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239 Ibrutinib Treatment Reduces Myeloid Derived Suppressor Cell Numbers and Function in Chronic Lymphocytic Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Overcoming Immunodeficiency in CLL
Hematology Disease Topics & Pathways:
Biological, Leukemia, Diseases, Therapies, CLL, enzyme inhibitors, Lymphoid Malignancies
Saturday, December 1, 2018: 5:00 PM
San Diego Ballroom B (Marriott Marquis San Diego Marina)

Gerardo Ferrer, PhD1*, Byeongho Jung, BS2*, Aslam Rukhsana, MD1*, Pui Yan Chiu3*, Andrea Nicola Mazzarello, PhD1*, Florenca Palacios, PhD1*, Shih-Shih Chen, PhD1, Xiao J. Yan, MD, PhD1, Jacqueline C. Barrientos, MD, MS1,4,5*, Jan A. Burger, MD, PhD6, Jonathan E. Kolitz, MD1,7,8, Steven L. Allen, MD1,7,8, Kanti R Rai, MD1,5,7, Barbara Sherry, PhD7,9 and Nicholas Chiorazzi, MD1,5,7

1Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY
2Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Northwell Health System, Manhasset, NY
3Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Northwell Health System, Manhasset, NY
4Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY
5Department of Medicine, Northwell Health, Manhasset, NY
6Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
8Monter Cancer Center, Northwell Health, Lake Success, NY
9Center for Immunology & Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY

In chronic lymphocytic leukemia (CLL), bidirectional interactions of leukemic B cells with components of a complex, yet incompletely defined tumor microenvironment (TME) are critical for leukemic cell survival and proliferation. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, blocks signals that are crucial for survival of CLL cells which are delivered by the B cell receptor (BCR) and certain other receptors. However since BTK and its family members are expressed by other cell types, ibrutinib can also affect non-leukemic cells, thereby altering their function. Here, we focused on understanding how myeloid-derived suppressor cells (MDSCs), a non-leukemic cell type within the TME, and their main target, T cells, are affected by ibrutinib therapy.

Using blood cells from a set of 20 previously untreated patients receiving ibrutinib, we analyzed circulating MDSCs and their subsets 15 days before and 1, 2 and 3 months after treatment initiation. As anticipated, at the first month time point the absolute CLL B-cell count increased significantly (P=0.024), followed by a progressive reduction at consecutive time points (P<0.001). In contrast, absolute MDSC numbers slowly and continuously decreased over time, achieving a significant reduction by the third month (P=0.009). When dividing MDSCs into their cellular subsets, the same pattern was observed for granulocyte-like MDSCs (gMDSCs) (P=0.005) but not for monocyte-like MDSCs (mMDSCs); for the latter an insignificant change was found. Of note, when comparing the changes of MDSC and gMDSC numbers to that of CLL B-cell counts, MDSC and gMDSC neared statistical significance at month one (P<0.1) and achieved significance at the second month (MDSCs: P<0.001; gMDSCs: P=0.033).

We also observed differences in T-cell subpopulations shortly after ibrutinib treatment began. T cell counts increased significantly at the second month compared to pre-treatment (P=0.024); this was the case for both CD4+ and CD8+ cells (P = 0.022 and 0.010, respectively). In addition, CD8+ T cells maintained significance through the third month (P = 0.033). When exploring T cell subsets defined by cytokine production, we observed a spike at the second month of CD4+IL17F+ and of CD8+IL17F+, CD8+IL17A+ and CD8+FoxP3+ T cells. However, by the 3rd month, only the IFNγ-producing subset of CD4+ and CD8+ T cells were significantly higher (P = 0.049 and 0.042, respectively).

Next we analyzed the function of gMDSCs and mMDSCs in the presence of ibrutinib in vitro, addressing the two main effects of these cells on T lymphocytes: suppression of T-cell proliferation and modulation of T-cell differentiation. Specifically, ibrutinib did not directly reduce T-cell expansion in the absence of MDSCs and did not alter the effect of CLL gMDSCs nor mMDSCs on T-cell proliferation, since the significant reduction induced by gMDSCs (P=0.047) and the insignificant, variable effect of mMDSCs were unchanged by the drug. However when we analyzed the influence of gMDSCs, mMDSCs and monocytes on naïve CD4+ T-cell differentiation in the presence or absence of ibrutinib, to our surprise the only T cell subpopulation directly compromised by ibrutinib was the Th1/IFNγ-producing subset. This was opposite that observed in co-cultures with gMDSCs, mMDSCs or normal monocytes in the presence of ibrutinib where Th1 cells expanded significantly (P= 0.021, 0.010, and 0.005, respectively). In the latter co-cultures not containing ibrutinib, more IL-4-producing (Th2) cells were found. Additionally, ibrutinib had a positive effect on IL-22+ (Th22) and FoxP3+ (Treg) cell numbers in the presence of MDSCs and monocytes.

In summary, opposite to what we observed for CLL B and T cells, MDSC counts fell progressively after initiating ibrutinib therapy, possibly due to a direct effect of ibrutinib on BTK in MDSCs or an indirect effect mediated by diminishing signals from CLL B cells that would normally be delivered after BCR engagement. Ibrutinib did not directly alter the T cell suppressive ability of MDSCs, but it did skew T-cell differentiation to Th1 cells when MDSCs were present, in line with our finding higher Th1 cells in the blood after 3 months of treatment. Thus over time, ibrutinib shifts the CLL TME from an immunosuppressive to a more immune effective one.

Disclosures: Chen: Beigene: Research Funding; Verastem: Research Funding; Pharmacyclics: Research Funding. Barrientos: Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy. Kolitz: Magellan Health: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Verastem: Consultancy, Honoraria. Rai: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees. Chiorazzi: Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.

*signifies non-member of ASH