Since its introduction in the early 1980s, intravesical instillation of live bacillus Calmette-Guérin (BCG) remains the gold standard immunotherapeutic approach for eradication of carcinoma-in-situ of the bladder and for prevention of recurrence for patients with papillary high-risk non-muscle invasive bladder cancer (NMIBC). Despite the success of BCG, response is not uniform and limited options exist for unresponsive tumors. Currently, there is no combination therapy in use to enhance BCG’s activity. To address this unmet need, this article examined a novel approach to boosting BCG activity using low-dose rapamycin (Sirolimus).
In this immunopharmacodynamic trial, patients with non-muscle invasive bladder cancer were randomized in a double-blind fashion to oral rapamycin (0.5 mg or 2.0 mg) or placebo in a 1:1:1 ratio for 4 weeks while the patients concurrently received intravesical BCG. The primary endpoint was circulating (peripheral blood) ex vivo γδ T cell proliferation in response to live BCG, measured as a change from baseline. Secondary endpoints included safety and tolerability and measurement of urine γδ T cells as a surrogate of local (urothelial) immune responses.
A total of 31 patients were randomized. The drug was well-tolerated and adverse events were similar across the groups. Patients receiving 2.0 mg rapamycin experience a significant increase in proliferation of BCG-specific γδ T cells compared to patients receiving placebo, thereby meeting the study's primary endpoint defined a priori. In addition, compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells during intravesical BCG therapy (p=0.02).
This trial demonstrates the feasibility and safety of combining oral rapamycin with intravesical BCG – a concept currently being studied in a phase II trial (NCT04375813). This study is one of the earliest to analyze urinary immune cells as a surrogate of bladder tumor-infiltrating lymphocytes within the context of a clinical trial. Further work is needed to understand how rapamycin boosts BCG efficacy, work that is currently being explored by the investigators
Written by: Niannian Ji, Neelam Mukherjee, Ryan M Reyes, Jonathan Gelfond, Martin Javors, Joshua J Meeks, David J McConkey, Zhen-Ju Shu, Chethan Ramamurthy, Ryan Dennett, Tyler J Curiel, Robert S Svatek
Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA., Department of Epidemiology and Biostatistics, UT Health San Antonio, San Antonio, Texas, USA., Department of Psychiatry, UT Health San Antonio, San Antonio, Texas, USA., Departments of Urology, and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA., Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, Maryland, USA., Experimental Developmental Therapeutics (EDT) Program, Mays Cancer Center at UT Health MD Anderson, San Antonio, Texas, USA .
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