Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer.
Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ-producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients' response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses.
Unité d'Immunobiologie des Cellules Dendritiques, Department of Immunology, Institut Pasteur, F-75724 Paris, France.
Claire
C
Biot
Cyrill A
CA
Rentsch
Joel R
JR
Gsponer
Frédéric D
FD
Birkhäuser
Hélène
H
Jusforgues-Saklani
Fabrice
F
Lemaître
Charlotte
C
Auriau
Alexander
A
Bachmann
Philippe
P
Bousso
Caroline
C
Demangel
Lucie
L
Peduto
George N
GN
Thalmann
Matthew L
ML
Albert
D000283:Administration, Intravesical; D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000628:therapy*
D001500:BCG Vaccine