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1. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Author

Kevin Litchfield, Stacey Stanislaw, Lavinia Spain, Lisa L. Gallegos, Andrew Rowan, Desiree Schnidrig, Heidi Rosenbaum, Alexandre Harle, Lewis Au, Samantha M. Hill, Zayd Tippu, Jennifer Thomas, Lisa Thompson, Hang Xu, Stuart Horswell, Aoune Barhoumi, Carol Jones, Katherine F. Leith, Daniel L. Burgess, Thomas B.K. Watkins, Emilia Lim, Nicolai J. Birkbak, Philippe Lamy, Iver Nordentoft, Lars Dyrskjøt, Lisa Pickering, Stephen Hazell, Mariam Jamal-Hanjani, James Larkin, Charles Swanton, Nelson R. Alexander, Samra Turajlic, Chris Abbosh, Kai-Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Forster, Siow-Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam Janes, Peter Van Loo, Katey Enfield, Nicholas McGranahan, Ariana Huebner, Sergio Quezada, Stephan Beck, Peter Parker, Henning Walczak, Tariq Enver, Rob Hynds, Mary Falzon, Ian Proctor, Ron Sinclair, Chi-wah Lok, Zoe Rhodes, David Moore, Teresa Marafioti, Elaine Borg, Miriam Mitchison, Reena Khiroya, Giorgia Trevisan, Peter Ellery, Mark Linch, Sebastian Brandner, Crispin Hiley, Selvaraju Veeriah, Maryam Razaq, Heather Shaw, Gert Attard, Mita Afroza Akther, Cristina Naceur-Lombardelli, Lizi Manzano, Maise Al-Bakir, Simranpreet Summan, Nnenna Kanu, Sophie Ward, Uzma Asghar, Faye Gishen, Adrian Tookman, Paddy Stone, Caroline Stirling, Andrew Furness, Kim Edmonds, Nikki Hunter, Sarah Sarker, Sarah Vaughan, Mary Mangwende, Karla Pearce, Scott Shepherd, Haixi Yan, Ben Shum, Eleanor Carlyle, Steve Hazell, Annika Fendler, Fiona Byrne, Nadia Yousaf, Sanjay Popat, Olivia Curtis, Gordon Stamp, Antonia Toncheva, Emma Nye, Aida Murra, Justine Korteweg, Nahid Sheikh, Debra Josephs, Ashish Chandra, James Spicer, Ula Mahadeva, Anna Green, Ruby Stewart, Lara-Rose Iredale, Tina Mackay, Ben Deakin, Debra Enting, Sarah Rudman, Sharmistha Ghosh, Lena Karapagniotou, Elias Pintus, Andrew Tutt, Sarah Howlett, Vasiliki Michalarea, James Brenton, Carlos Caldas, Rebecca Fitzgerald, Merche Jimenez-Linan, Elena Provenzano, Alison Cluroe, Grant Stewart, Colin Watts, Richard Gilbertson, Ultan McDermott, Simon Tavare, Emma Beddowes, Patricia Roxburgh, Andrew Biankin, Anthony Chalmers, Sioban Fraser, Karin Oien, Andrew Kidd, Kevin Blyth, Matt Krebs, Fiona Blackhall, Yvonne Summers, Caroline Dive, Richard Marais, Fabio Gomes, Mat Carter, Jo Dransfield, John Le Quesne, Dean Fennell, Jacqui Shaw, Babu Naidu, Shobhit Baijal, Bruce Tanchel, Gerald Langman, Andrew Robinson, Martin Collard, Peter Cockcroft, Charlotte Ferris, Hollie Bancroft, Amy Kerr, Gary Middleton, Joanne Webb, Salma Kadiri, Peter Colloby, Bernard Olisemeke, Rodelaine Wilson, Ian Tomlinson, Sanjay Jogai, Christian Ottensmeier, David Harrison, Massimo Loda, Adrienne Flanagan, Mairead McKenzie, Allan Hackshaw, Jonathan Ledermann, Abby Sharp, Laura Farrelly, and Hayley Bridger

Subjects
tumor sampling, tumor sequencing, representative sampling, molecular profiling, tumor hetereogeneity, biomarkers, Biology (General), QH301-705.5
Abstract

Summary: Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

Published
2020
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2. Sotrovimab restores neutralization against current Omicron subvariants in patients with blood cancer

Author

Mary Y. Wu, Scott T.C. Shepherd, Annika Fendler, Edward J. Carr, Lewis Au, Ruth Harvey, Giulia Dowgier, Agnieszka Hobbs, Lou S. Herman, Martina Ragno, Lorin Adams, Andreas M. Schmitt, Zayd Tippu, Benjamin Shum, Sheima Farag, Aljosja Rogiers, Nicola O’Reilly, Philip Bawumia, Callie Smith, Eleanor Carlyle, Kim Edmonds, Lyra Del Rosario, Karla Lingard, Mary Mangwende, Lucy Holt, Hamid Ahmod, Justine Korteweg, Tara Foley, Taja Barber, Stephanie Hepworth, Andrea Emslie-Henry, Niamh Caulfield-Lynch, Fiona Byrne, Daqi Deng, Bryan Williams, Michael Brown, Simon Caidan, Mike Gavrielides, James I. MacRae, Gavin Kelly, Kema Peat, Denise Kelly, Aida Murra, Kayleigh Kelly, Molly O’Flaherty, Sanjay Popat, Nadia Yousaf, Shaman Jhanji, Kate Tatham, David Cunningham, Nicholas Van As, Kate Young, Andrew J.S. Furness, Lisa Pickering, Rupert Beale, Charles Swanton, Sonia Gandhi, Steve Gamblin, David L.V. Bauer, George Kassiotis, Michael Howell, Susanna Walker, Emma Nicholson, James Larkin, Emma C. Wall, and Samra Turajlic

Subjects
Cancer Research, Oncology
Published
2023

3. Data from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Author

Samra Turajlic, Mariam Jamal-Hanjani, Charles Swanton, Kevin Litchfield, James Larkin, Anna Green, Ula Mahadeva, Ruby Stewart, Lisa Pickering, Andrew J.S. Furness, Kate Young, Emma L. Nye, Gordon W.H. Stamp, Ian Proctor, Mary Falzon, David A. Moore, Miriam Mitchison, Elaine Borg, Cristina Naceur-Lombardelli, Jun Murai, Maise Al Bakir, Nicholas McGranahan, Ariana Huebner, Hang Xu, Aljosja Rogiers, Robert Mason, Joanna Lynch, Husayn Ahmed Pallikonda, Camille L. Gerard, Max Emmerich, Anne-Laure Cattin, Molly O'Flaherty, Charlotte Lewis, Justine Korteweg, Aida Murra, Jennifer Biano, Denise Kelly, Lauren Terry, Mary Mangwende, Sarah Vaughan, Sarah Sarker, Kayleigh Kelly, Kema Peat, Lauren Grostate, Karla Lingard, Zayd Tippu, Andreas M. Schmitt, Charlotte Spencer, Diana C.J. Spierings, Rene Wardenaar, Hilda van den Bos, Floris Foijer, Jaime Nobbs, Peta Hughes, Christina Messiou, Alexandra Renn, Nikki Hunter, Eleanor Carlyle, Kim Edmonds, Lewis Au, Elisa Piperni, Maria Goicoechea, Fiona Byrne, Benjamin Shum, Scott T.C. Shepherd, Desiree Schnidrig, Andrew Rowan, Irene Lobon, Alexander Coulton, and Lavinia Spain

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 intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, 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 nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. 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.Significance:Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.

Published
2023

4. Supplementary Figures S1-S25 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Author

Samra Turajlic, Mariam Jamal-Hanjani, Charles Swanton, Kevin Litchfield, James Larkin, Anna Green, Ula Mahadeva, Ruby Stewart, Lisa Pickering, Andrew J.S. Furness, Kate Young, Emma L. Nye, Gordon W.H. Stamp, Ian Proctor, Mary Falzon, David A. Moore, Miriam Mitchison, Elaine Borg, Cristina Naceur-Lombardelli, Jun Murai, Maise Al Bakir, Nicholas McGranahan, Ariana Huebner, Hang Xu, Aljosja Rogiers, Robert Mason, Joanna Lynch, Husayn Ahmed Pallikonda, Camille L. Gerard, Max Emmerich, Anne-Laure Cattin, Molly O'Flaherty, Charlotte Lewis, Justine Korteweg, Aida Murra, Jennifer Biano, Denise Kelly, Lauren Terry, Mary Mangwende, Sarah Vaughan, Sarah Sarker, Kayleigh Kelly, Kema Peat, Lauren Grostate, Karla Lingard, Zayd Tippu, Andreas M. Schmitt, Charlotte Spencer, Diana C.J. Spierings, Rene Wardenaar, Hilda van den Bos, Floris Foijer, Jaime Nobbs, Peta Hughes, Christina Messiou, Alexandra Renn, Nikki Hunter, Eleanor Carlyle, Kim Edmonds, Lewis Au, Elisa Piperni, Maria Goicoechea, Fiona Byrne, Benjamin Shum, Scott T.C. Shepherd, Desiree Schnidrig, Andrew Rowan, Irene Lobon, Alexander Coulton, and Lavinia Spain

Abstract

Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number sample trees. Supplementary figure 6: MEDICC tree of all exome samples demonstrating that samples cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes, with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all samples. Supplementary figure 13: Number of samples per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for samples with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk samples from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of samples for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of samples for which RNA-seq was performed faceted by tissue site.

Published
2023

5. Supplementary Tables S1-S8 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Author

Samra Turajlic, Mariam Jamal-Hanjani, Charles Swanton, Kevin Litchfield, James Larkin, Anna Green, Ula Mahadeva, Ruby Stewart, Lisa Pickering, Andrew J.S. Furness, Kate Young, Emma L. Nye, Gordon W.H. Stamp, Ian Proctor, Mary Falzon, David A. Moore, Miriam Mitchison, Elaine Borg, Cristina Naceur-Lombardelli, Jun Murai, Maise Al Bakir, Nicholas McGranahan, Ariana Huebner, Hang Xu, Aljosja Rogiers, Robert Mason, Joanna Lynch, Husayn Ahmed Pallikonda, Camille L. Gerard, Max Emmerich, Anne-Laure Cattin, Molly O'Flaherty, Charlotte Lewis, Justine Korteweg, Aida Murra, Jennifer Biano, Denise Kelly, Lauren Terry, Mary Mangwende, Sarah Vaughan, Sarah Sarker, Kayleigh Kelly, Kema Peat, Lauren Grostate, Karla Lingard, Zayd Tippu, Andreas M. Schmitt, Charlotte Spencer, Diana C.J. Spierings, Rene Wardenaar, Hilda van den Bos, Floris Foijer, Jaime Nobbs, Peta Hughes, Christina Messiou, Alexandra Renn, Nikki Hunter, Eleanor Carlyle, Kim Edmonds, Lewis Au, Elisa Piperni, Maria Goicoechea, Fiona Byrne, Benjamin Shum, Scott T.C. Shepherd, Desiree Schnidrig, Andrew Rowan, Irene Lobon, Alexander Coulton, and Lavinia Spain

Abstract

S. Table 1: List of PEACE Consortium members. S. Table 2: Sample database used for the study for Panel, Exome and RNASeq samples. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.

Published
2023

6. Omicron neutralising antibodies after third COVID-19 vaccine dose in patients with cancer

Author

Annika Fendler, Scott T C Shepherd, Lewis Au, Mary Wu, Ruth Harvey, Andreas M Schmitt, Zayd Tippu, Benjamin Shum, Sheima Farag, Aljosja Rogiers, Eleanor Carlyle, Kim Edmonds, Lyra Del Rosario, Karla Lingard, Mary Mangwende, Lucy Holt, Hamid Ahmod, Justine Korteweg, Tara Foley, Taja Barber, Andrea Emslie-Henry, Niamh Caulfield-Lynch, Fiona Byrne, Daqi Deng, Svend Kjaer, Ok-Ryul Song, Christophe Queval, Caitlin Kavanagh, Emma C Wall, Edward J Carr, Simon Caidan, Mike Gavrielides, James I MacRae, Gavin Kelly, Kema Peat, Denise Kelly, Aida Murra, Kayleigh Kelly, Molly O'Flaherty, Robyn L Shea, Gail Gardner, Darren Murray, Nadia Yousaf, Shaman Jhanji, Kate Tatham, David Cunningham, Nicholas Van As, Kate Young, Andrew J S Furness, Lisa Pickering, Rupert Beale, Charles Swanton, Sonia Gandhi, Steve Gamblin, David L V Bauer, George Kassiotis, Michael Howell, Emma Nicholson, Susanna Walker, James Larkin, and Samra Turajlic

Subjects
COVID-19 Vaccines, Letter, SARS-CoV-2, Neoplasms, Correspondence, COVID-19, Humans, General Medicine, Antibodies, Viral, Antibodies, Neutralizing
Published
2022

7. Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Author

Annika Fendler, Scott T.C. Shepherd, Lewis Au, Mary Wu, Ruth Harvey, Katalin A. Wilkinson, Andreas M. Schmitt, Zayd Tippu, Benjamin Shum, Sheima Farag, Aljosja Rogiers, Eleanor Carlyle, Kim Edmonds, Lyra Del Rosario, Karla Lingard, Mary Mangwende, Lucy Holt, Hamid Ahmod, Justine Korteweg, Tara Foley, Taja Barber, Andrea Emslie-Henry, Niamh Caulfield-Lynch, Fiona Byrne, Daqi Deng, Svend Kjaer, Ok-Ryul Song, Christophe J. Queval, Caitlin Kavanagh, Emma C. Wall, Edward J. Carr, Simon Caidan, Mike Gavrielides, James I. MacRae, Gavin Kelly, Kema Peat, Denise Kelly, Aida Murra, Kayleigh Kelly, Molly O’Flaherty, Robyn L. Shea, Gail Gardner, Darren Murray, Sanjay Popat, Nadia Yousaf, Shaman Jhanji, Kate Tatham, David Cunningham, Nicholas Van As, Kate Young, Andrew J.S. Furness, Lisa Pickering, Rupert Beale, Charles Swanton, Sonia Gandhi, Steve Gamblin, David L.V. Bauer, George Kassiotis, Michael Howell, Emma Nicholson, Susanna Walker, Robert J. Wilkinson, James Larkin, and Samra Turajlic

Subjects
Model organisms, COVID-19 Vaccines, Immunology, T cells, Infectious Disease, variants of concern, Antibodies, Viral, Biochemistry & Proteomics, General Biochemistry, Genetics and Molecular Biology, Signalling & Oncogenes, Ecology,Evolution & Ethology, Neoplasms, Humans, neutralizing antibodies, BNT162 Vaccine, Computational & Systems Biology, Chemical Biology & High Throughput, Human Biology & Physiology, SARS-CoV-2, blood cancer, FOS: Clinical medicine, Stem Cells, Clinical Studies as Topic, Genome Integrity & Repair, Immunity, Neurosciences, COVID-19, Cell Biology, Tumour Biology, Antibodies, Neutralizing, Metabolism, Cell Cycle & Chromosomes, Genetics & Genomics, Developmental Biology, Structural Biology & Biophysics
Abstract

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.

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

Author

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

Subjects
Cancer Research, IMPACT, Antibody Response, Alpha (ethology), CORONAVIRUS DISEASE 2019, Disease, Adaptive Immunity, Article, Immune system, SEROCONVERSION, Medicine, Neutralizing antibody, Cancer, Science & Technology, biology, SARS-CoV-2, business.industry, MORTALITY, COVID-19, medicine.disease, Titer, SEVERITY, Oncology, Immunology, Cohort, biology.protein, Prospective Study, Antibody, business, Neutralising Antibodies, Vaccine, Life Sciences & Biomedicine, T-cell Response
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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9. Immune responses following third COVID-19 vaccination are reduced in patients with hematologic malignancies compared to patients with solid cancer

Author

Annika Fendler, Scott T.C. Shepherd, Lewis Au, Katalin A. Wilkinson, Mary Wu, Andreas M. Schmitt, Zayd Tippu, Sheima Farag, Aljosja Rogiers, Ruth Harvey, Eleanor Carlyle, Kim Edmonds, Lyra Del Rosario, Karla Lingard, Mary Mangwende, Lucy Holt, Hamid Ahmod, Justine Korteweg, Tara Foley, Taja Barber, Andrea Emslie-Henry, Niamh Caulfield-Lynch, Fiona Byrne, Benjamin Shum, Camille L. Gerard, Daqi Deng, Svend Kjaer, Ok-Ryul Song, Christophe Queval, Caitlin Kavanagh, Emma C. Wall, Edward J. Carr, Sina Namjou, Simon Caidan, Mike Gavrielidis, James McRae, Gavin Kelly, Kema Peat, Denise Kelly, Aida Murra, Kayleigh Kelly, Molly O'Flaherty, Robyn L. Shea, Gail Gardner, Darren Murray, Nadia Yousaf, Shaman Jhanji, Nicholas Van As, Kate Young, Andre J.S. Furness, Lisa Pickering, Rupert Beale, Charles Swanton, Sonia Ghandi, Steve Gamblin, David L.V. Bauer, George Kassiotis, Michael Howell, Emma Nicholson, Robert J. Wilkinson, James Larkin, and Samra Turajlic

Abstract

Not all patients with cancer, in particular those with hematogic malignancies, develop functional immunity against SARS-CoV-2 variants of concern (VOC) following COVID-19 vaccines. Durability of vaccine-induced immunity after two doses and the impact of a third dose were evaluated in CAPTURE (NCT03226886), a longitudinal prospective cohort study of vaccine responses in patients with cancer. In evaluating 316 patients, at a median of 111 days following two doses of either BNT16b2 or ChadOX, we observed a time-dependant decline in neutralising antibody titres (NAbT) in a proportion of patients, where NAbTs became undetectable against Delta and Beta in 17% and 15% of patients, respectively. Vaccine-induced T cell responses declined in 44% of patients. Patients with breakthrough infections following two vaccines doses were characterised by absent/low NAbT to Delta prior to infection. Administration of the third vaccine dose boosted NAb responses against VOC in the majority of patients with cancer, especially those with solid cancer. In patients with hematologic malignancies who had undetectable NAbT against Delta after two vaccine doses, 54% did not develop NAb against both Beta and Delta following the third dose. Third vaccine dose boosted T cell responses were boosted in patients with both solid and hematologic malignancies. These results provide critical information on vaccine responses in patients with cancer, especially against VOCs and support widespread access to a third COVID-19 vaccination in this patient group.

Published
2021

10. Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: The CAPTURE study

Author

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

Subjects
Male, Cancer Research, T-Lymphocytes, Antibody Response, Adaptive Immunity, IMMUNOGENICITY, Antibodies, Viral, COVID-19 VACCINATION, Immunogenicity, Vaccine, Neoplasms, Longitudinal Studies, Prospective Studies, Neutralizing antibody, Prospective cohort study, Cancer, Aged, 80 and over, Immunity, Cellular, biology, Vaccination, Middle Aged, Acquired immune system, Kidney Neoplasms, Oncology, Female, Antibody, Life Sciences & Biomedicine, Neutralising Antibodies, T-cell Response, Adult, COVID-19 Vaccines, Article, MALIGNANCIES, Crick COVID19 consortium, Immunity, VACCINES, ChAdOx1 nCoV-19, medicine, Humans, Seroconversion, Carcinoma, Renal Cell, Pandemics, BNT162 Vaccine, Aged, Science & Technology, business.industry, SARS-CoV-2, MORTALITY, COVID-19, medicine.disease, Antibodies, Neutralizing, DEMOGRAPHICS, Immunology, biology.protein, Prospective Study, business, Vaccine
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
2021

11. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author

Sanjay Popat, Lewis Au, Jan Attig, Catherine Horsfield, Hayley Bridger, Kitty Chan, Haixi Yan, David Moore, Lara-Rose Iredale, Salma Kadiri, Sebastian Brandner, Rebecca C. Fitzgerald, Bruce Tanchel, Maise Al-Bakir, Katey S. S. Enfield, Merche Jimenez-Linan, Andrew P. Robinson, Kim Edmonds, Stuart Horswell, Elena Provenzano, Andrew V. Biankin, Benny Chain, Scott Shepherd, Antonia Toncheva, Carlos Caldas, Gerald Langman, Fabio Gomes, I Puccio, Amy Kerr, Sharmistha Ghosh, Caroline Dive, James Larkin, Siow Ming Lee, Nicholas McGranahan, Peter Ellery, Charlotte Spencer, Dionysis Papadatos-Pastos, Charles Swanton, Maryam Razaq, Richard J. Gilbertson, Rachael Thompson, William Drake, Lyra Del Rosario, Debra Enting, Lisa Pickering, Crispin T. Hiley, David A Moore, Christian H. Ottensmeier, Ehsan Ghorani, Simon Chowdhury, Simon Tavaré, Sophie Ward, Gordon Stamp, Peter J. Parker, Sam M. Janes, Giorgia Trevisan, Mary Falzon, Ultan McDermott, Christopher Abbosh, Fiona Byrne, Kroopa Joshi, Kim Dhillon, George Kassiotis, James L. Reading, Heather Shaw, Tariq Enver, Dean A. Fennell, Jonathan Ledermann, Annika Fendler, Emma Beddowes, Peter Cockcroft, Mary Mangwende, Desiree Schnidrig, Ian Tomlinson, Mark Linch, Ben Challacombe, Vasiliki Michalarea, Yvonne Summers, Fiona H Blackhall, Robert Mason, Emma Nye, Robert E. Hynds, Debra H. Josephs, Mariana Werner Sunderland, Adrian Tookman, Emilia L. Lim, Paddy Stone, Cristina Naceur-Lombardelli, Bernard Olisemeke, Teresa Marafioti, Mat Carter, Grant D. Stewart, Sanjay Jogai, Richard Marais, Imran Uddin, Kevin Litchfield, Daniel Hochhauser, Alexander Polson, William Yang, Hang Xu, Peter Hill, Jonathon Olsburgh, Gordon Beattie, Justine Korteweg, Nnenna Kanu, Martin Forster, Andrew Tutt, Ben Shum, Elias Pintus, Alison Cluroe, Matt Krebs, Patricia Roxburgh, Caroline Stirling, Selvaraju Veeriah, Olivia Curtis, Marc Robert de Massy, Emine Hatipoglu, Tom Lund, Kai-Keen Shiu, Tina Mackay, Pablo D. Becker, Faye Gishen, Massimo Loda, Aida Murra, Karin A. Oien, Joanne Webb, Jose Lopez, Sarah Sarker, Adrienne M. Flanagan, Ula Mahadeva, Ian Proctor, Ruby Stewart, John Le Quesne, Elaine Borg, Archana Fernando, Babu Naidu, Andrew Rowan, Abby Sharp, Mairead McKenzie, Ayse Akarca, Anthony J. Chalmers, James Spicer, Gary Middleton, Hollie Bancroft, Jo Dransfield, Nicos Fotiadis, Charlotte Ferris, Ron Sinclair, Mary Varia, Peter Van Loo, Lavinia Spain, Lena Karapagniotou, Nikki Hunter, Roberto Salgado, Sarah Vaughan, Chi-wah Lok, Karen Harrison-Phipps, Hema Verma, Jacqui Shaw, Rodelaine Wilson, Zoe Rhodes, Anna Green, Reena Khiroya, Miriam Mitchison, Ashish Chandra, Colin Watts, Peter Colloby, Uzma Asghar, Laura Farrelly, Tim O'Brien, Stephan Beck, Steve Hazell, Tanya Ahmad, Martin Collard, John Bridgewater, James D. Brenton, Sarah Rudman, Eleanor Carlyle, Andrew C. Kidd, Lizi Manzano, Sergio A. Quezada, Sioban Fraser, Allan Hackshaw, Nadia Yousaf, Samra Turajlic, Henning Walczak, David Nicol, Mariam Jamal-Hanjani, Sarah Howlett, Andrew Furness, Simranpreet Summan, Kevin G. Blyth, S. Baijal, Gert Attard, Marcos Duran Vasquez, Mita Afroza Akther, Karla Lingard, Ben Deakin, Ariana Huebner, and David G. Harrison

Subjects
Cancer Research, Receptors, Antigen, T-Cell, Biology, CD8-Positive T-Lymphocytes, Clinical Trials, Phase II as Topic, Antigen, Immunity, Exome Sequencing, medicine, Tumor Microenvironment, Humans, Prospective Studies, Spotlight, Mode of action, Receptor, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, Sequence Analysis, RNA, Gene Expression Profiling, T-cell receptor, Endogenous Retroviruses, Genomics, medicine.disease, Kidney Neoplasms, Clear cell renal cell carcinoma, Nivolumab, Oncology, Drug Resistance, Neoplasm, Cancer research, Tumor Escape, Single-Cell Analysis, CD8
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
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12. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue

Author

Richard Marais, Andrew Furness, Thomas B.K. Watkins, Maise Al-Bakir, Dionysis Papadatos-Pastos, Maryam Razaq, Mairead McKenzie, Lisa Pickering, Peter Ellery, Jonathan Ledermann, Andrew V. Biankin, Richard J. Gilbertson, Peter Cockcroft, Mary Mangwende, Sophie Ward, Mary Falzon, Cristina Naceur-Lombardelli, Carlos Caldas, Karla Pearce, Jacqui Shaw, Salma Kadiri, Lars Dyrskjøt, Mark Linch, Daniel Burgess, Nelson Alexander, Christian H. Ottensmeier, Kevin G. Blyth, Lisa L. Gallegos, Rodelaine Wilson, Hayley Bridger, Fiona H Blackhall, Peter J. Parker, Charles Swanton, Allan Hackshaw, Gert Attard, Gordon Stamp, Dean A. Fennell, Debra H. Josephs, Andrew P. Robinson, Kim Edmonds, Tina Mackay, Mita Afroza Akther, Miriam Mitchison, Sam M. Janes, Giorgia Trevisan, Adrienne M. Flanagan, Alison Cluroe, Henning Walczak, Stuart Horswell, Lena Karapagniotou, Simon Tavaré, Sarah Sarker, Teresa Marafioti, Matt Krebs, Anna Green, Philippe Lamy, Reena Khiroya, Samantha M. Hill, Andrew Tutt, Ashish Chandra, Selvaraju Veeriah, Faye Gishen, Lisa Thompson, Sarah Vaughan, Stacey Stanislaw, Kevin Litchfield, Colin Watts, Caroline Dive, Zayd Tippu, Ron Sinclair, Merche Jimenez-Linan, Lavinia Spain, Lizi Manzano, Zoe Rhodes, Caroline Stirling, Elena Provenzano, Andrew Rowan, Katey S. S. Enfield, Vasiliki Michalarea, Nahid Sheikh, Antonia Toncheva, Charlotte Ferris, James Spicer, Kai-Keen Shiu, Aida Murra, Gerald Langman, Scott Thomas Colville Shepherd, Nicholas McGranahan, Fabio Gomes, Daniel Hochhauser, Hang Xu, Sergio A. Quezada, James Larkin, Siow Ming Lee, Chi-wah Lok, Massimo Loda, Gary Middleton, Hollie Bancroft, Jo Dransfield, David Moore, Jennifer Thomas, Rebecca C. Fitzgerald, Peter Colloby, Annika Fendler, Emma Beddowes, Ultan McDermott, Christopher Abbosh, Uzma Asghar, Martin Forster, John Le Quesne, Katherine F. Leith, Paddy Stone, Bernard Olisemeke, Bruce Tanchel, Laura Farrelly, Grant D. Stewart, Justine Korteweg, Sanjay Jogai, Nnenna Kanu, Desiree Schnidrig, Heidi Rosenbaum, Elaine Borg, Mat Carter, Anthony J. Chalmers, Andrew C. Kidd, Alexandre Harlé, Ula Mahadeva, Crispin T. Hiley, Fiona Byrne, Heather Shaw, Mariam Jamal-Hanjani, Karin A. Oien, Ian Proctor, Joanne Webb, Sioban Fraser, Sarah Howlett, Ruby Stewart, Peter Van Loo, Nadia Yousaf, Tanya Ahmad, Martin Collard, Sanjay Popat, James D. Brenton, Sarah Rudman, Lewis Au, David G. Harrison, Elias Pintus, Patricia Roxburgh, Olivia Curtis, Ben Deakin, Ariana Huebner, Debra Enting, Simranpreet Summan, S. Baijal, Iver Nordentoft, Carol Jones, Haixi Yan, Sebastian Brandner, Tariq Enver, Lara-Rose Iredale, Yvonne Summers, Babu Naidu, Abby Sharp, Stephen Hazell, Aoune Barhoumi, Emma Nye, Robert E. Hynds, Sharmistha Ghosh, Emilia L. Lim, Ben Shum, Nikki Hunter, John Bridgewater, Eleanor Carlyle, Stephan Beck, Nicolai Juul Birkbak, Steve Hazell, Samra Turajlic, Amy Kerr, Ian Tomlinson, Adrian Tookman, Litchfield, Kevin [0000-0002-3725-0914], Birkbak, Nicolai J [0000-0003-1613-9587], Nordentoft, Iver [0000-0003-4856-4086], Dyrskjøt, Lars [0000-0001-7061-9851], Apollo - University of Cambridge Repository, Division of genetics and epidemiology, The institute of cancer research [London], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), The Royal Marsden, University of Arizona, University of Western Ontario, Physic and Astronomy Department, University of Western Ontario (UWO), Center for Biological Sequence Analysis [Lyngby], Technical University of Denmark [Lyngby] (DTU), Laboratoire d'Astrophysique de Marseille (LAM), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Aarhus University Hospital, Cancer Research UK Lung Cancer Centre of Excellence [Londres, Royaume-Uni], University College of London [London] (UCL), Comprehensive Cancer Center, UCL Cancer Institute [University College London], The Wellcome Trust Sanger Institute [Cambridge], Research Department of Pathology, Innovation North - Faculty of Information and Technology, Leeds Metropolitan University, Department of histopathology, University College Hospital, Mammalian Genetics Laboratory, Centre for Research on Adaptive Nanostructures and Nanodevices, Trinity College Dublin, Cancer Research UK London Research Institute, Guy's and St Thomas' Hospital [London], Breakthrough Breast Cancer Centre, London Institute of Cancer, Cancer Research UK Cambridge Research Institute and Department of Oncology, University of Cambridge, University of Cambridge [UK] (CAM), Cancer Division [Sydney, Australia] (The Kinghorn Cancer Centre), Garvan Institute of Medical Research [Sydney, Australia], Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, University of Leicester, Experimental Cancer Medicine Centre, University of Southampton-Faculty of Medicine, Moses, Wittemyer, Harrison and Woodruff, P.C., University of Oxford, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), and Garvan Institute of medical research

Subjects
0301 basic medicine, tumor sequencing, medicine.medical_specialty, Sampling protocol, tumor mutational burden, tumor sampling, Lung Neoplasms, molecular profiling, Biopsy, homogenization, Tissue sample, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Biomarkers, Tumor, Humans, Solid tumor, lcsh:QH301-705.5, Representative sampling, medicine.diagnostic_test, Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Clonal structure, biomarkers, High-Throughput Nucleotide Sequencing, Tumor tissue, tumor hetereogeneity, Tumor Burden, 030104 developmental biology, lcsh:Biology (General), representative sampling, Urinary Bladder Neoplasms, Mutation, Radiology, 030217 neurology & neurosurgery
Abstract

International audience; Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias isinherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mmbiopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB butlow clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.

Published
2020

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