Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma. J Immunol 2013 Jun 01;190(11):5620-8
Date
04/26/2013Pubmed ID
23616570Pubmed Central ID
PMC3891840DOI
10.4049/jimmunol.1202005Scopus ID
2-s2.0-84878099006 (requires institutional sign-in at Scopus site) 83 CitationsAbstract
Early phase clinical trials targeting the programmed death receptor-1/ligand-1 (PD-1/PD-L1) pathway to overcome tumor-mediated immunosuppression have reported promising results for a variety of cancers. This pathway appears to play an important role in the failure of immune reactivity to malignant plasma cells in multiple myeloma patients, as the tumor cells express relatively high levels of PD-L1, and T cells show increased PD-1 expression. In the current study, we demonstrate that PD-1/PD-L1 blockade with a PD-L1-specific Ab elicits rejection of a murine myeloma when combined with lymphodepleting irradiation. This particular combined approach by itself has not previously been shown to be efficacious in other tumor models. The antitumor effect of lymphodepletion/anti-PD-L1 therapy was most robust when tumor Ag-experienced T cells were present either through cell transfer or survival after nonmyeloablative irradiation. In vivo depletion of CD4 or CD8 T cells completely eliminated antitumor efficacy of the lymphodepletion/anti-PD-L1 therapy, indicating that both T cell subsets are necessary for tumor rejection. Elimination of myeloma by T cells occurs relatively quickly as tumor cells in the bone marrow were nearly nondetectable by 5 d after the first anti-PD-L1 treatment, suggesting that antimyeloma reactivity is primarily mediated by preactivated T cells, rather than newly generated myeloma-reactive T cells. Anti-PD-L1 plus lymphodepletion failed to improve survival in two solid tumor models, but demonstrated significant efficacy in two hematologic malignancy models. In summary, our results support the clinical testing of lymphodepletion and PD-1/PD-L1 blockade as a novel approach for improving the survival of patients with multiple myeloma.
Author List
Kearl TJ, Jing W, Gershan JA, Johnson BDAuthors
Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of WisconsinTyce J. Kearl MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
B7-H1 Antigen
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Disease Models, Animal
Gene Expression
Lymphocyte Depletion
Lymphocytes, Tumor-Infiltrating
Mice
Multiple Myeloma
Programmed Cell Death 1 Receptor
Whole-Body Irradiation
