Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study

Abstract

BackgroundAlthough 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.MethodsA 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.ResultsThirty-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).ConclusionsFour 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.

CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

“…49 CD122 (to which IL-2c directs IL-2) is expressed on conventional T (CD4 + and CD8 + ), NK, and γδ T cells, all of which are important in localized human BC treatment with BCG. 50 We explored immune cell contributions to IL-2c and αPD-L1 treatment success in mouse BC models and found that surprisingly, conventional T cells, specifically CD8 + T cells, were dispensable for IL-2c treatment effects, despite their necessity for αPD-L1 efficacy here, as also shown by others. 24 As CD8 + T cell content in BC is a favorable prognostic indicator, 25 the relative independence of IL-2c efficacy on CD8 + T cells in orthotopic BC and reliance on γδ T cells that do not affect αPD-L1 efficacy suggests that these agents could combine clinically for improved treatment efficacy.…”

BCG in Bladder Cancer Immunotherapy

“…A recent study confirmed that BCG induces T cell dependent tumor-specific immunity and suggested that BCG-specific γδT cells are required for induction of tumor-specific immunity mediated by conventional αβT. In this study, enhancement of γδT cell responses by treating mice with the mTOR inhibitor rapamycin enhanced the efficacy of BCG [80], a finding that has prompted clinical studies of this combination [81].…”

CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation

“…Thus, strategies to boost function of either cell type could improve IL-2c efficacy, such as ultra-low dose rapamycin, which we demonstrated to be a safe and tolerable γδ T cell adjuvant in early phase BC trials when combined with BCG immune therapy. 45 …”