PMID- 33653802 OWN - NLM STAT- MEDLINE DCOM- 20211217 LR - 20211217 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 3 DP - 2021 Mar TI - Rapamycin enhances BCG-specific gammadelta T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study. LID - 10.1136/jitc-2020-001941 [doi] LID - e001941 AB - BACKGROUND: 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 gammadelta T cells, which are critical for BCG's antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC. METHODS: A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific gammadelta 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. RESULTS: Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1-2. One (12.5%) patient randomized to 2.0 mg 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 gammadelta T cells from baseline per group was as follows: -26% (-51% to 24%) for placebo, 9.6% (-59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (-31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-alpha (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary gammadelta T cells at the first week of BCG (p=0.02). CONCLUSIONS: Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific gammadelta 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. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Ji, Niannian AU - Ji N AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA. AD - Department of Urology, UT Health San Antonio, San Antonio, Texas, USA. FAU - Mukherjee, Neelam AU - Mukherjee N AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA. AD - Department of Urology, UT Health San Antonio, San Antonio, Texas, USA. FAU - Reyes, Ryan M AU - Reyes RM AUID- ORCID: 0000-0002-9562-5809 AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA. AD - Division of Hematology/Medical Oncology, UT Health San Antonio, San Antonio, Texas, USA. FAU - Gelfond, Jonathan AU - Gelfond J AD - Department of Epidemiology and Biostatistics, UT Health San Antonio, San Antonio, Texas, USA. FAU - Javors, Martin AU - Javors M AD - Department of Psychiatry, UT Health San Antonio, San Antonio, Texas, USA. FAU - Meeks, Joshua J AU - Meeks JJ AD - Departments of Urology, and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. FAU - McConkey, David J AU - McConkey DJ AD - Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Shu, Zhen-Ju AU - Shu ZJ AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA. AD - Department of Urology, UT Health San Antonio, San Antonio, Texas, USA. FAU - Ramamurthy, Chethan AU - Ramamurthy C AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA. AD - Division of Hematology/Medical Oncology, UT Health San Antonio, San Antonio, Texas, USA. FAU - Dennett, Ryan AU - Dennett R AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA. AD - Department of Urology, UT Health San Antonio, San Antonio, Texas, USA. FAU - Curiel, Tyler J AU - Curiel TJ AUID- ORCID: 0000-0001-6962-9411 AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA. AD - Division of Hematology/Medical Oncology, UT Health San Antonio, San Antonio, Texas, USA. FAU - Svatek, Robert S AU - Svatek RS AUID- ORCID: 0000-0002-0239-1338 AD - Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA svatek@uthscsa.edu. AD - Department of Urology, UT Health San Antonio, San Antonio, Texas, USA. LA - eng SI - ClinicalTrials.gov/NCT02753309 GR - T32 AG021890/AG/NIA NIH HHS/United States GR - T32 GM113896/GM/NIGMS NIH HHS/United States GR - TL1 TR002647/TR/NCATS NIH HHS/United States GR - P30 AG044271/AG/NIA NIH HHS/United States GR - P30 CA054174/CA/NCI NIH HHS/United States GR - KL2 TR000118/TR/NCATS NIH HHS/United States GR - P30 AG013319/AG/NIA NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Adjuvants, Immunologic) RN - 0 (BCG Vaccine) RN - 0 (Cytokines) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adjuvants, Immunologic/*administration & dosage/adverse effects MH - Administration, Intravesical MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects MH - BCG Vaccine/*administration & dosage/adverse effects MH - Cytokines/urine MH - Double-Blind Method MH - Female MH - Humans MH - Intraepithelial Lymphocytes/*drug effects/immunology/metabolism MH - Male MH - Middle Aged MH - Neoplasm Grading MH - Neoplasm Invasiveness MH - Neoplasm Staging MH - Phenotype MH - Sirolimus/*administration & dosage/adverse effects MH - Time Factors MH - Treatment Outcome MH - Tumor Microenvironment MH - Urinary Bladder Neoplasms/*drug therapy/immunology/pathology/urine MH - Urine/chemistry/cytology PMC - PMC7929866 OTO - NOTNLM OT - immunity OT - immunotherapy OT - innate OT - urinary bladder neoplasms COIS- Competing interests: The studies related to this manuscript were conducted abided by research ethics and approved by IRB guidelines for clinical sample use. All authors have consent for publishing the data from the studies. RS discloses other roles as Consultant for FerGene and Clinical Research Support for JBL(SWOG), FKD and Decipher Biosciences. All other authors disclose no conflict of interest. EDAT- 2021/03/04 06:00 MHDA- 2021/12/18 06:00 PMCR- 2021/03/02 CRDT- 2021/03/03 05:38 PHST- 2021/01/26 00:00 [accepted] PHST- 2021/03/03 05:38 [entrez] PHST- 2021/03/04 06:00 [pubmed] PHST- 2021/12/18 06:00 [medline] PHST- 2021/03/02 00:00 [pmc-release] AID - jitc-2020-001941 [pii] AID - 10.1136/jitc-2020-001941 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Mar;9(3):e001941. doi: 10.1136/jitc-2020-001941.