Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study
Open Access
- 2 March 2021
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 9 (3), e001941
- https://doi.org/10.1136/jitc-2020-001941
Abstract
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 γδ 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 γδ 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 γδ 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-α (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 γδ 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 γδ 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.This publication has 44 references indexed in Scilit:
- Rapamycin-Induced Enhancement of Vaccine Efficacy in MicePublished by Springer Science and Business Media LLC ,2011
- Rapamycin increases the yield and effector function of human γδ T cells stimulated in vitroCancer Immunology, Immunotherapy, 2010
- Human γδ T lymphocytes induce robust NK cell–mediated antitumor cytotoxicity through CD137 engagementBlood, 2010
- mTOR regulates memory CD8 T-cell differentiationNature, 2009
- Molecular Analyte Profiling of the Early Events and Tissue Conditioning Following Intravesical Bacillus Calmette-Guerin Therapy in Patients With Superficial Bladder CancerJournal of Urology, 2009
- Bladder cancer in the elderly: clinical outcomes, basic mechanisms, and future research directionNature Reviews Urology, 2009
- A New Recombinant Bacille Calmette‐Guérin Vaccine Safely Induces Significantly Enhanced Tuberculosis‐Specific Immunity in Human VolunteersThe Journal of Infectious Diseases, 2008
- Design of aging intervention studies: the NIA interventions testing programAGE, 2008
- Management of BCG Failures in Superficial Bladder Cancer: A ReviewEuropean Urology, 2006
- Distinct Time Effects of Vaccination on Long-Term Proliferative and IFN-γ–producing T Cell Memory to Smallpox in HumansThe Journal of Experimental Medicine, 2004