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Lurie Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100011249","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,4,4]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:p>Intravenous immune checkpoint inhibition achieves a 40% 3-month response in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ. Yet, only half of the early responders will continue to be disease-free by 12 months, and resistance mechanisms are poorly defined. We performed spatial profiling of BCG-unresponsive tumors from patients responsive or resistant to intravenous pembrolizumab treatment, analyzing samples both before initiating and 3\u2009months post-intravenous pembrolizumab treatment. We analyzed 119 regions of interest, which included 59 pairs of epithelial and adjacent stromal segments across five patients: two responders and three non-responders. We demonstrate that BCG unresponsive tumors with an inflamed PanCK+ tumor\u2009area and an infiltrated stromal segment respond better to intravenous pembrolizumab. Furthermore, using segment-specific gene signatures generated from a cohort of BCG unresponsive NMIBC treated with intravesical BCG+pembrolizumab, we find that non-inflamed, immune-cold tumors that do not respond to intravenous pembrolizumab exhibit a favorable outcome to the combined application of BCG and pembrolizumab. For the first time, we have identified molecular features of tumors associated with response and resistance to intravenous pembrolizumab in BCG unresponsive NMIBCs. Further research with more patients and alternative checkpoint inhibitors is essential to validate our findings. We anticipate that using a transcriptomics signature like the one described here can help identify tumors with a higher possibility of responding to intravenous pembrolizumab.<\/jats:p>","DOI":"10.1136\/jitc-2023-008571","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:09:47Z","timestamp":1713312587000},"page":"e008571","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Spatial comparison of molecular features associated with resistance to pembrolizumab in BCG unresponsive bladder cancer"],"prefix":"10.1136","volume":"12","author":[{"given":"Khyati","family":"Meghani","sequence":"first","affiliation":[{"name":"Departments of Urology, and Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noah","family":"Frydenlund","sequence":"additional","affiliation":[{"name":"Departments of Urology, and Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanni","family":"Yu","sequence":"additional","affiliation":[{"name":"Departments of Urology, and Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonnie","family":"Choy","sequence":"additional","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-5510","authenticated-orcid":false,"given":"Joshua J","family":"Meeks","sequence":"additional","affiliation":[{"name":"Departments of Urology, and Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, Illinois, USA"},{"name":"Jesse Brown VA Medical Center, Chicago, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"2025100310054501000_12.4.e008571.1","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/s41585-021-00481-1","article-title":"100 years of Bacillus Calmette\u2013Gu\u00e9rin Immunotherapy: from cattle to COVID-19","volume":"18","author":"Lobo","year":"2021","journal-title":"Nat Rev Urol"},{"key":"2025100310054501000_12.4.e008571.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00147-9"},{"key":"2025100310054501000_12.4.e008571.3","doi-asserted-by":"crossref","unstructured":"Boormans JL , Wit R , Kulkarni GS , et al . n.d. 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