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- Open Access
Myeloid cell biology and inhibition of anti-tumor immune responses by MPDL3280A in urothelial bladder cancer
Journal for ImmunoTherapy of Cancervolume 2, Article number: P131 (2014)
Treatment options for metastatic urothelial bladder cancer (UBC) are limited. Mutational complexity is known to be high in UBC and may correlate with increased immunogenicity. MPDL3280A, a human PD-L1 monoclonal antibody containing an engineered Fc-domain designed to promote a Th1-driven response, has demonstrated a RECIST response rate of 43% in diagnostically selected, pretreated patients with UBC. A total of 68 patients (67 with efficacy evaluable) were enrolled in the UBC cohort of the Phase I study; 45% were PD-L1 IHC diagnostic positive as defined by expression of PD-L1 on ≥ 5% of tumor-infiltrating immune cells. In the prescreened UBC population, the prevalence of PD-L1-positive patients was 27%.
Comprehensive gene expression analyses of UBC tumors were conducted to interrogate the tumor immune microenvironment in PD-L1-positive tumors and to identify potential mechanisms associated with response or resistance to MPDL3280A. In this study, PD-L1-positive tumors exhibited a high prevalence of gene expression markers associated with T-effector cells (Teff), including perforin, IFNγ, CD8A, granzyme B, granzyme A and EOMES. Additionally, a low baseline signature of genes associated with myeloid cell markers, including IL1B and IL8, appeared to be statistically significantly associated (P<0.01) with MPDL3280A response, suggesting a potential role for myeloid biology in resistance to MPDL3280A treatment in UBC.
Tumor burden markers, including CA-125, CA19-9 and human chorionic gonadotropin (HCG), have been associated with chemotherapy response markers in UBC. A marked decrease in these markers, including CEA, CA19-9, CA-125 and HCG, was observed with MPDL3280A response after 1 treatment cycle, potentially enabling an on-treatment monitoring alternative for response to therapy. Similarly, evaluation of cytokines on treatment identified markers, including IL-6 and IL-10, elevated as early as Cycle 2 only in patients without response to MPDL3280A. These circulating cytokines and tumor-associated gene signatures suggest potential mechanisms associated with resistance and response to MPDL3280A in UBC and provide a rationale for informed combination strategies to further improve treatment benefit in this indication.