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Impact of chemotherapy alone, and chemotherapy plus ipilimumab, on circulating immune cells in patients with metastatic bladder cancer
  1. Matthew D Galsky1,
  2. Hahn Noah2,
  3. Alexander Starodub3,
  4. Ralph J Hauke4,
  5. Przemyslaw Twardowski5,
  6. Mark Fleming6,
  7. Jingjing Qi6,
  8. Guru Sonpavde7,
  9. Manishkumar Patel6,
  10. Jun Zhu6,
  11. Uma Chippada-Venkata6,
  12. Costantine Albany8,
  13. Li Wang6,
  14. Miriam Merad6,
  15. William Oh9,
  16. Nina Bhardwaj1,
  17. Sacha Gnjatic6 and
  18. Seunghee Kim-Schulze6
  1. Aff1 grid.59734.3c0000000106702351Icahn School of Medicine at Mount Sinai New York NY USA
  2. Aff2 grid.416167.3Mt. Sinai New York NY USA
  3. Aff3 grid.411569.e0000000404402154IU Health Goshen Center for Cancer Care Goshen IN USA
  4. Aff4 Nebraska Cancer Center Omaha NE USA
  5. Aff5 grid.410425.60000000404218357City of Hope Duarte CA USA
  6. Aff6 grid.59734.3c0000000106702351Mount Sinai School of Medicine New York NY USA
  7. Aff7 grid.265892.20000000106344187University of Alabama at Birmingham Birmingham AL USA
  8. Aff8 grid.257413.60000000122873919Indiana University Indianapolis IN USA
  9. Aff9 grid.59734.3c0000000106702351Division of Hematology/Medical OncologyThe Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai New York NY USA

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Meeting abstracts


Metastatic bladder cancer (MBC) is a relatively chemosensitive neoplasm yet response durations are generally short-lived. Recently, immune checkpoint blockade has demonstrated unparalleled activity in heavily pre-treated patients (pts) with MBC. The role of standard chemotherapy on the immune system of patients with MBC, and optimal approaches to combining chemotherapy and immune checkpoint blockade, has not been comprehensively explored.


Pts with MBC were enrolled on a Phase II trial of chemotherapy + CTLA4 blockade. Patients received 2 cycles of gemcitabine + cisplatin (GC) followed by 4 cycles of GC + ipilimumab (GCI). Flow cytometry was performed on peripheral blood mononuclear cells at baseline, after GC, and after GCI to determine the impact of treatment on the frequency and phenotype of CD4+ and CD8+ T cells, regulatory T cells (CD4+CD25+CD127-CD45RA-Tregs), and myeloid-derived suppressor cells. Comparisons between time-points were made using Wilcoxon's rank test. Plasma collected from patients was assayed for the expression of 41 cytokines and chemokines by multiplex assay at these same timepoints.


The trial has completed enrollment (n=36) and flow cytometry data are available for the complete treatment sequence on 27 pts as of 5/2015 (Table). Hierarchical cluster analysis of the cytokine/chemokine panel and cellular immunophenotype demonstrated clustering of post-GC alone specimens and post-GC + ipilimumab specimens. The % of CD4+ and CD8+ T cells was significantly increased after addition of ipilimumab. The level of cytokines involved in proinflammatory and T cell activation such as IL-12, IL-7, IL-15, IFNγ, IFNα and IL-1-α and –ß was higher in the post-GC + ipilimumab than those in post-GC.

Table 1


Gemcitabine plus cisplatin alone did not demonstrate significant favorable or unfavorable effects on the circulating immunocytes profiled. The addition of ipilimumab induced pharmacodynamic changes including an increase in circulating CD4+ and CD8+ T cells and modulation of the peripheral blood cytokine/chemokine milieu generally suggestive of an immunostimulatory effect. The immunomodulatory effects of treatment, interpreted in the context of the clinical outcome data, may help refine an understanding of the mechanistic basis of anticancer effects and inform subsequent rational combinations of chemotherapy plus immune checkpoint blockade.