Citations 2
Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset
Chung, Jiil , Negm, Logine , Bianchi, Vanessa , Das, Anirban , Liu, Zhihui Amy , Sudhaman, Sumedha, Aronson, Melyssa , Brunga, Ledia , Forster, Victoria J. , Komosa, Martin, Davidson, Scott , Lees, Jodi, Tomboc, Patrick , Samuel, David , Bendel, Anne , Knipstein, Jeffrey , Schneider, Kami Wolfe , Reschke, Agnes , Zelcer, Shayna , Zorzi, Alexandra P., Bedgood, Raymond , Peterson, Lindsay L. , Rhode, Sara , Damme, An Van , Scheers, Isabelle , Robbins, Gabriel , Vanan, Magimairajan , Burke, Carol A. , Villani, Anita , Malkin, David , Durno, Carol , Hawkins, Cynthia , Maruvka, Yosef E. , Tabori, Uri , Das, Anirban , Aronson, Melyssa , Forster, Victoria , Davidson, Scott , Tomboc, Patrick , Knipstein, Jeffrey , Schneider, Kami Wolfe , Reschke, Agnes , McWilliams, Robert R , Foulkes, William D , Bedgood, Raymond , Peterson, Lindsay , Van Damme, An , Robbins, Gabriel , Vanan, Magimairajan Issai , Meyn, M Stephen , Auer, Rebecca , Leach, Brandie , Villani, Anita , Malkin, David , Bouffet, Eric , Hawkins, Cynthia , Maruvka, Yosef E , Tabori, Uri , Burke, Carol A , Stengs, Lucie K. , Sudhaman, Sumedha , Edwards, Melissa , Farah, Roula Antoine , McWilliams, Robert R. , Foulkes, William D. , Gardner, Sharon L , Bouffet, Éric , Huang, Annie , Taylor, Michael D. , Shlien, Adam , Getz, Gad
Journal of Clinical Oncology | October 14, 2022 | Volume: 41 | Issue: 4 | Pages: 766-777
PURPOSE Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10 −12 ), immunohistochemistry (86%, P = 4.6 × 10 −3 ), or tumor mutational burden (80%, P = 9.1 × 10 −4 ). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10 −5 ). CONCLUSION LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.
Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients
Samson, Adel , West, Emma J. , Carmichael, Jonathan , Scott, Karen J. , Turnbull, Samantha , Kuszlewicz, Bethany, Dave, Rajiv , Peckham-Cooper, Adam , Tidswell, Emma, Kingston, Jennifer , Johnpulle, Michelle, Jennings, Victoria A. , Stojkowitz, Nicolas, Lusky, Monika, Prasad, Rajendra , Toogood, Giles J. , Bell, John C. , Twelves, Chris , Harrington, Kevin J. , Vile, Richard G. , Pandha, Hardev , Errington‐Mais, Fiona , Ralph, Christy , Newton, Darren , Anthoney, Alan , Melcher, Alan , Collinson, Fiona , Dave, Rajiv V , Bendjama, Kaidre , Bell, John , Twelves, Christopher , Errington-Mais, Fiona , Ralph, Christy , Newton, Darren J , Collinson, Fiona , Melcher, Alan A , Harrington, Kevin , Silva, Bárbara da , Auer, Rebecca
Cancer Immunology Research | April 19, 2022 | Volume: 10 | Issue: 6 | Pages: 745-756
Abstract Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.