TY - JOUR
T1 - Adaptive immune resistance to intravesical BCG in non–muscle invasive bladder cancer
T2 - Implications for prospective BCG-unresponsive trials
AU - Kates, Max
AU - Matoso, Andres
AU - Choi, Woonyoung
AU - Baras, Alexander S.
AU - Daniels, Marcus J.
AU - Lombardo, Kara
AU - Brant, Aaron
AU - Mikkilineni, Nina
AU - McConkey, David J.
AU - Kamat, Ashish M.
AU - Svatek, Robert S.
AU - Porten, Sima P.
AU - Meeks, Joshua J.
AU - Lerner, Seth P.
AU - Dinney, Colin P.
AU - Black, Peter C.
AU - McKiernan, James M.
AU - Anderson, Chris
AU - Drake, Charles G.
AU - Bivalacqua, Trinity J.
N1 - Funding Information:
D.J. McConkey reports receiving commercial research grants from AstraZeneca and Ranier Pharmaceuticals and reports receiving speakers bureau honoraria from Janssen and H3 Biomedicine. A.M. Kamat is an employee/paid consultant for IBCG, TMC Innovation, Theralase, BioClin Therapeutics, Cepheid, Medac, Asieris, Pfizer, Abbott Molecular, US Biotest, Ferring, Imagin, Cold Genesys, Roviant, Sessen Bio, Merck, Bristol-Myers Squibb, Eisai, Arquer, MDx Health, AstraZeneca, and Photo-cure; reports receiving commercial research grants from Merck, Bristol-Myers Squibb, Photocure, and FKD Industries; and holds ownership interest (including patents) in CyPRIT with UT MD Anderson Cancer Center. R.S. Svatek is an employee/paid consultant for GoldGenesys, Ferring Pharmaceuticals, and Photocure. J.J. Meeks is an employee/paid consultant for Merck, AstraZeneca, Ferring, and Janssen, and reports receiving commercial research grants from Epizyme, AbbVie, and Tesaro. S.P. Lerner is an employee/paid consultant for Anchiano Therapeutics, Roche/Genentech, Ferring, Merck, QED, Verity, and Vaxiion; reports receiving commercial research grants from Roche/GNE, JBL, Viventia, Vaxiion, UroGen, FKD, and ENDO; reports receiving speakers bureau honoraria from Nucleix, Dava Oncology, and MSD Korea; and holds ownership interest (including patents) in the Broad Institute. C.P. Dinney is an employee/paid consultant for FKD Therapies OY and NCI; reports receiving commercial research grants from NCI; and reports receiving speakers bureau honoraria from ASCO-SITC, Johns Hopkins Hospital, and Dana Farber Harvard Cancer Center. P.C. Black is an employee/paid consultant for Roche, Merck, AstraZeneca, Bristol-Myers Squibb, Ferring, and Janssen, and reports receiving commercial research grants from iProgen and GlaxoSmithKline. C.G. Drake is an employee/paid consultant for Bayer, Bristol-Myers Squibb, Compugen, F-Star, Genocea, Janssen, Merck, Merck-Serono, Pfizer, Pierre Fabre, Roche/Genentech, Shattuck Labs, Tizona Therapeutics, and Werewolf; reports receiving speakers bureau honoraria from Bristol-Myers Squibb; and holds ownership interest (including patents) in Harpoon, Compugen, Tizona, Shattuck Labs, Urogen, and Kleo. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
M. Kates was supported by a Clinician Scientist Development Grant, CSDG-19-001-01-CCE, from the American Cancer Society.
PY - 2020/2/15
Y1 - 2020/2/15
N2 - Purpose: To characterize immune cell expression among patients with non–muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG). Experimental Design: Patients with NMIBC treated with intravesical BCG (2008–2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1+ staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naive population was then validated in a separate cohort. Results: The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (P < 0.01). PD-L1+ cells in BCG nonresponders colocalized with CD8+ T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4+ T cells was very low among PD-L1+ nonresponders (12%) and high among PD-L1- nonresponders (50%, P < 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PDL1 (22C3) staining was similar (26%). Conclusions: One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.
AB - Purpose: To characterize immune cell expression among patients with non–muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG). Experimental Design: Patients with NMIBC treated with intravesical BCG (2008–2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1+ staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naive population was then validated in a separate cohort. Results: The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (P < 0.01). PD-L1+ cells in BCG nonresponders colocalized with CD8+ T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4+ T cells was very low among PD-L1+ nonresponders (12%) and high among PD-L1- nonresponders (50%, P < 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PDL1 (22C3) staining was similar (26%). Conclusions: One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.
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U2 - 10.1158/1078-0432.CCR-19-1920
DO - 10.1158/1078-0432.CCR-19-1920
M3 - Article
C2 - 31712383
AN - SCOPUS:85076106603
VL - 26
SP - 882
EP - 891
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 4
ER -