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2. Deep learning to achieve clinically applicable segmentation of head and neck anatomy for radiotherapy

Author

Nikolov, Stanislav, Blackwell, Sam, Zverovitch, Alexei, Mendes, Ruheena, Livne, Michelle, De Fauw, Jeffrey, Patel, Yojan, Meyer, Clemens, Askham, Harry, Romera-Paredes, Bernardino, Kelly, Christopher, Karthikesalingam, Alan, Chu, Carlton, Carnell, Dawn, Boon, Cheng, D'Souza, Derek, Moinuddin, Syed Ali, Garie, Bethany, McQuinlan, Yasmin, Ireland, Sarah, Hampton, Kiarna, Fuller, Krystle, Montgomery, Hugh, Rees, Geraint, Suleyman, Mustafa, Back, Trevor, Hughes, Cían, Ledsam, Joseph R., and Ronneberger, Olaf

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning, Computer Science - Neural and Evolutionary Computing, Physics - Medical Physics, Statistics - Machine Learning
Abstract

Over half a million individuals are diagnosed with head and neck cancer each year worldwide. Radiotherapy is an important curative treatment for this disease, but it requires manual time consuming delineation of radio-sensitive organs at risk (OARs). This planning process can delay treatment, while also introducing inter-operator variability with resulting downstream radiation dose differences. While auto-segmentation algorithms offer a potentially time-saving solution, the challenges in defining, quantifying and achieving expert performance remain. Adopting a deep learning approach, we demonstrate a 3D U-Net architecture that achieves expert-level performance in delineating 21 distinct head and neck OARs commonly segmented in clinical practice. The model was trained on a dataset of 663 deidentified computed tomography (CT) scans acquired in routine clinical practice and with both segmentations taken from clinical practice and segmentations created by experienced radiographers as part of this research, all in accordance with consensus OAR definitions. We demonstrate the model's clinical applicability by assessing its performance on a test set of 21 CT scans from clinical practice, each with the 21 OARs segmented by two independent experts. We also introduce surface Dice similarity coefficient (surface DSC), a new metric for the comparison of organ delineation, to quantify deviation between OAR surface contours rather than volumes, better reflecting the clinical task of correcting errors in the automated organ segmentations. The model's generalisability is then demonstrated on two distinct open source datasets, reflecting different centres and countries to model training. With appropriate validation studies and regulatory approvals, this system could improve the efficiency, consistency, and safety of radiotherapy pathways.

Published
2018

6. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Author

Abbosh, Christopher, Birkbak, Nicolai J., Wilson, Gareth A., Jamal-Hanjani, Mariam, Constantin, Tudor, Salari, Raheleh, Le Quesne, John, Moore, David A., Veeriah, Selvaraju, Rosenthal, Rachel, Marafioti, Teresa, Kirkizlar, Eser, Watkins, Thomas B. K., McGranahan, Nicholas, Ward, Sophia, Martinson, Luke, Riley, Joan, Fraioli, Francesco, Al Bakir, Maise, Grnroos, Eva, Zambrana, Francisco, Endozo, Raymondo, Bi, Wenya Linda, Fennessy, Fiona M., Sponer, Nicole, Johnson, Diana, Laycock, Joanne, Shafi, Seema, Czyzewska-Khan, Justyna, Rowan, Andrew, Chambers, Tim, Matthews, Nik, Turajlic, Samra, Hiley, Crispin, Lee, Siow Ming, Forster, Martin D., Ahmad, Tanya, Falzon, Mary, Borg, Elaine, Lawrence, David, Hayward, Martin, Kolvekar, Shyam, Panagiotopoulos, Nikolaos, Janes, Sam M., Thakrar, Ricky, Ahmed, Asia, Blackhall, Fiona, Summers, Yvonne, Hafez, Dina, Naik, Ashwini, Ganguly, Apratim, Kareht, Stephanie, Shah, Rajesh, Joseph, Leena, Marie Quinn, Anne, Crosbie, Phil A., Naidu, Babu, Middleton, Gary, Langman, Gerald, Trotter, Simon, Nicolson, Marianne, Remmen, Hardy, Kerr, Keith, Chetty, Mahendran, Gomersall, Lesley, Fennell, Dean A., Nakas, Apostolos, Rathinam, Sridhar, Anand, Girija, Khan, Sajid, Russell, Peter, Ezhil, Veni, Ismail, Babikir, Irvin-Sellers, Melanie, Prakash, Vineet, Lester, Jason F., Kornaszewska, Malgorzata, Attanoos, Richard, Adams, Haydn, Davies, Helen, Oukrif, Dahmane, Akarca, Ayse U., Hartley, John A., Lowe, Helen L., Lock, Sara, Iles, Natasha, Bell, Harriet, Ngai, Yenting, Elgar, Greg, Szallasi, Zoltan, Schwarz, Roland F., Herrero, Javier, Stewart, Aengus, Quezada, Sergio A., Peggs, Karl S., Van Loo, Peter, Dive, Caroline, Lin, C. Jimmy, Rabinowitz, Matthew, Aerts, Hugo J. W. L., Hackshaw, Allan, Shaw, Jacqui A., Zimmermann, Bernhard G., Swanton, Charles, Bosshard-Carter, Leticia, Goh, Gerald, Gorman, Pat, Murugaesu, Nirupa, Hynds, Robert E., Horswell, Stuart, Bakir, Maise Al, Mitter, Richard, Escudero, Mickael, Xu, Hang, Goldman, Jacki, Stone, Richard Kevin, Denner, Tamara, Biggs, Jennifer, Costa, Marta, Begum, Sharmin, Phillimore, Ben, Nye, Emma, Graca, Sofia, Joshi, Kroopa, Furness, Andrew, Ben Aissa, Assma, Wong, Yien Ning Sophia, Georgiou, Andy, Simeon, Celia, Hector, Gemma, Smith, Amy, Aranda, Marie, Novelli, Marco, Papadatos-Pastos, Dionysis, Carnell, Dawn, Mendes, Ruheena, George, Jeremy, Navani, Neal, Taylor, Magali, Choudhary, Junaid, Califano, Raffaele, Taylor, Paul, Krysiak, Piotr, Rammohan, Kendadai, Fontaine, Eustace, Booton, Richard, Evison, Matthew, Moss, Stuart, Idries, Faiza, Bishop, Paul, Chaturvedi, Anshuman, Quinn, Anne Marie, Doran, Helen, Leek, Angela, Harrison, Phil, Moore, Katrina, Waddington, Rachael, Novasio, Juliette, Rogan, Jane, Smith, Elaine, Tugwood, Jonathan, Brady, Ged, Rothwell, Dominic G., Chemi, Francesca, Pierce, Jackie, Gulati, Sakshi, Bellamy, Mary, Bancroft, Hollie, Kerr, Amy, Kadiri, Salma, Webb, Joanne, Djearaman, Madava, Quesne, John Le, Thomas, Anne, Walter, Harriet, Monteiro, William, Marshall, Hilary, Nelson, Louise, Bennett, Jonathan, Primrose, Lindsay, Amadi, Anita, Palmer, Shirley, Miller, Joy, Buchan, Keith, Edwards, Alison, Morgan, Fiona, Verjee, Azmina, MacKenzie, Mairead, Wilcox, Maggie, Smith, Sean, Gower, Nicole, Ottensmeier, Christian, Chee, Serena, Johnson, Benjamin, Alzetani, Aiman, Shaw, Emily, Lim, Eric, De Sousa, Paulo, Barbosa, Monica Tavares, Bowman, Alex, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Proli, Chiara, Cufari, Maria Elena, Ronquillo, John Carlo, Kwayie, Angela, Bhayani, Harshil, Hamilton, Morag, Bakar, Yusura, Mensah, Natalie, Ambrose, Lyn, Devaraj, Anand, Buderi, Silviu, Finch, Jonathan, Azcarate, Leire, Chavan, Hema, Green, Sophie, Mashinga, Hillaria, Nicholson, Andrew G., Lau, Kelvin, Sheaff, Michael, Schmid, Peter, Conibear, John, Light, Teresa, Horey, Tracey, Danson, Sarah, Bury, Jonathan, Edwards, John, Hill, Jennifer, Matthews, Sue, Kitsanta, Yota, Suvarna, Kim, Fisher, Patricia, Keerio, Allah Dino, Shackcloth, Michael, Gosney, John, Postmus, Pieter, Feeney, Sarah, Asante-Siaw, Julius, Dentro, Stefan, and Dessimoz, Christophe

Subjects
Lung cancer -- Genetic aspects -- Development and progression, DNA sequencing -- Methods, Phylogeny -- Observations, Cancer metastasis -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies., Author(s): Christopher Abbosh [1]; Nicolai J. Birkbak [1, 2]; Gareth A. Wilson [1, 2]; Mariam Jamal-Hanjani [1]; Tudor Constantin [3]; Raheleh Salari [3]; John Le Quesne [4]; David A. Moore [...]

Published
2017
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7. International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System

Author

Lechner, Matt, additional, Takahashi, Yoko, additional, Turri-Zanoni, Mario, additional, Ferrari, Marco, additional, Liu, Jacklyn, additional, Counsell, Nicholas, additional, Mattavelli, Davide, additional, Rampinelli, Vittorio, additional, Vermi, William, additional, Lombardi, Davide, additional, Saade, Rami, additional, Park, Ki Wan, additional, Schartinger, Volker H., additional, Franchi, Alessandro, additional, Facco, Carla, additional, Sessa, Fausto, additional, Battocchio, Simonetta, additional, Fenton, Tim R., additional, Vaz, Francis M., additional, O'Flynn, Paul, additional, Howard, David, additional, Stimpson, Paul, additional, Wang, Simon, additional, Hannan, S. Alam, additional, Unadkat, Samit, additional, Hughes, Jonathan, additional, Dwivedi, Raghav, additional, Forde, Cillian T., additional, Randhawa, Premjit, additional, Gane, Simon, additional, Joseph, Jonathan, additional, Andrews, Peter J., additional, Dave, Manas, additional, Fleming, Jason C., additional, Thomson, David, additional, Zhu, Tianyu, additional, Teschendorff, Andrew, additional, Royle, Gary, additional, Steele, Christopher, additional, Jimenez, Joaquin E., additional, Laco, Jan, additional, Wang, Eric W., additional, Snyderman, Carl, additional, Lacy, Peter D., additional, Woods, Robbie, additional, O'Neill, James P., additional, Saraswathula, Anirudh, additional, Kaur, Raman Preet, additional, Zhao, Tianna, additional, Ramanathan, Murugappan, additional, Gallia, Gary L., additional, London, Nyall R., additional, Le, Quynh-Thu, additional, West, Robert B., additional, Patel, Zara M., additional, Nayak, Jayakar V., additional, Hwang, Peter H., additional, Hermsen, Mario, additional, Llorente, Jose, additional, Facchetti, Fabio, additional, Nicolai, Piero, additional, Bossi, Paolo, additional, Castelnuovo, Paolo, additional, Jay, Amrita, additional, Carnell, Dawn, additional, Forster, Martin D., additional, Bell, Diana M., additional, Lund, Valerie J., additional, and Hanna, Ehab Y., additional

Published
2022
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8. Multicenter Analysis of Clinical Outcomes of Sinonasal Mucosal Melanoma

Author

Lechner, Matt, additional, Takahashi, Yoko, additional, Turri-Zanoni, Mario, additional, Ferrari, Marco, additional, Liu, Jacklyn, additional, Counsell, Nicholas, additional, Mattavelli, Davide, additional, Rampinelli, Vittorio, additional, Lombardi, Davide, additional, Saade, Rami, additional, Park, Ki Wan, additional, Schartinger, Volker H., additional, Franchi, Alessandro, additional, Maragliano, Roberta, additional, Battocchio, Simonetta, additional, Emanuel, Oscar, additional, Fenton, Tim, additional, Vaz, Francis M., additional, O'Flynn, Paul, additional, Howard, David, additional, Stimpson, Paul, additional, Wang, Simon, additional, Hannan, S. Alam, additional, Unadkat, Samit, additional, Hughes, Jonathan, additional, Dwivedi, Raghav, additional, Forde, Cillian T., additional, Randhawa, Premjit, additional, Gane, Simon, additional, Joseph, Jonathan, additional, Andrews, Peter J., additional, Zhu, Tianyu, additional, Teschendorff, Andrew, additional, Royle, Gary, additional, Bewicke-Copley, Helen, additional, Steele, Christopher, additional, Williams, Luke, additional, Jimenez-Garcia, Joaquin E., additional, Wang, Eric W., additional, Snyderman, Carl, additional, Lacy, Peter, additional, Woods, Robbie, additional, O'Neill, James P., additional, Le, Quynh-Thu, additional, West, Robert B., additional, Patel, Zara M., additional, Nayak, Jayakar, additional, Hwang, Peter H., additional, Hermsen, Mario, additional, Llorente, Jose, additional, Facchetti, Fabio, additional, Nicolai, Piero, additional, Bossi, Paolo, additional, Castelnuovo, Paolo, additional, Jay, Amrita, additional, Carnell, Dawn, additional, Forster, Martin D., additional, Bell, Diana M., additional, Lund, Valerie J., additional, and Hanna, Ehab Y., additional

Published
2022
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9. Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma

Author

Lechner, Matt, primary, Takahashi, Yoko, additional, Turri-Zanoni, Mario, additional, Liu, Jacklyn, additional, Counsell, Nicholas, additional, Hermsen, Mario, additional, Kaur, Raman Preet, additional, Zhao, Tianna, additional, Ramanathan, Murugappan, additional, Schartinger, Volker H., additional, Emanuel, Oscar, additional, Helman, Sam, additional, Varghese, Jordan, additional, Dudas, Jozsef, additional, Riechelmann, Herbert, additional, Sprung, Susanne, additional, Haybaeck, Johannes, additional, Howard, David, additional, Engel, Nils Wolfgang, additional, Stewart, Sarah, additional, Brooks, Laura, additional, Pickles, Jessica C., additional, Jacques, Thomas S., additional, Fenton, Tim R., additional, Williams, Luke, additional, Vaz, Francis M., additional, O'Flynn, Paul, additional, Stimpson, Paul, additional, Wang, Simon, additional, Hannan, S. Alam, additional, Unadkat, Samit, additional, Hughes, Jonathan, additional, Dwivedi, Raghav, additional, Forde, Cillian T., additional, Randhawa, Premjit, additional, Gane, Simon, additional, Joseph, Jonathan, additional, Andrews, Peter J., additional, Royle, Gary, additional, Franchi, Alessandro, additional, Maragliano, Roberta, additional, Battocchio, Simonetta, additional, Bewicke-Copley, Helen, additional, Pipinikas, Christodoulos, additional, Webster, Amy, additional, Thirlwell, Chrissie, additional, Ho, Debbie, additional, Teschendorff, Andrew, additional, Zhu, Tianyu, additional, Steele, Christopher D., additional, Pillay, Nischalan, additional, Vanhaesebroeck, Bart, additional, Mohyeldin, Ahmed, additional, Fernandez-Miranda, Juan, additional, Park, Ki Wan, additional, Le, Quynh-Thu, additional, West, Robert B., additional, Saade, Rami, additional, Manes, R. Peter, additional, Omay, Sacit Bulent, additional, Vining, Eugenia M., additional, Judson, Benjamin L., additional, Yarbrough, Wendell G., additional, Sansovini, Maddalena, additional, Silvia, Nicolini, additional, Grassi, Ilaria, additional, Bongiovanni, Alberto, additional, Capper, David, additional, Schüller, Ulrich, additional, Thavaraj, Selvam, additional, Sandison, Ann, additional, Surda, Pavol, additional, Hopkins, Claire, additional, Ferrari, Marco, additional, Mattavelli, Davide, additional, Rampinelli, Vittorio, additional, Facchetti, Fabio, additional, Nicolai, Piero, additional, Bossi, Paolo, additional, Henriquez, Oswaldo A., additional, Magliocca, Kelly, additional, Solares, C. Arturo, additional, Wise, Sarah K., additional, Llorente, Jose L., additional, Patel, Zara M., additional, Nayak, Jayakar V., additional, Hwang, Peter H., additional, Lacy, Peter D., additional, Woods, Robbie, additional, O'Neill, James P., additional, Jay, Amrita, additional, Carnell, Dawn, additional, Forster, Martin D., additional, Ishii, Masaru, additional, London, Nyall R., additional, Bell, Diana M., additional, Gallia, Gary L., additional, Castelnuovo, Paolo, additional, Severi, Stefano, additional, Lund, Valerie J., additional, and Hanna, Ehab Y., additional

Published
2022
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10. Clinically Applicable Segmentation of Head and Neck Anatomy for Radiotherapy: Deep Learning Algorithm Development and Validation Study

Author

Nikolov, Stanislav, primary, Blackwell, Sam, additional, Zverovitch, Alexei, additional, Mendes, Ruheena, additional, Livne, Michelle, additional, De Fauw, Jeffrey, additional, Patel, Yojan, additional, Meyer, Clemens, additional, Askham, Harry, additional, Romera-Paredes, Bernadino, additional, Kelly, Christopher, additional, Karthikesalingam, Alan, additional, Chu, Carlton, additional, Carnell, Dawn, additional, Boon, Cheng, additional, D'Souza, Derek, additional, Moinuddin, Syed Ali, additional, Garie, Bethany, additional, McQuinlan, Yasmin, additional, Ireland, Sarah, additional, Hampton, Kiarna, additional, Fuller, Krystle, additional, Montgomery, Hugh, additional, Rees, Geraint, additional, Suleyman, Mustafa, additional, Back, Trevor, additional, Hughes, Cían Owen, additional, Ledsam, Joseph R, additional, and Ronneberger, Olaf, additional

Published
2021
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11. Utility of diffusion MRI characteristics of cervical lymph nodes as disease classifier between patients with head and neck squamous cell carcinoma and healthy volunteers

Author

Papoutsaki, Marianthi‐Vasiliki, primary, Sidhu, Harbir Singh, additional, Dikaios, Nikolaos, additional, Singh, Saurabh, additional, Atkinson, David, additional, Kanber, Baris, additional, Beale, Timothy, additional, Morley, Simon, additional, Forster, Martin, additional, Carnell, Dawn, additional, Mendes, Ruheena, additional, and Punwani, Shonit, additional

Published
2021
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14. Multicenter Study on Clinical Outcomes of Olfactory Neuroblastoma

Author

Lechner, Matt, additional, Takahashi, Yoko, additional, Hermsen, Mario, additional, Turri-Zanoni, Mario, additional, Schartinger, Volker, additional, Bell, Diana M., additional, Helman, Sam, additional, Varghese, Jordan, additional, Magliocca, Kelly, additional, Dudas, Jozsef, additional, Riechelmann, Herbert, additional, Kaur, Raman, additional, Sprung, Susanne, additional, Howard, David, additional, Engel, Nils, additional, Zhao, Tianna, additional, Liu, Jacklyn, additional, Facchetti, Fabio, additional, Maragliano, Roberta, additional, Battocchio, Simonetta, additional, Franchi, Alessandro, additional, Carnell, Dawn, additional, Capper, David, additional, Schueller, Ulrich, additional, Forster, Martin, additional, Forde, Cillian, additional, Jay, Amrita, additional, Manes, R. Peter, additional, Judson, Benjamin L., additional, Vining, Eugenia, additional, Woods, Robbie, additional, Solares, C. Arturo, additional, O'Neill, James P., additional, Nicolai, Piero, additional, Surda, Pavol, additional, Bossi, Paolo, additional, Rampinelli, Vittorio, additional, Henriquez, Oswaldo A., additional, Hopkins, Claire, additional, Thavaraj, Selbam, additional, Yarbrough, Wendell G., additional, London, Nyall R., additional, Gallia, Gary L., additional, Wise, Sarah K., additional, Llorente, Jose L., additional, Castelnuovo, Paolo, additional, Hanna, Ehab Y., additional, and Lund, Valerie J., additional

Published
2021
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15. Clinically Applicable Segmentation of Head and Neck Anatomy for Radiotherapy: Deep Learning Algorithm Development and Validation Study (Preprint)

Author

Nikolov, Stanislav, primary, Blackwell, Sam, additional, Zverovitch, Alexei, additional, Mendes, Ruheena, additional, Livne, Michelle, additional, De Fauw, Jeffrey, additional, Patel, Yojan, additional, Meyer, Clemens, additional, Askham, Harry, additional, Romera-Paredes, Bernadino, additional, Kelly, Christopher, additional, Karthikesalingam, Alan, additional, Chu, Carlton, additional, Carnell, Dawn, additional, Boon, Cheng, additional, D'Souza, Derek, additional, Moinuddin, Syed Ali, additional, Garie, Bethany, additional, McQuinlan, Yasmin, additional, Ireland, Sarah, additional, Hampton, Kiarna, additional, Fuller, Krystle, additional, Montgomery, Hugh, additional, Rees, Geraint, additional, Suleyman, Mustafa, additional, Back, Trevor, additional, Hughes, Cían Owen, additional, Ledsam, Joseph R, additional, and Ronneberger, Olaf, additional

Published
2020
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16. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies

Author

Arce Vargas, Frederick, Furness, Andrew J.S., Litchfield, Kevin, Joshi, Kroopa, Rosenthal, Rachel, Ghorani, Ehsan, Solomon, Isabelle, Lesko, Marta H., Ruef, Nora, Roddie, Claire, Henry, Jake Y., Spain, Lavinia, Ben Aissa, Assma, Georgiou, Andrew, Wong, Yien Ning Sophia, Smith, Myles, Strauss, Dirk, Hayes, Andrew, Nicol, David, O'Brien, Tim, Mårtensson, Linda, Ljungars, Anne, Teige, Ingrid, Frendéus, Björn, Pule, Martin, Marafioti, Teresa, Gore, Martin, Larkin, James, Turajlic, Samra, Swanton, Charles, Peggs, Karl S., Quezada, Sergio A., Harrington, Kevin, Melcher, Alan, Wotherspoon, Andrew, Francis, Nicholas, Challacombe, Ben, Fernando, Archana, Hazell, Steve, Chandra, Ashish, Pickering, Lisa, Lynch, Joanna, Rudman, Sarah, Chowdhury, Simon, Harrison-Phipps, Karen, Varia, Mary, Horsfield, Catherine, Polson, Alexander, Stamp, Gordon, O'Donnell, Marie, Drake, William, Hill, Peter, Hrouda, David, Mayer, Eric, Olsburgh, Jonathan, Kooiman, Gordon, O'Connor, Kevin, Stewart, Grant, Aitchison, Michael, Tran, Maxine, Fotiadis, Nicos, Verma, Hema, Lopez, Jose, Lester, Jason, Morgan, Fiona, Kornaszewska, Malgorzata, Attanoos, Richard, Adams, Haydn, Davies, Helen, Fennell, Dean, Shaw, Jacqui, Le Quesne, John, Nakas, Apostolos, Rathinam, Sridhar, Monteiro, William, Marshall, Hilary, Nelson, Louise, Bennett, Jonathan, Riley, Joan, Primrose, Lindsay, Martinson, Luke, Anand, Girija, Khan, Sajid, Nicolson, Marianne, Kerr, Keith, Palmer, Shirley, Remmen, Hardy, Miller, Joy, Buchan, Keith, Chetty, Mahendran, Gomersall, Lesley, Lock, Sara, Naidu, Babu, Langman, Gerald, Trotter, Simon, Bellamy, Mary, Bancroft, Hollie, Kerr, Amy, Kadiri, Salma, Webb, Joanne, Middleton, Gary, Djearaman, Madava, Summers, Yvonne, Califano, Raffaele, Taylor, Paul, Shah, Rajesh, Krysiak, Piotr, Rammohan, Kendadai, Fontaine, Eustace, Booton, Richard, Evison, Matthew, Crosbie, Phil, Moss, Stuart, Idries, Faiza, Novasio, Juliette, Joseph, Leena, Bishop, Paul, Chaturvedi, Anshuman, Marie Quinn, Anne, Doran, Helen, leek, Angela, Harrison, Phil, Moore, Katrina, Waddington, Rachael, Blackhall, Fiona, Rogan, Jane, Smith, Elaine, Dive, Caroline, Brady, Ged, Rothwell, Dominic, Gulati, Sakshi, Chemie, Francesca, Tugwood, Jonathan, Pierce, Jackie, Lawrence, David, Hayward, Martin, Panagiotopoulos, Nikolaos, George, Robert, Patrini, Davide, Falzon, Mary, Borg, Elaine, Khiroya, Reena, Jamal-Hanjani, Mariam, Wilson, Gareth, Juul Birkbak, Nicolai, Watkins, Thomas, McGranahan, Nicholas, Abbosh, Christopher, Horswell, Stuart, Mitter, Richard, Escudero, Mickael, Stewart, Aengus, Rowan, Andrew, Hiley, Crispin, Goldman, Jacki, Ahmed, Asia, Taylor, Magali, Choudhary, Junaid, Shaw, Penny, Veeriah, Raju, Czyzewska-Khan, Justyna, Johnson, Diana, Laycock, Joanne, Hynds, Robert, Werner Sunderland, Mariana, Reading, James, Novelli, Marco, Oukrif, Dahmane, Janes, Sam, Forster, Martin, Ahmad, Tanya, Ming Lee, Siow, van Loo, Peter, Herrero, Javier, Hartley, John, Kevin Stone, Richard, Denner, Tamara, Costa, Marta, Begum, Sharmin, Phillimore, Ben, Chambers, Tim, Nye, Emma, Ward, Sophie, Elgar, Greg, Al-Bakir, Maise, Carnell, Dawn, Mendes, Ruheena, George, Jeremy, Navani, Neal, Papadatos-Pastos, Dionysis, Scarci, Marco, Gorman, Pat, Lowe, Helen, Ensell, Leah, Moore, David, MacKenzie, Mairead, Wilcox, Maggie, Bell, Harriet, Hackshaw, Allan, Ngai, Yenting, Smith, Sean, Gower, Nicole, Ottensmeier, Christian, Chee, Serena, Johnson, Benjamin, Alzetani, Aiman, Shaw, Emily, Lim, Eric, De Sousa, Paulo, Tavares Barbosa, Monica, Nicholson, Andrew, Bowman, Alex, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Proli, Chiara, Elena Cufari, Maria, Carlo Ronquillo, John, Kwayie, Angela, Bhayani, Harshil, Hamilton, Morag, Bakar, Yusura, Mensah, Natalie, Ambrose, Lyn, Devaraj, Anand, Buderi, Silviu, Finch, Jonathan, Azcarate, Leire, Chavan, Hema, Green, Sophie, Mashinga, Hillaria, Lau, Kelvin, Sheaff, Michael, Schmid, Peter, Conibear, John, Ezhil, Veni, Prakash, Vineet, Danson, Sarah, Bury, Jonathan, Edwards, John, Hill, Jennifer, Matthews, Sue, Kitsanta, Yota, Suvarna, Kim, Shackcloth, Michael, Gosney, John, Postmus, Pieter, Feeney, Sarah, Asante-Siaw, Julius, Russell, Peter, Light, Teresa, Horey, Tracey, Blyth, Kevin, Dick, Craig, and Kirk, Alan

Abstract

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

Published
2018

17. Fc-Optimized Anti-CD25 depletes tumor-infiltrating regulatory T Cells and synergizes with PD-1 Blockade to eradicate established tumors

Author

Arce Vargas, Frederick, Furness, Andrew J.S., Solomon, Isabelle, Joshi, Kroopa, Mekkaoui, Leila, Lesko, Marta H., Miranda Rota, Enrique, Dahan, Rony, Georgiou, Andrew, Sledzinska, Anna, Ben Aissa, Assma, Franz, Dafne, Werner Sunderland, Mariana, Wong, Yien Ning Sophia, Henry, Jake Y., O’Brien, Tim, Nicol, David, Challacombe, Ben, Beers, Stephen A., Turajlic, Samra, Gore, Martin, Larkin, James, Swanton, Charles, Chester, Kerry A., Pule, Martin, Ravetch, Jeffrey V., Marafioti, Teresa, Peggs, Karl S., Quezada, Sergio A., Spain, Lavinia, Wotherspoon, Andrew, Francis, Nicholas, Smith, Myles, Strauss, Dirk, Hayes, Andrew, Soultati, Aspasia, Stares, Mark, Lynch, Joanna, Fotiadis, Nicos, Fernando, Archana, Hazell, Steve, Chandra, Ashish, Pickering, Lisa, Rudman, Sarah, Chowdhury, Simon, Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Shafi, Seema, Czyzewska-Khan, Justyna, Johnson, Diana, Laycock, Joanne, Bosshard-Carter, Leticia, Goh, Gerald, Rosenthal, Rachel, Gorman, Pat, Murugaesu, Nirupa, Hynds, Robert E., Wilson, Gareth, Birkbak, Nicolai J., Watkins, Thomas B.K., McGranahan, Nicholas, Horswell, Stuart, Mitter, Richard, Escudero, Mickael, Stewart, Aengus, Van Loo, Peter, Rowan, Andrew, Xu, Hang, Hiley, Crispin, Abbosh, Christopher, Goldman, Jacki, Stone, Richard Kevin, Denner, Tamara, Matthews, Nik, Elgar, Greg, Ward, Sophia, Biggs, Jennifer, Costa, Marta, Begum, Sharmin, Phillimore, Ben, Chambers, Tim, Nye, Emma, Graca, Sofia, Al Bakir, Maise, Hartley, John A., Lowe, Helen L., Herrero, Javier, Lawrence, David, Hayward, Martin, Panagiotopoulos, Nikolaos, Kolvekar, Shyam, Falzon, Mary, Borg, Elaine, Simeon, Celia, Hector, Gemma, Smith, Amy, Aranda, Marie, Novelli, Marco, Oukrif, Dahmane, Janes, Sam M., Thakrar, Ricky, Forster, Martin, Ahmad, Tanya, Lee, Siow Ming, Papadatos-Pastos, Dionysis, Carnell, Dawn, Mendes, Ruheena, George, Jeremy, Navani, Neal, Ahmed, Asia, Taylor, Magali, Choudhary, Junaid, Summers, Yvonne, Califano, Raffaele, Taylor, Paul, Shah, Rajesh, Krysiak, Piotr, Rammohan, Kendadai, Fontaine, Eustace, Booton, Richard, Evison, Matthew, Crosbie, Phil, Moss, Stuart, Idries, Faiza, Joseph, Leena, Bishop, Paul, Chaturved, Anshuman, Quinn, Anne Marie, Doran, Helen, Leek, Angela, Harrison, Phil, Moore, Katrina, Waddington, Rachael, Novasio, Juliette, Blackhall, Fiona, Rogan, Jane, Smith, Elaine, Dive, Caroline, Tugwood, Jonathan, Brady, Ged, Rothwell, Dominic G., Chemi, Francesca, Pierce, Jackie, Gulati, Sakshi, Naidu, Babu, Langman, Gerald, Trotter, Simon, Bellamy, Mary, Bancroft, Hollie, Kerr, Amy, Kadiri, Salma, Webb, Joanne, Middleton, Gary, Djearaman, Madava, Fennell, Dean, Shaw, Jacqui A., Le Quesne, John, Moore, David, Nakas, Apostolos, Rathinam, Sridhar, Monteiro, William, Marshall, Hilary, Nelson, Louise, Bennett, Jonathan, Riley, Joan, Primrose, Lindsay, Martinson, Luke, Anand, Girija, Khan, Sajid, Amadi, Anita, Nicolson, Marianne, Kerr, Keith, Palmer, Shirley, Remmen, Hardy, Miller, Joy, Buchan, Keith, Chetty, Mahendran, Gomersall, Lesley, Lester, Jason, Edwards, Alison, Morgan, Fiona, Adams, Haydn, Davies, Helen, Kornaszewska, Malgorzata, Attanoos, Richard, Lock, Sara, Verjee, Azmina, MacKenzie, Mairead, Wilcox, Maggie, Bell, Harriet, Iles, Natasha, Hackshaw, Allan, Ngai, Yenting, Smith, Sean, Gower, Nicole, Ottensmeier, Christian, Chee, Serena, Johnson, Benjamin, Alzetani, Aiman, Shaw, Emily, Lim, Eric, De Sousa, Paulo, Barbosa, Monica Tavares, Bowman, Alex, Jorda, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Proli, Chiara, Cufari, Maria Elena, Ronquillo, John Carlo, Kwayie, Angela, Bhayani, Harshil, Hamilton, Morag, Bakar, Yusura, Mensah, Natalie, Ambrose, Lyn, Devaraj, Anand, Buderi, Silviu, Finch, Jonathan, Azcarate, Leire, Chavan, Hema, Green, Sophie, Mashinga, Hillaria, Nicholson, Andrew G., Lau, Kelvin, Sheaff, Michael, Schmid, Peter, Conibear, John, Ezhil, Veni, Ismail, Babikir, Irvin-sellers, Melanie, Prakash, Vineet, Russell, Peter, Light, Teresa, Horey, Tracey, Danson, Sarah, Bury, Jonathan, Edwards, John, Hill, Jennifer, Matthews, Sue, Kitsanta, Yota, Suvarna, Kim, Fisher, Patricia, Keerio, Allah Dino, Shackcloth, Michael, Gosney, John, Postmus, Pieter, Feeney, Sarah, and Asante-Siaw, Julius

Subjects
hemic and immune systems, chemical and pharmacologic phenomena, R1
Abstract

Summary\ud \ud CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

Published
2017

18. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Author

McGranahan, Nicholas, primary, Rosenthal, Rachel, additional, Hiley, Crispin T., additional, Rowan, Andrew J., additional, Watkins, Thomas B.K., additional, Wilson, Gareth A., additional, Birkbak, Nicolai J., additional, Veeriah, Selvaraju, additional, Van Loo, Peter, additional, Herrero, Javier, additional, Swanton, Charles, additional, Jamal-Hanjani, Mariam, additional, Shafi, Seema, additional, Czyzewska-Khan, Justyna, additional, Johnson, Diana, additional, Laycock, Joanne, additional, Bosshard-Carter, Leticia, additional, Gorman, Pat, additional, Hynds, Robert E., additional, Wilson, Gareth, additional, McGranahan, Nicholas, additional, Horswell, Stuart, additional, Mitter, Richard, additional, Escudero, Mickael, additional, Stewart, Aengus, additional, Rowan, Andrew, additional, Xu, Hang, additional, Turajlic, Samra, additional, Hiley, Crispin, additional, Abbosh, Christopher, additional, Goldman, Jacki, additional, Stone, Richard Kevin, additional, Denner, Tamara, additional, Matthews, Nik, additional, Elgar, Greg, additional, Ward, Sophia, additional, Costa, Marta, additional, Begum, Sharmin, additional, Phillimore, Ben, additional, Chambers, Tim, additional, Nye, Emma, additional, Graca, Sofia, additional, Al Bakir, Maise, additional, Joshi, Kroopa, additional, Furness, Andrew, additional, Ben Aissa, Assma, additional, Wong, Yien Ning Sophia, additional, Georgiou, Andy, additional, Quezada, Sergio, additional, Hartley, John A., additional, Lowe, Helen L., additional, Lawrence, David, additional, Hayward, Martin, additional, Panagiotopoulos, Nikolaos, additional, Kolvekar, Shyam, additional, Falzon, Mary, additional, Borg, Elaine, additional, Marafioti, Teresa, additional, Simeon, Celia, additional, Hector, Gemma, additional, Smith, Amy, additional, Aranda, Marie, additional, Novelli, Marco, additional, Oukrif, Dahmane, additional, Janes, Sam M., additional, Thakrar, Ricky, additional, Forster, Martin, additional, Ahmad, Tanya, additional, Lee, Siow Ming, additional, Papadatos-Pastos, Dionysis, additional, Carnell, Dawn, additional, Mendes, Ruheena, additional, George, Jeremy, additional, Navani, Neal, additional, Ahmed, Asia, additional, Taylor, Magali, additional, Choudhary, Junaid, additional, Summers, Yvonne, additional, Califano, Raffaele, additional, Taylor, Paul, additional, Shah, Rajesh, additional, Krysiak, Piotr, additional, Rammohan, Kendadai, additional, Fontaine, Eustace, additional, Booton, Richard, additional, Evison, Matthew, additional, Crosbie, Phil, additional, Moss, Stuart, additional, Idries, Faiza, additional, Joseph, Leena, additional, Bishop, Paul, additional, Chaturved, Anshuman, additional, Quinn, Anne Marie, additional, Doran, Helen, additional, Leek, Angela, additional, Harrison, Phil, additional, Moore, Katrina, additional, Waddington, Rachael, additional, Novasio, Juliette, additional, Blackhall, Fiona, additional, Rogan, Jane, additional, Smith, Elaine, additional, Dive, Caroline, additional, Tugwood, Jonathan, additional, Brady, Ged, additional, Rothwell, Dominic G., additional, Chemi, Francesca, additional, Pierce, Jackie, additional, Gulati, Sakshi, additional, Naidu, Babu, additional, Langman, Gerald, additional, Trotter, Simon, additional, Bellamy, Mary, additional, Bancroft, Hollie, additional, Kerr, Amy, additional, Kadiri, Salma, additional, Webb, Joanne, additional, Middleton, Gary, additional, Djearaman, Madava, additional, Fennell, Dean, additional, Shaw, Jacqui A., additional, Le Quesne, John, additional, Moore, David, additional, Nakas, Apostolos, additional, Rathinam, Sridhar, additional, Monteiro, William, additional, Marshall, Hilary, additional, Nelson, Louise, additional, Bennett, Jonathan, additional, Riley, Joan, additional, Primrose, Lindsay, additional, Martinson, Luke, additional, Anand, Girija, additional, Khan, Sajid, additional, Amadi, Anita, additional, Nicolson, Marianne, additional, Kerr, Keith, additional, Palmer, Shirley, additional, Remmen, Hardy, additional, Miller, Joy, additional, Buchan, Keith, additional, Chetty, Mahendran, additional, Gomersall, Lesley, additional, Lester, Jason, additional, Edwards, Alison, additional, Morgan, Fiona, additional, Adams, Haydn, additional, Davies, Helen, additional, Kornaszewska, Malgorzata, additional, Attanoos, Richard, additional, Lock, Sara, additional, Verjee, Azmina, additional, MacKenzie, Mairead, additional, Wilcox, Maggie, additional, Bell, Harriet, additional, Hackshaw, Allan, additional, Ngai, Yenting, additional, Smith, Sean, additional, Gower, Nicole, additional, Ottensmeier, Christian, additional, Chee, Serena, additional, Johnson, Benjamin, additional, Alzetani, Aiman, additional, Shaw, Emily, additional, Lim, Eric, additional, De Sousa, Paulo, additional, Barbosa, Monica Tavares, additional, Bowman, Alex, additional, Jordan, Simon, additional, Rice, Alexandra, additional, Raubenheimer, Hilgardt, additional, Proli, Chiara, additional, Cufari, Maria Elena, additional, Ronquillo, John Carlo, additional, Kwayie, Angela, additional, Bhayani, Harshil, additional, Hamilton, Morag, additional, Bakar, Yusura, additional, Mensah, Natalie, additional, Ambrose, Lyn, additional, Devaraj, Anand, additional, Buderi, Silviu, additional, Finch, Jonathan, additional, Azcarate, Leire, additional, Chavan, Hema, additional, Green, Sophie, additional, Mashinga, Hillaria, additional, Nicholson, Andrew G., additional, Lau, Kelvin, additional, Sheaff, Michael, additional, Schmid, Peter, additional, Conibear, John, additional, Ezhil, Veni, additional, Ismail, Babikir, additional, Irvin-sellers, Melanie, additional, Prakash, Vineet, additional, Russell, Peter, additional, Light, Teresa, additional, Horey, Tracey, additional, Danson, Sarah, additional, Bury, Jonathan, additional, Edwards, John, additional, Hill, Jennifer, additional, Matthews, Sue, additional, Kitsanta, Yota, additional, Suvarna, Kim, additional, Fisher, Patricia, additional, Keerio, Allah Dino, additional, Shackcloth, Michael, additional, Gosney, John, additional, Postmus, Pieter, additional, Feeney, Sarah, additional, Asante-Siaw, Julius, additional, Aerts, Hugo J.W.L., additional, Dentro, Stefan, additional, and Dessimoz, Christophe, additional

Published
2017
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21. Photochemical internalization

Author

Jerjes, Waseem, primary, Mosse, Charles, additional, Hamdoon, Zaid, additional, Carnell, Dawn, additional, Berg, Kristian, additional, Høgset, Anders, additional, and Hopper, Colin, additional

Published
2010
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22. Hypoxia in Prostate Cancer: Correlation of BOLD-MRI With Pimonidazole Immunohistochemistry—Initial Observations

Author

Hoskin, Peter J., primary, Carnell, Dawn M., additional, Taylor, N. Jane, additional, Smith, Rowena E., additional, Stirling, J. James, additional, Daley, Frances M., additional, Saunders, Michele I., additional, Bentzen, Søren M., additional, Collins, David J., additional, d’Arcy, James A., additional, and Padhani, Anwar P., additional

Published
2007
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