Lenalidomide augments the efficacy of bacillus Calmette-Guerin (BCG) immunotherapy in vivo.
OBJECTIVE
Intravesical bacillus Calmette-Guerin (BCG) is the gold standard for high-grade non-muscle-invasive bladder cancer (NMIBC); however, some patients do not respond to initial therapy while others relapse and/or progress. Therefore, combination strategies that can enhance the efficacy and sustainability of BCG are needed. Herein, we explore the efficacy of lenalidomide, a thalidomide derivative with immunomodulatory effects, in combination with BCG, both in vitro and in vivo.


METHODS
We explored the outcomes of lenalidomide in combination with BCG in vivo using the MBT-2 cell line implanted in C3H immunocompetent mice. Apoptosis, cell proliferation, and microvessel density were measured by immunohistochemistry. In vitro, we performed Western blotting for cell cycle and apoptosis regulatory proteins and a chromatin condensation assay to evaluate TNF-α and FasL in combination with lenalidomide.


RESULTS
In the mouse model, combination therapy with BCG and lenalidomide resulted in a statistically significant decrease in tumor size compared with the control group. IHC demonstrated a nonsignificant increase in apoptosis in the combination condition and no effect on cellular proliferation. Microvessel density was decreased in all treated conditions. In vitro, caspase-3 activation and chromatin condensation studies demonstrated increased cell death in the combinations of lenalidomide and TNF-α.


CONCLUSIONS
The immunomodulatory molecule lenalidomide augments the response to BCG in an in vivo mouse model. This provides the rationale for studying the combination in patients with high grade NMIBC.
Department of Urology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Goodwin G
GG
Jinesh
Department of Urology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Eugene Kang
EK
Lee
Department of Urology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Jonathan
J
Tran
Department of Urology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Ashish M
AM
Kamat
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001500:BCG Vaccine / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D053222:Fas Ligand Protein / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D000077269:Lenalidomide; D051379:Mice; D008809:Mice, Inbred C3H; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D001500:BCG Vaccine; D053222:Fas Ligand Protein; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D053148:Caspase 3; D000077269:Lenalidomide