title: Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.
abstract: Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452-62. ©2016 AACR.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Vandeveer
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Fallon
authors.affiliation: EMD Serono Research and Development Institute, Billerica, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Tighe
authors.affiliation: EMD Serono Research and Development Institute, Billerica, Massachusetts.
authors.forename: Helen
authors.initials: H
authors.lastname: Sabzevari
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. js141c@nih.gov.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: John W
authors.initials: JW
authors.lastname: Greiner
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology; D009368:Neoplasm Transplantation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C000609138:avelumab