Percutaneous BCG enhances innate effector antitumor cytotoxicity during treatment of bladder cancer: a translational clinical trial

Abstract

Background: Intravesical bacillus Calmette-Guérin (BCG) is the gold standard immunologic agent for treating patients with high-grade non-muscle invasive bladder cancer (NMIBC). Nevertheless, relapse rates remain high and BCG unresponsive NMIBC often requires bladder removal. Preclinical data suggest that priming with percutaneous BCG vaccine could improve response to intravesical BCG. Methods: A single-arm trial (NCT02326168) was performed to study the safety, immunogenicity, and preliminary efficacy of priming. Percutaneous BCG was given 21 days prior to intravesical BCG instillation in patients (n = 13) with high-risk NMIBC. Immune responses were monitored and compared to a sequentially enrolled cohort of nine control patients receiving only intravesical BCG. The effect of BCG on natural killer (NK) and γδ T cell in vitro cytotoxicity was tested. γδ T cell subsets were determined by T cell receptor gene expression with NanoString. Results: Priming was well tolerated and caused no grade ≥3 adverse events. The 3-month disease-free rate for prime patients was 85% (target goal ≥ 75%). Priming boosted BCG-specific immunity at 3 months and increased the activation status of in vitro expanded circulating NK and γδ T cells and their cytotoxicity against bladder cancer cells through receptor NKG2D. BCG enhanced the cytotoxicity of NK and γδ T cells against K562, RT4, and UM-UC6 but not against T24, UM-UC-3, or UM-UC-14 cells. Infiltrating γδ T cell subsets identified in the bladder includes γ9δ2 and γ8δ2. Conclusions: BCG priming is safe and tolerable. Poor sensitivity to NK and γδ T cell cytotoxicity by some bladder tumors represents a potential BCG-resistance mechanism.

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

“…17 γδ T cells are required for effective BCG treatment of mouse bladder cancer 16 and BCG enhances cytotoxicity of γδ T cells against human bladder cancer. 18 Our group and others have shown that rapamycin increases the proliferative capacity and effector function of γδ T cells. [19][20][21] Moreover, rapamycin boosts human γδ T cellmediated killing of human squamous cell carcinoma in a mouse xenograft model.…”

“…Human urinary cytokine-luminex assay Urine samples were diluted 1:20 with high-performance liquid chromatography grade water and measured for urinary creatinine level according to the manufacturer's instructions using the Creatinine Colorimetric Assay Kit (Cayman Chemical) and a Synergy 2 plate reader (BioTek). 18 Undiluted or diluted (1:1) samples were also run in duplicates using a Milliplex MAP 6-plex human cytokine panel (Millipore), and analyzed using FLEXMAP 3D and xPONENT software (Luminex). Average cytokine concentration of each urine sample was normalized based on its creatinine level to correct for bladder urine volume (at 100 mg/dL creatinine).…”

<p>Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer: An Update</p>

“…41,49 It is worth noting that Ji et al (2019) recently demonstrated the safety of BCG priming in NMIBC patients as well as the different responses of enhanced innate effector cells against some specific BC cell lines, suggesting a potential BCG resistance mechanism that could explain BCG nonresponsivity in some individuals. 50 On the other hand, optimum maintenance schedule has not been clarified. 51 Differences among the studies in the tumor stage of patients, treatment schedules, dose, BCG substrain and other parameters complicate the aim of achieving the best BCG maintenance schedule, and consequently, further research is needed to maximize the effect of the current treatment.…”

Trial watch: IDO inhibitors in cancer therapy

“…The Phase II study NCT03519256, enrolling subjects with high-risk, non-MIBC, is monitoring the therapeutic profile of BMS-986205 combined with two drugs already approved for some types of bladder cancer such as nivolumab [200][201][202][203][204] and the toll like receptor 2 (TLR2)/TLR4 agonist [205][206][207][208][209] bacillus Calmette-Guérin (BCG). [210][211][212] Along similar lines, the Phase III study NCT03661320 compared the efficacy, tolerability and safety of three therapeutic regimens for MIBC: neoadjuvant standard of care chemotherapy with cisplatin [213][214][215][216][217] and gemcitabine, 218,219 (NAC) versus NAC combined with nivolumab or nivolumab plus BMS-986205, followed by continuation of adjuvant immunotherapy (nivolumab with or without the IDO1 inhibitor) post radical cystectomy. 220 Additionally, four ongoing studies aim at elucidating the therapeutic profile of BMS-986205 in combination with nivolumab in patients affected by endometrial carcinoma or endometrial carcinosarcoma (NCT04106414), unresectable or metastatic HCC (NCT03695250), stage II to IV HNSCC (NCT03854032), as well as stage III or IV melanoma (NCT04007588).…”

“…The Phase II study NCT03519256, enrolling subjects with high-risk, non-MIBC, is monitoring the therapeutic profile of BMS-986205 combined with two drugs already approved for some types of bladder cancer such as nivolumab 200 - 204 and the toll like receptor 2 (TLR2)/TLR4 agonist 205 - 209 bacillus Calmette–Guérin (BCG). 210 – 212 Along similar lines, the Phase III study NCT03661320 compared the efficacy, tolerability and safety of three therapeutic regimens for MIBC: neoadjuvant standard of care chemotherapy with cisplatin 213 - 217 and gemcitabine, 218 , 219 (NAC) versus NAC combined with nivolumab or nivolumab plus BMS-986205, followed by continuation of adjuvant immunotherapy (nivolumab with or without the IDO1 inhibitor) post radical cystectomy. 220 …”