOSOMES, *TUMOR microenvironment
Abstract

Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus–negative (HPV– ) head and neck squamous cancer (HNSC), associated with an immune-cold tumor microenvironment (TME) signal, and recent evidence suggested that this TME-cold phenotype was greatly enhanced with 9p21 deletion size, notably encompassing band 9p24.1 (3). Here, we report multi-omic, -threshold and continuous-variable dissection of 9p21 and 9p24 loci (including depth and degree of somatic alteration of each band at each locus, and each gene at each band) and TME of four HPV– HNSC cohorts. Preferential 9p24 deletion, CD8 T-cell immune-cold associations were observed, driven by 9p24.1 loss, and in turn by an essential telomeric regulatory gene element, JAK2-CD274. Surprisingly, same genetic region gains were immune hot. Related 9p21-TME analyses were less evident. Inherent 9p-band-level influences on anti-PD1 ICT survival rates, coincident with TME patterns, were also observed. At a 9p24.1 whole-transcriptome expression threshold of 60th percentile, ICT survival rate exceeded that of lower expression percentiles and of chemotherapy; below this transcript threshold, ICT survival was inferior to chemotherapy, the latter unaffected by 9p24.1 expression level (P-values < 0.01, including in a PD-L1 immunohistochemistry-positive patient subgroup). Whole-exome analyses of 10 solid-tumor types suggest that these 9p-related ICT findings could be relevant to squamous cancers, in which 9p24.1 gain/immune-hot associations exist. [ABSTRACT FROM AUTHOR]

Published
2022
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