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Poster Presentation
Myeloid cell biology and inhibition of anti-tumor immune responses by MPDL3280A in urothelial bladder cancer
  1. Yuanyuan Xiao1,
  2. Christina Rabe2,
  3. Marcin Kowanetz1,
  4. Thomas Powles3,
  5. Nicholas J Vogelzang4,
  6. Daniel P Petrylak5,
  7. Yohann Loriot6,
  8. Mitchell Denker1,
  9. Rin Nakamura1,
  10. Qun J Wu1,
  11. Teiko Sumiyoshi1,
  12. Zachary Boyd1,
  13. Siew-leng M Teng1,
  14. Xiaodong Shen1,
  15. Gregg Fine1,
  16. Daniel S Chen1 and
  17. Priti S Hegde1
  1. Aff1 grid.418158.10000000405344718Genentech, Inc. San Francisco CA USA
  2. Aff2 grid.424277.0Roche Diagnostics GmbH Germany
  3. Aff3 grid.4868.20000000121711133Barts Cancer InstituteQueen Mary University of London London UK
  4. Aff4 University of Nevada School of Medicine and US Oncology/Comprehensive Cancer Centers of Nevada NV USA
  5. Aff5 grid.433818.5Yale Cancer Center New Haven CT USA
  6. Aff6 grid.14925.3b0000000122849388Gustave Roussy Villejuif France

https://doi.org/10.1186/2051-1426-2-S3-P131

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    Meeting abstracts

    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.