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

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.

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THE EFFECT OF TREATMENT ON CYTOKINE LEVELS IN NON MUSCLE INVASIVE BLADDER CANCER

10.22541/au.160666762.21229852/v1 ◽

2020 ◽

Author(s):

Oktay Ucer ◽

Gokhan Temeltas ◽

Talha Muezzinoglu ◽

Zeki Ari ◽

Funda Kosova

Keyword(s):

Bladder Cancer ◽

Invasive Bladder Cancer ◽

Control Group ◽

Muscle Invasive Bladder Cancer ◽

Bcg Therapy ◽

Cytokine Levels ◽

Intravesical Bcg ◽

Effect Of Treatment ◽

The Mean ◽

Muscle Invasive

Objectives The aim of the present study was to investigate the effect of treatment on IL-1, IL-6, IL-8 and neopterin levels in patients with non-muscle invasive bladder cancer (NMIBC). Methods Thirty patients with NMIBC and 30 age-matched controls were included in the study. Preoperative, postoperative first control (at two weeks after second transurethral resection of bladder tumor (TURBT)) and second control (at the end of intravesical immunotherapy) blood samples were analyzed by ELISA to determine IL-1, IL-6, IL-8 and neopterin levels. The mean cytokine levels of the patients were statistically compared as well as comparing the patients’ and controls’ levels. Results There were no statistically significant differences between the mean IL-1, IL-6, IL-8 and neopterin levels of the patient and control group before initial TURBT. In the patient group, there were no statistically significant differences in the IL-6 and IL-8 levels after both TURBT and intravesical BCG therapy. The mean of preoperative IL-1 and neopterin levels significantly decrease after TURBT (p<0.05=). However this reduction do not continue after intravesical BCG instillations. Conclusions The finding of this study showed that the IL-1, IL-6, IL-8 and neopterin levels of the patients with NMIBC were similar to the levels of healthy controls. The IL-1 and neopterin levels significantly decreased after TURBT. But this reductions did not continue after intravesical BCG instillation. These findings demonstrate that IL-1 and neopterin levels decrease after TURBT due to the reduction of tumor weight or tumor removal.

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Is there a role for urine cytology following BCG therapy for non-muscle-invasive bladder cancer (NMIBC)?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.404 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 404-404

Author(s):

Sarah Prattley ◽

Ruth Jarvis ◽

Jon Featherstone ◽

Krishna Narahari ◽

Murali Varma ◽

...

Keyword(s):

Bladder Cancer ◽

Urine Cytology ◽

Invasive Bladder Cancer ◽

Positive Cytology ◽

Muscle Invasive Bladder Cancer ◽

Flexible Cystoscopy ◽

Bcg Therapy ◽

Intravesical Bcg ◽

Muscle Invasive ◽

Intravesical Bcg Therapy

404 Background: Voided urine cytology has been used as an adjunct in the diagnosis of non-muscle invasive bladder cancer (NMIBC), with a sensitivity and specificity ranging between 13-75% and 76-100% respectively. There is limited data on the accuracy and utility of cytology following BCG therapy. We reviewed the results of cytology in patients undergoing induction and maintenance BCG immunotherapy in our institution. Methods: Newly diagnosed patients who had received induction and maintenance intravesical BCG therapy from 2004 - 2019 were identified from a prospective database and their outcomes reviewed retrospectively. Histopathology results of biopsies / resected specimens and voided urine cytology results were examined for 273 patients. Results: A total of 2567 cytology results and 638 biopsy results were recorded. The average age was 73.2 years and median number of BCG treatments was four (induction followed by three maintenance courses). Median follow up was 38 months. 94 patients (34.4%) had recurrence following BCG therapy. Of those 33 patients (12.1%) had progression to muscle invasive disease. The number of cytology samples per patient after BCG therapy ranged from 1-23 (median 7), with several patients having repeated, potentially unnecessary negative urine cytology. Overall accuracy of cytology (n = 526) was sensitivity 44.2%, specificity 84.7%, PPV 38.9%, NPV 87.3%. Patients that had an erythematous bladder or red patch at flexible cystoscopy underwent subgroup analysis; this gave a very high NPV of 95.9%, with additional sensitivity being 65.5%, specificity 85.9% and PPV 33.3%. Number of positive cytology results (Chi2 = 44.30, P = 0.002), any positive cytology (Chi2 = 27.94, P < 0.001) and positive cytology after induction BCG therapy (Chi2 = 30.381, P < 0.001) were all strongly associated with recurrence. Conclusions: Positive urine cytology in patients undergoing intravesical BCG therapy predicts increased risk of recurrence and has good specificity. We would recommend using voided urine cytology in patients who have an erythematous bladder or red patch at flexible cystoscopy. If the cytology is positive then proceed to biopsy, however, if it is negative continue with surveillance. [Table: see text]

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