{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:21:50Z","timestamp":1790742110327,"version":"4.1.0"},"reference-count":42,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"unspecified","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,1,26]]},"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of \u03b3\u03b4 T cells, which are critical for BCG\u2019s antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A randomized double-blind trial of oral rapamycin (0.5 or 2.0\u2009mg daily) versus placebo for 1\u2009month was conducted in patients with NMIBC concurrently receiving 3\u2009weekly BCG instillations (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02753309\">NCT02753309<\/jats:ext-link>\n                      ). The primary outcome was induction of BCG-specific \u03b3\u03b4 T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0\u2009mg, and 12 rapamycin 0.5\u2009mg). AEs were similar across groups and most were grade 1\u20132. One (12.5%) patient randomized to 2.0\u2009mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific \u03b3\u03b4 T cells from baseline per group was as follows: \u221226% (\u221251% to 24%) for placebo, 9.6% (\u221259% to 117%) for rapamycin 0.5\u2009mg (versus placebo, p=0.18), and 78.8% (\u221231% to 115%) for rapamycin 2.0\u2009mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-\u03b1 (p=0.04) over time for patients on rapamycin 2.0\u2009mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0\u2009mg rapamycin had increased urinary \u03b3\u03b4 T cells at the first week of BCG (p=0.02).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Four weeks of 0.5 and 2.0\u2009mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific \u03b3\u03b4 T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2020-001941","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T11:03:41Z","timestamp":1614683021000},"page":"e001941","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Rapamycin enhances BCG-specific \u03b3\u03b4 T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct02753309","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02753309","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04375813","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Niannian","family":"Ji","sequence":"first","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Department of Urology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelam","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Department of Urology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9562-5809","authenticated-orcid":false,"given":"Ryan M","family":"Reyes","sequence":"additional","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Division of Hematology\/Medical Oncology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Gelfond","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Javors","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Meeks","sequence":"additional","affiliation":[{"name":"Departments of Urology, and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J","family":"McConkey","sequence":"additional","affiliation":[{"name":"Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Ju","family":"Shu","sequence":"additional","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Department of Urology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chethan","family":"Ramamurthy","sequence":"additional","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Division of Hematology\/Medical Oncology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Dennett","sequence":"additional","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Department of Urology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6962-9411","authenticated-orcid":false,"given":"Tyler J","family":"Curiel","sequence":"additional","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Division of Hematology\/Medical Oncology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0239-1338","authenticated-orcid":false,"given":"Robert S","family":"Svatek","sequence":"additional","affiliation":[{"name":"Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA"},{"name":"Department of Urology, UT Health San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"2025100304320006000_9.3.e001941.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-5347(17)58737-6"},{"key":"2025100304320006000_9.3.e001941.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199110243251703"},{"key":"2025100304320006000_9.3.e001941.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)67707-5"},{"key":"2025100304320006000_9.3.e001941.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2006.01.017"},{"key":"2025100304320006000_9.3.e001941.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1928"},{"key":"2025100304320006000_9.3.e001941.6","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-430-8_18"},{"key":"2025100304320006000_9.3.e001941.7","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003586"},{"key":"2025100304320006000_9.3.e001941.8","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2018.1479627","article-title":"Clinically-relevant rapamycin treatment regimens enhance CD8+ effector memory T cell function In the skin and allow their infiltration into cutaneous squamous cell carcinoma","volume":"7","author":"Jung","year":"2018","journal-title":"Oncoimmunology"},{"key":"2025100304320006000_9.3.e001941.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature08155"},{"key":"2025100304320006000_9.3.e001941.10","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1016\/S0022-5347(17)35678-1","article-title":"T-Cell subsets required for intravesical BCG immunotherapy for bladder cancer","volume":"150","author":"Ratliff","year":"1993","journal-title":"J Urol"},{"key":"2025100304320006000_9.3.e001941.11","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009892"},{"key":"2025100304320006000_9.3.e001941.12","first-page":"135","article-title":"Bladder cancer in the elderly: clinical outcomes, basic mechanisms, and future research direction","volume":"6","author":"Taylor","year":"2009","journal-title":"Nat Clin Pract Urol"},{"key":"2025100304320006000_9.3.e001941.13","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ebiom.2016.01.019","article-title":"Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells","volume":"4","author":"Scholz","year":"2016","journal-title":"EBioMedicine"},{"key":"2025100304320006000_9.3.e001941.14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402390"},{"key":"2025100304320006000_9.3.e001941.15","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.4049\/jimmunol.161.2.1045","article-title":"Bacille Calmette-Gu\u00e9rin vaccination enhances human gamma delta T cell responsiveness to mycobacteria suggestive of a memory-like phenotype","volume":"161","author":"Hoft","year":"1998","journal-title":"J Immunol"},{"key":"2025100304320006000_9.3.e001941.16","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201040773"},{"key":"2025100304320006000_9.3.e001941.17","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90135-9"},{"key":"2025100304320006000_9.3.e001941.18","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2019.1614857","article-title":"Percutaneous BCG enhances innate effector antitumor cytotoxicity during treatment of bladder cancer: a translational clinical trial","volume":"8","author":"Ji","year":"2019","journal-title":"Oncoimmunology"},{"key":"2025100304320006000_9.3.e001941.19","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5A0116-053RR"},{"key":"2025100304320006000_9.3.e001941.20","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-0091"},{"key":"2025100304320006000_9.3.e001941.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-010-0945-7"},{"key":"2025100304320006000_9.3.e001941.22","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(01)66424-3"},{"key":"2025100304320006000_9.3.e001941.23","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-003-0384-9"},{"key":"2025100304320006000_9.3.e001941.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(01)64210-1"},{"key":"2025100304320006000_9.3.e001941.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)66983-2"},{"key":"2025100304320006000_9.3.e001941.26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20181003"},{"key":"2025100304320006000_9.3.e001941.27","doi-asserted-by":"crossref","first-page":"6977","DOI":"10.4049\/jimmunol.161.12.6977","article-title":"Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model: NK and T cell-mediated effects antagonized by B cells","volume":"161","author":"Chapoval","year":"1998","journal-title":"J Immunol"},{"key":"2025100304320006000_9.3.e001941.28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-07-234211"},{"key":"2025100304320006000_9.3.e001941.29","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20032083"},{"key":"2025100304320006000_9.3.e001941.30","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80091-6"},{"key":"2025100304320006000_9.3.e001941.31","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.12.1711"},{"key":"2025100304320006000_9.3.e001941.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2008.11.124"},{"key":"2025100304320006000_9.3.e001941.33","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1781"},{"key":"2025100304320006000_9.3.e001941.34","doi-asserted-by":"publisher","DOI":"10.1086\/592450"},{"key":"2025100304320006000_9.3.e001941.35","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.eururo.2020.04.066","article-title":"Treatment of high-grade non-muscle-invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: results of the European association of urology research foundation randomised phase III clinical trial \"NIMBUS\"","volume":"78","author":"Grimm","year":"2020","journal-title":"Eur Urol"},{"key":"2025100304320006000_9.3.e001941.36","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30109-2"},{"key":"2025100304320006000_9.3.e001941.37","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0215(20010601)92:5<697::AID-IJC1245>3.0.CO;2-Z"},{"key":"2025100304320006000_9.3.e001941.38","doi-asserted-by":"crossref","first-page":"36492","DOI":"10.18632\/oncotarget.26362","article-title":"Intratumoral CD56\n                  bright\n                natural killer cells are associated with improved survival in bladder cancer","volume":"9","author":"Mukherjee","year":"2018","journal-title":"Oncotarget"},{"key":"2025100304320006000_9.3.e001941.39","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.28164"},{"key":"2025100304320006000_9.3.e001941.40","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glw064"},{"key":"2025100304320006000_9.3.e001941.41","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12405"},{"key":"2025100304320006000_9.3.e001941.42","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-008-9048-1"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2020-001941","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T11:32:08Z","timestamp":1759491128000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2020-001941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,2]]},"published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1136\/jitc-2020-001941"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2020-001941","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3]]}}}