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1. Late-stage metastatic melanoma emerges through a diversity of evolutionary pathways

Author

Spain, Lavinia, Coulton, Alexander, Lobon, Irene, Rowan, Andrew, Schnidrig, Desiree, Shepherd, Scott TC, Shum, Benjamin, Byrne, Fiona, Goicoechea, Maria, Piperni, Elisa, Au, Lewis, Edmonds, Kim, Carlyle, Eleanor, Hunter, Nikki, Renn, Alexandra, Messiou, Christina, Hughes, Peta, Nobbs, Jaime, Foijer, Floris, van den Bos, Hilda, Wardenaar, Rene, Spierings, Diana CJ, Spencer, Charlotte, Schmitt, Andreas M, Tippu, Zayd, Lingard, Karla, Grostate, Lauren, Peat, Kema, Kelly, Kayleigh, Sarker, Sarah, Vaughan, Sarah, Mangwende, Mary, Terry, Lauren, Kelly, Denise, Biano, Jennifer, Murra, Aida, Korteweg, Justine, Lewis, Charlotte, OFlaherty, Molly, Cattin, Anne-Laure, Emmerich, Max, Gerard, Camille L, Pallikonda, Husayn Ahmed, Lynch, Joanna, Mason, Robert, Rogiers, Aljosja, Xu, Hang, Huebner, Ariana, McGranahan, Nicholas, Al Bakir, Maise, Murai, Jun, Naceur-Lombardelli, Cristina, Borg, Elaine, Mitchison, Miriam, Moore, David A, Falzon, Mary, Proctor, Ian, Stamp, Gordon WH, Nye, Emma L, Young, Kate, Furness, Andrew JS, Pickering, Lisa, Stewart, Ruby, Mahadeva, Ula, Green, Anna, Larkin, James, Litchfield, Kevin, Swanton, Charles, Jamal-Hanjani, Mariam, Consortium, The PEACE, and Turajlic, Samra

Subjects
Chemical Biology & High Throughput, Signalling & Oncogenes, Human Biology & Physiology, Ecology,Evolution & Ethology, Genome Integrity & Repair, Tumour Biology, Genetics & Genomics, Computational & Systems Biology
Abstract

Understanding the evolutionary pathways to metastasis and resistance to immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present the most comprehensive intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy programme, including 222 exome, 493 panel-sequenced, 161 RNA-seq, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI non-responders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one of the patients. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.

Published
2023
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2. Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

Author

Fu, Xiao, Zhao, Yue, Lopez, Jose I., Rowan, Andrew, Au, Lewis, Fendler, Annika, Hazell, Steve, Xu, Hang, Horswell, Stuart, Shepherd, Scott T. C., Spencer, Charlotte E., Spain, Lavinia, Byrne, Fiona, Stamp, Gordon, O’Brien, Tim, Nicol, David, Augustine, Marcellus, Chandra, Ashish, Rudman, Sarah, Toncheva, Antonia, Furness, Andrew J. S., Pickering, Lisa, Kumar, Santosh, Koh, Dow-Mu, Messiou, Christina, Dafydd, Derfel ap, Orton, Matthew R., Doran, Simon J., Larkin, James, Swanton, Charles, Sahai, Erik, Litchfield, Kevin, Turajlic, Samra, Ben Challacombe, Chowdhury, Simon, Drake, William, Fernando, Archana, Fotiadis, Nicos, Hatipoglu, Emine, Harrison-Phipps, Karen, Hill, Peter, Horsfield, Catherine, Marafioti, Teresa, Olsburgh, Jonathon, Polson, Alexander, Quezada, Sergio, Varia, Mary, Verma, Hema, and Bates, Paul A.

Subjects
0303 health sciences, Ecology, Models, Biological, Article, Computational biology and bioinformatics, Clonal Evolution, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Neoplasms, Cancer genomics, Molecular evolution, Humans, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology
Abstract

Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution., A combined modelling and tumour analysis approach is used to study the temporal and spatial patterns of subclone evolution in the TRACERx renal study. Studying the tumour shape and spatial features of clonal diversity in early-stage tumours may allow the prediction of tumour progression and patterns of subclone diversification over time.

Published
2021

3. Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay

Author

Orlando, Francesco, Romanel, Alessandro, Trujillo, Blanca, Sigouros, Michael, Wetterskog, Daniel, Quaini, Orsetta, Leone, Gianmarco, Xiang, Jenny Z, Wingate, Anna, Tagawa, Scott, Jayaram, Anuradha, Linch, Mark, Swanton, Charles, Jamal-Hanjani, Mariam, Abbosh, Chris, Zaccaria, Simone, Hessey, Sonya, Shiu, Kai-Keen, Bridgewater, John, Hochhauser, Daniel, Forster, Martin, Lee, Siow-Ming, Ahmad, Tanya, Papadatos-Pastos, Dionysis, Janes, Sam, Van Loo, Peter, Enfield, Katey, McGranahan, Nicholas, Huebner, Ariana, Quezada, Sergio, Beck, Stephan, Parker, Peter, Enver, Tariq, Hynds, Robert E, Dijkstra, Krijn, Pearce, David R, Falzon, Mary, Proctor, Ian, Sinclair, Ron, Lok, Chi-wah, Rhodes, Zoe, Moore, David, Marafioti, Teresa, Mitchison, Miriam, Ellery, Peter, Sivakumar, Monica, Brandner, Sebastian, Rowan, Andrew, Hiley, Crispin, Veeriah, Selvaraju, Shaw, Heather, Attard, Gert, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Prymas, Paulina, Watkins, Tom, Bailey, Chris, Ruiz, Carlos Martinez, Litchfield, Kevin, Al-Bakir, Maise, Kanu, Nnenna, Ward, Sophie, Lim, Emilia, Reading, James, Chain, Benny, Alba, Blanca Trujillo, Akay, Melek, Flanagan, Adrienne, Biswas, Dhruva, Pich, Oriol, Dietzen, Michelle, Puttick, Clare, Colliver, Emma, Magness, Alistair, Angelova, Mihaela, Black, James, Lucas, Olivia, Hill, William, Liu, Wing-Kin, Frankell, Alexander, Magno, Neil, Athanasopoulou, Foteini, Wilson, Gareth, Rosenthal, Rachel, Salgado, Roberto, Lee, Claudia, Grigoriadis, Kristiana, Al-Sawaf, Othman, Karasaki, Takahiro, Bunkum, Abigail, Noorani, Imran, Benafif, Sarah, Barbe, Vittorio, Bola, Supreet, Vainauskas, Osvaldas, Hasan, Mahedi, Lise, Stefano, Leone, GianMarco, Alifrangis, Constantine, McGovern, Ursula, Thol, Kerstin, Gamble, Samuel, Ung, Seng Kuong, Sahwangarrom, Teerapon, Marin, Claudia Peinador, Wong, Sophia, Pawlik, Piotr, Gishen, Faye, Tookman, Adrian, Stone, Paddy, Stirling, Caroline, Turajlic, Samra, Larkin, James, Pickering, Lisa, Furness, Andrew, Young, Kate, Drake, Will, Edmonds, Kim, Hunter, Nikki, Mangwende, Mary, Pearce, Karla, Grostate, Lauren, Au, Lewis, Spain, Lavinia, Shepherd, Scott, Yan, Haixi, Shum, Ben, Tippu, Zayd, Hanley, Brian, Spencer, Charlotte, Emmerich, Max, Gerard, Camille, Schmitt, Andreas Michael, Del Rosario, Lyra, Carlyle, Eleanor, Lewis, Charlotte, Holt, Lucy, Lucanas, Analyn, O'Flaherty, Molly, Hazell, Steve, Mudhar, Hardeep, Messiou, Christina, Latifoltojar, Arash, Fendler, Annika, Byrne, Fiona, Pallinkonda, Husayn, Lobon, Irene, Coulton, Alex, Cattin, Anne Laure, Deng, Daqi, Feng, Geoffrey Hugang, Rowan, Andew, Yousaf, Nadia, Popat, Sanjay, Curtis, Olivia, Milner-Watts, Charlotte, Stamp, Gordon, Nye, Emma, Murra, Aida, Korteweg, Justine, Kelly, Denise, Terry, Lauren, Biano, Jennifer, Peat, Kema, Kelly, Kayleigh, Hill, Peter, Josephs, Debra, Irshad, Sheeba, Chandra, Ashish, Spicer, James, Mahadeva, Ula, Green, Anna, Stewart, Ruby, Iredale, Lara-Rose, Mackay, Tina, Deakin, Ben, Enting, Debra, Rudman, Sarah, Ghosh, Sharmistha, Karapagniotou, Lena, Pintus, Elias, Tutt, Andrew, Howlett, Sarah, Michalarea, Vasiliki, Brenton, James, Caldas, Carlos, Fitzgerald, Rebecca, Jimenez-Linan, Merche, Provenzano, Elena, Cluroe, Alison, Paterson, Anna, Aitken, Sarah, Allinson, Kieren, Stewart, Grant, McDermott, Ultan, Beddowes, Emma, Maughan, Tim, Ansorge, Olaf, Campbell, Peter, Roxburgh, Patricia, Fraser, Sioban, Kidd, Andrew, Blyth, Kevin, Le Quesne, John, Krebs, Matthew, Blackhall, Fiona, Summers, Yvonne, Oliveira, Pedro, Ortega-Franco, Ana, Dive, Caroline, Gomes, Fabio, Carter, Mat, Dransfield, Jo, Thomas, Anne, Fennell, Dean, Shaw, Jacqui, Naidu, Babu, Baijal, Shobhit, Tanchel, Bruce, Langman, Gerald, Robinson, Andrew, Collard, Martin, Cockcroft, Peter, Ferris, Charlotte, Bancroft, Hollie, Kerr, Amy, Middleton, Gary, Webb, Joanne, Kadiri, Salma, Colloby, Peter, Olisemeke, Bernard, Wilson, Rodelaine, Tomlinson, Ian, McNeish, Iain, Jogai, Sanjay, Holden, Samantha, Fernandes, Tania, Hampton, Blanche, McKenzie, Mairead, Hackshaw, Allan, Sharp, Abby, Chan, Kitty, Farrelly, Laura, Bridger, Hayley, Leslie, Rachel, Consortium, PEACE, Rubin, Mark A, Wyatt, Alexander W, Beltran, Himisha, Attard, Gerhardt, and Demichelis, Francesca

Subjects
Chemical Biology & High Throughput, Signalling & Oncogenes, Human Biology & Physiology, Ecology,Evolution & Ethology, Genome Integrity & Repair, Tumour Biology, Genetics & Genomics, Computational & Systems Biology
Abstract

Sequencing of cell-free DNA (cfDNA) in cancer patients’ plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with

Published
2022
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4. Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study

Author

Fendler, Annika, Shepherd, Scott TC, Au, Lewis, Wilkinson, Katalin A, Wu, Mary, Byrne, Fiona, Cerrone, Maddalena, Schmitt, Andreas M, Joharatnam-Hogan, Nalinie, Shum, Benjamin, Tippu, Zayd, Rzeniewicz, Karolina, Boos, Laura Amanda, Harvey, Ruth, Carlyle, Eleanor, Edmonds, Kim, Del Rosario, Lyra, Sarker, Sarah, Lingard, Karla, Mangwende, Mary, Holt, Lucy, Ahmod, Hamid, Korteweg, Justine, Foley, Tara, Bazin, Jessica, Gordon, William, Barber, Taja, Emslie-Henry, Andrea, Xie, Wenyi, Gerard, Camille L, Deng, Daqi, Wall, Emma C, Agua-Doce, Ana, Namjou, Sina, Caidan, Simon, Gavrielides, Mike, MacRae, James I, Kelly, Gavin, Peat, Kema, Kelly, Denise, Murra, Aida, Kelly, Kayleigh, O���Flaherty, Molly, Dowdie, Lauren, Ash, Natalie, Gronthoud, Firza, Shea, Robyn L, Gardner, Gail, Murray, Darren, Kinnaird, Fiona, Cui, Wanyuan, Pascual, Javier, Rodney, Simon, Mencel, Justin, Curtis, Olivia, Stephenson, Clemency, Robinson, Anna, Oza, Bhavna, Farag, Sheima, Leslie, Isla, Rogiers, Aljosja, Iyengar, Sunil, Ethell, Mark, Messiou, Christina, Cunningham, David, Chau, Ian, Starling, Naureen, Turner, Nicholas, Welsh, Liam, van As, Nicholas, Jones, Robin L, Droney, Joanne, Banerjee, Susana, Tatham, Kate C, O���Brien, Mary, Harrington, Kevin, Bhide, Shreerang, Okines, Alicia, Reid, Alison, Young, Kate, Furness, Andrew JS, Pickering, Lisa, Swanton, Charles, Consortium, The Crick COVID-19, Gandhi, Sonia, Gamblin, Steve, Bauer, David LV, Kassiotis, George, Kumar, Sacheen, Yousaf, Nadia, Jhanji, Shaman, Nicholson, Emma, Howell, Michael, Walker, Susanna, Wilkinson, Robert J, Larkin, James, Turajlic, Samra, and Consortium, The CAPTURE

Subjects
Model organisms, Chemical Biology & High Throughput, Human Biology & Physiology, FOS: Clinical medicine, Stem Cells, Genome Integrity & Repair, Immunology, Neurosciences, Infectious Disease, Cell Biology, Tumour Biology, Biochemistry & Proteomics, Signalling & Oncogenes, Metabolism, Ecology,Evolution & Ethology, Cell Cycle & Chromosomes, Genetics & Genomics, Developmental Biology, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.

Published
2022
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5. Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

Author

Fu, Xiao, Zhao, Yue, Lopez, Jose I, Rowan, Andrew, Au, Lewis, Fendler, Annika, Hazell, Steve, Xu, Hang, Horswell, Stuart, Shepherd, Scott TC, Spencer, Charlotte E, Spain, Lavinia, Byrne, Fiona, Stamp, Gordon, O'Brien, Tim, Nicol, David, Augustine, Marcellus, Chandra, Ashish, Rudman, Sarah, Toncheva, Antonia, Furness, Andrew JS, Pickering, Lisa, Kumar, Santosh, Koh, Dow-Mu, Messiou, Christina, Dafydd, Derfel ap, Orton, Matthew R, Doran, Simon J, Larkin, James, Swanton, Charles, Sahai, Erik, Litchfield, Kevin, Turajlic, Samra, Consortium, TRACERx Renal, and Bates, Paul A

Subjects
Model organisms, Chemical Biology & High Throughput, Signalling & Oncogenes, Human Biology & Physiology, Ecology,Evolution & Ethology, Genome Integrity & Repair, Cell Biology, Tumour Biology, Genetics & Genomics, Imaging, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.

Published
2022
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6. Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study

Author

Fendler, Annika, Au, Lewis, Shepherd, Scott TC, Byrne, Fiona, Cerrone, Maddalena, Boos, Laura Amanda, Rzeniewicz, Karolina, Gordon, William, Shum, Benjamin, Gerard, Camille L, Ward, Barry, Xie, Wenyi, Schmitt, Andreas M, Joharatnam-Hogan, Nalinie, Cornish, Georgina H, Pule, Martin, Mekkaoui, Leila, Ng, Kevin W, Carlyle, Eleanor, Edmonds, Kim, Del Rosario, Lyra, Sarker, Sarah, Lingard, Karla, Mangwende, Mary, Holt, Lucy, Ahmod, Hamid, Stone, Richard, Gomes, Camila, Flynn, Helen R, Agua-Doce, Ana, Hobson, Philip, Caidan, Simon, Howell, Michael, Wu, Mary, Goldstone, Robert, Crawford, Margaret, Cubitt, Laura, Patel, Harshil, Gavrielides, Mike, Nye, Emma, Snijders, Ambrosius P, MacRae, James I, Nicod, Jerome, Gronthoud, Firza, Shea, Robyn L, Messiou, Christina, Cunningham, David, Chau, Ian, Starling, Naureen, Turner, Nicholas, Welsh, Liam, van As, Nicholas, Jones, Robin L, Droney, Joanne, Banerjee, Susana, Tatham, Kate C, Jhanji, Shaman, O���Brien, Mary, Curtis, Olivia, Harrington, Kevin, Bhide, Shreerang, Bazin, Jessica, Robinson, Anna, Stephenson, Clemency, Slattery, Tim, Khan, Yasir, Tippu, Zayd, Leslie, Isla, Gennatas, Spyridon, Okines, Alicia, Reid, Alison, Young, Kate, Furness, Andrew JS, Pickering, Lisa, Gandhi, Sonia, Gamblin, Steve, Swanton, Charles, Consortium, The Crick COVID-19, Nicholson, Emma, Kumar, Sacheen, Yousaf, Nadia, Wilkinson, Katalin A, Swerdlow, Anthony, Harvey, Ruth, Kassiotis, George, Larkin, James, Wilkinson, Robert J, Turajlic, Samra, and consortium, The CAPTURE

Subjects
Model organisms, Chemical Biology & High Throughput, Human Biology & Physiology, FOS: Clinical medicine, Stem Cells, Genome Integrity & Repair, Immunology, Neurosciences, Infectious Disease, Cell Biology, Tumour Biology, Biochemistry & Proteomics, Signalling & Oncogenes, Metabolism, Ecology,Evolution & Ethology, Cell Cycle & Chromosomes, Genetics & Genomics, Developmental Biology, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.

Published
2022
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7. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author

Au, Lewis, Hatipoglu, Emine, Robert De Massy, Marc, Litchfield, Kevin, Beattie, Gordon, Rowan, Andrew, Schnidrig, Desiree, Thompson, Rachael, Byrne, Fiona, Horswell, Stuart, Fotiadis, Nicos, Hazell, Steve, Nicol, David, Shepherd, Scott TC, Fendler, Annika, Mason, Robert, Del Rosario, Lyra, Edmonds, Kim, Lingard, Karla, Sarker, Sarah, Mangwende, Mary, Carlyle, Eleanor, Attig, Jan, Joshi, Kroopa, Uddin, Imran, Becker, Pablo D, Sunderland, Mariana Werner, Akarca, Ayse, Puccio, Ignazio, Yang, William W, Lund, Tom, Dhillon, Kim, Vasquez, Marcos Duran, Ghorani, Ehsan, Xu, Hang, Spencer, Charlotte, López, José I, Green, Anna, Mahadeva, Ula, Borg, Elaine, Mitchison, Miriam, Moore, David A, Proctor, Ian, Falzon, Mary, Pickering, Lisa, Furness, Andrew JS, Reading, James L, Salgado, Roberto, Marafioti, Teresa, Jamal-Hanjani, Mariam, PEACE Consortium, Kassiotis, George, Chain, Benny, Larkin, James, Swanton, Charles, Quezada, Sergio A, Turajlic, Samra, TRACERx Renal Consortium, and Apollo - University of Cambridge Repository

Subjects
multiregion, Receptors, Antigen, T-Cell, clear cell renal cell carcinoma, CD8-Positive T-Lymphocytes, autopsy, Clinical Trials, Phase II as Topic, Exome Sequencing, Tumor Microenvironment, Humans, TCR clonal replacement, Prospective Studies, TCR clonal maintenance, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, nivolumab, Sequence Analysis, RNA, Gene Expression Profiling, Endogenous Retroviruses, Genomics, Kidney Neoplasms, human endogenous retrovirus, Drug Resistance, Neoplasm, anti-PD-1, Tumor Escape, T cell receptor, Single-Cell Analysis
Abstract

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Published
2021

8. Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial

Author

Halabi, Susan, Yang, Qian, Carmack, Andrea, Zhang, Shiqi, Foo, Wen-Chi, Eisen, Tim, Stadler, Walter, Jones, Robert J., Garcia, Jorge, Picus, Joel, Hawkins, Robert, Hainsworth, John, Kollmannsberger, Christian, Logan, Theodore, Puzanov, Igor, Pickering, Lisa, Ryan, Christopher, Protheroe, Andrew, George, Daniel, and Armstrong, Andrew

Abstract

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intentionto- treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor-risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Published
2021

9. Angiokines associated with outcomes after sunitinib or everolimus treatment in patients with non-clear cell renal cell carcinoma

Author

Armstrong, Andrew J., Nixon, Andrew B., Carmack, Andrea, Eisen, Tim, Stadler, Walter M., Jones, Robert J., Garcia, Jorge A., Vaishampayan, Ulka N., Picus, Joel, Hawkins, Robert E., Hainsworth, John D., Kollmannsberger, Christian K., Logan, Theodore F., Puzanov, Igor, Pickering, Lisa M., Ryan, Christopher W., Protheroe, Andrew, George, Daniel J., and Halabi, Susan

Subjects
urologic and male genital diseases
Abstract

Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. \ud \ud Experimental Design: ASPEN (NCT01108445) was an international, randomized, open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1 criteria. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival. \ud \ud Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 89 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 87 PFS and 62 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), HGF, and VCAM-1, and these were also associated with poor risk disease. SDF-1 was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. OPN, HGF, TIMP-1, VCAM-1, PDGF-AA and IL-6 levels increased with progression on everolimus, while OPN, PlGF, TIMP-1, VEGF, and soluble VEGFR-2 and VCAM-1 increased with progression on sunitinib. \ud \ud Conclusions: In patients with metastatic non-clear cell RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.

Published
2021

10. Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2

Author

Au, Lewis, Fendler, Annika, Shepherd, Scott TC, Rzeniewicz, Karolina, Cerrone, Maddalena, Byrne, Fiona, Carlyle, Eleanor, Edmonds, Kim, Del Rosario, Lyra, Shon, John, Haynes, Winston A, Ward, Barry, Shum, Ben, Gordon, William, Gerard, Camille L, Xie, Wenyi, Joharatnam-Hogan, Nalinie, Young, Kate, Pickering, Lisa, Furness, Andrew JS, Larkin, James, Harvey, Ruth, Kassiotis, George, Gandhi, Sonia, Consortium, Crick COVID-19, Swanton, Charles, Fribbens, Charlotte, Wilkinson, Katalin A, Wilkinson, Robert J, Lau, David K, Banerjee, Susana, Starling, Naureen, Chau, Ian, Consortium, CAPTURE, and Turajlic, Samra

Subjects
Model organisms, Chemical Biology & High Throughput, Human Biology & Physiology, FOS: Clinical medicine, Stem Cells, Genome Integrity & Repair, Immunology, Neurosciences, Infectious Disease, Cell Biology, Tumour Biology, Signalling & Oncogenes, Ecology,Evolution & Ethology, Genetics & Genomics, Computational & Systems Biology
Abstract

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.

Published
2021
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11. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Author

Turajlic, Samra, Xu, Hang, Litchfield, Kevin, Rowan, Andrew, Horswell, Stuart, Chambers, Tim, O'Brien, Tim, Lopez, Jose I, Watkins, Thomas BK, Nicol, David, Stares, Mark, Challacombe, Ben, Hazell, Steve, Chandra, Ashish, Mitchell, Thomas J, Au, Lewis, Eichler-Jonsson, Claudia, Jabbar, Faiz, Soultati, Aspasia, Chowdhury, Simon, Rudman, Sarah, Lynch, Joanna, Fernando, Archana, Stamp, Gordon, Nye, Emma, Stewart, Aengus, Xing, Wei, Smith, Jonathan C, Escudero, Mickael, Huffman, Adam, Matthews, Nik, Elgar, Greg, Phillimore, Ben, Costa, Marta, Begum, Sharmin, Ward, Sophia, Salm, Max, Boeing, Stefan, Fisher, Rosalie, Spain, Lavinia, Navas, Carolina, Grönroos, Eva, Hobor, Sebastijan, Sharma, Sarkhara, Aurangzeb, Ismaeel, Lall, Sharanpreet, Polson, Alexander, Varia, Mary, Horsfield, Catherine, Fotiadis, Nicos, Pickering, Lisa, Schwarz, Roland F, Silva, Bruno, Herrero, Javier, Luscombe, Nick M, Jamal-Hanjani, Mariam, Rosenthal, Rachel, Birkbak, Nicolai J, Wilson, Gareth A, Pipek, Orsolya, Ribli, Dezso, Krzystanek, Marcin, Csabai, Istvan, Szallasi, Zoltan, Gore, Martin, McGranahan, Nicholas, Van Loo, Peter, Campbell, Peter, Larkin, James, Swanton, Charles, TRACERx Renal Consortium, Mitchell, Thomas [0000-0003-0761-9503], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, intratumor heterogeneity, branched evolution, linear evolution, renal cell cancer, Chromosomes, Clonal Evolution, Evolution, Molecular, Genetic Heterogeneity, deterministic evolution, Biomarkers, Tumor, metastasis, Humans, Longitudinal Studies, Prospective Studies, Neoplasm Metastasis, Carcinoma, Renal Cell, Alleles, Phylogeny, Aged, Aged, 80 and over, cancer evolution, Models, Statistical, tumor diversity, Genetic Variation, punctuated evolution, Sequence Analysis, DNA, Middle Aged, Prognosis, Kidney Neoplasms, Phenotype, Mutation, Disease Progression, Female, chromosome instability
Abstract

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Published
2018
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12. Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

Author

Mitchell, Thomas J, Turajlic, Samra, Rowan, Andrew, Nicol, David, Farmery, James HR, O'Brien, Tim, Martincorena, Inigo, Tarpey, Patrick, Angelopoulos, Nicos, Yates, Lucy R, Butler, Adam P, Raine, Keiran, Stewart, Grant D, Challacombe, Ben, Fernando, Archana, Lopez, Jose I, Hazell, Steve, Chandra, Ashish, Chowdhury, Simon, Rudman, Sarah, Soultati, Aspasia, Stamp, Gordon, Fotiadis, Nicos, Pickering, Lisa, Au, Lewis, Spain, Lavinia, Lynch, Joanna, Stares, Mark, Teague, Jon, Maura, Francesco, Wedge, David C, Horswell, Stuart, Chambers, Tim, Litchfield, Kevin, Xu, Hang, Stewart, Aengus, Elaidi, Reza, Oudard, Stéphane, McGranahan, Nicholas, Csabai, Istvan, Gore, Martin, Futreal, P Andrew, Larkin, James, Lynch, Andy G, Szallasi, Zoltan, Swanton, Charles, Campbell, Peter J, TRACERx Renal Consortium, Mitchell, Thomas [0000-0003-0761-9503], Stewart, Grant [0000-0003-3188-9140], Lynch, Andy [0000-0002-7876-7338], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, cancer evolution, Genome, Human, Gene Dosage, clear cell renal cell carcinoma, Middle Aged, Kidney Neoplasms, Von Hippel-Lindau Tumor Suppressor Protein, Mutation, Disease Progression, chromothripsis, Chromosomes, Human, Pair 5, Humans, Female, Chromosomes, Human, Pair 3, Prospective Studies, 5' Untranslated Regions, Carcinoma, Renal Cell, Telomerase, Aged
Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Published
2018
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13. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

Author

Turajlic, Samra, Xu, Hang, Litchfield, Kevin, Rowan, Andrew, Chambers, Tim, Lopez, Jose I, Nicol, David, O'Brien, Tim, Larkin, James, Horswell, Stuart, Stares, Mark, Au, Lewis, Jamal-Hanjani, Mariam, Challacombe, Ben, Chandra, Ashish, Hazell, Steve, Eichler-Jonsson, Claudia, Soultati, Aspasia, Chowdhury, Simon, Rudman, Sarah, Lynch, Joanna, Fernando, Archana, Stamp, Gordon, Nye, Emma, Jabbar, Faiz, Spain, Lavinia, Lall, Sharanpreet, Guarch, Rosa, Falzon, Mary, Proctor, Ian, Pickering, Lisa, Gore, Martin, Watkins, Thomas BK, Ward, Sophia, Stewart, Aengus, DiNatale, Renzo, Becerra, Maria F, Reznik, Ed, Hsieh, James J, Richmond, Todd A, Mayhew, George F, Hill, Samantha M, McNally, Catherine D, Jones, Carol, Rosenbaum, Heidi, Stanislaw, Stacey, Burgess, Daniel L, Alexander, Nelson R, Swanton, Charles, PEACE, TRACERx Renal Consortium, Turajlic, Samra [0000-0001-8846-136X], Litchfield, Kevin [0000-0002-3725-0914], Lopez, Jose I [0000-0003-0842-5348], Horswell, Stuart [0000-0003-2787-1933], Spain, Lavinia [0000-0002-9356-8812], Stewart, Aengus [0000-0001-5182-653X], DiNatale, Renzo [0000-0002-7867-2881], Mayhew, George F [0000-0003-0609-6018], Swanton, Charles [0000-0002-4299-3018], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, evolution of metastasis, Biopsy, renal cell cancer, loss of 9p, solitary metastasis, metastasis, Humans, Longitudinal Studies, Prospective Studies, Neoplasm Metastasis, Carcinoma, Renal Cell, Aged, Aged, 80 and over, Chromosomes, Human, Pair 14, Chromosome Mapping, Thrombosis, Middle Aged, Kidney Neoplasms, oligometastasis, Phenotype, Treatment Outcome, Mutation, Disease Progression, Female, chromosome instability, metastasectomy, Chromosomes, Human, Pair 9, Biomarkers, cytoreductive nephrectomy
Abstract

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Published
2018

14. 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

15. 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

16. Selection of metastasis competent subclones in the tumour interior

Author

Zhao, Yue, Fu, Xiao, Lopez, Jose I., Rowan, Andrew, Au, Lewis, Fendler, Annika, Hazell, Steve, Xu, Hang, Horswell, Stuart, Shepherd, Scott T. C., Spain, Lavinia, Byrne, Fiona, Stamp, Gordon, O’Brien, Tim, Nicol, David, Augustine, Marcellus, Chandra, Ashish, Rudman, Sarah, Toncheva, Antonia, Pickering, Lisa, Sahai, Erik, Larkin, James, Bates, Paul A., Swanton, Charles, Turajlic, Samra, Challacombe, Ben, Chowdhury, Simon, Drake, William, Fernando, Archana, Fotiadis, Nicos, Furness, Andrew, Hatipoglu, Emine, Harrison-Phipps, Karen, Hill, Peter, Horsfield, Catherine, Marafioti, Teresa, Olsburgh, Jonathon, Polson, Alexander, Quezada, Sergio, Varia, Mary, Verma, Hema, and Litchfield, Kevin

Subjects
0301 basic medicine, DNA Copy Number Variations, Somatic cell, Genomics, Biology, medicine.disease_cause, Article, Metastasis, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Biopsy, medicine, Humans, Ecology, Evolution, Behavior and Systematics, Selection (genetic algorithm), Mutation, Ecology, medicine.diagnostic_test, medicine.disease, Phenotype, Clear cell renal cell carcinoma, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research
Abstract

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.

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