Pulling the Plug on Cancer Cell Communication. Stephen M. Ansell, MD, PhD Mayo Clinic

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1 Pulling the Plug on Cancer Cell Communication Stephen M. Ansell, MD, PhD Mayo Clinic

2 Why do Waldenstrom s cells need to communicate? Waldenstrom s cells need activating signals to stay alive. WM cells send messages to surrounding cells to prevent themselves from being killed by the immune system Without this communication the cells die

3 Waldenstrom cells don t grow in isolation - Cell Line Development Unsorted IgM ELISA EBV Screen FACS Functional Studies CD19 + /CD138 + Sorted IgH Gene Analysis Array CGH Gene Expression Analysis

4 Waldenstrom cells don t grow in isolation Out of 48 specimens 1 cell line (MWCL-1) Diagnosis: Waldenstrom macroglobulinemia, 73 year old male Light Chain: Kappa, BM Involvement: 50%, IgM: 2.4 g/dl, B2M 6.15mcg/ml Unsorted IgM ELISA: Secretes high levels of IgM EBV Screen: EBV positive by PCR FACS: Positive for kappa, CD19, CD20, CD38, CD138, BCMA, TACI Functional Studies: IL-4, IL-6, IL-21, IGF and BAFF IgH gene usage in the tumor biopsy and the cell line is clonal for VH3-15 MYD88 L265P mutation - heterozygous WM cells are fragile and die easily when the communication is removed Hodge et al. Blood. 2011

5 Why do Waldenstrom s cells need to communicate? Waldenstrom s cells need activating signals to stay alive and function normally Growth BLyS, IL-6 IgM production BLyS, IL-6, IL-21 WM cells send messages to surrounding cells to prevent themselves from being killed by the immune system Shut down the immune response PD-L1 Without this communication the WM cells die

6 Waldenstrom s cells need activating signals to stay alive and function

7 Cells communicate by cytokine networks

8 What s the goal of the communication? Lymphocytes to Plasma cells making Antibodies

9 What are they talking about? Lymphocytes to plasma cells to antibodies the B-cell receptor pathway

10 What s are they talking about? Lymphocytes to plasma cells making antibodies the Toll-like receptor pathway

11 What s the end result? Various types of Immunoglobulins

12 What went wrong in Waldenström macroglobulinemia? Lymphoplasmacytic infiltrate IgM protein Anemia, lymphadenopathy, hyperviscosity Cell growth and IgM production still depends on communication

13 Problem 1: The monoclonal protein The protein in WM is IgM, not IgG The protein molecules are all identical The protein production appears poorly controlled High IgM levels can result in clinical symptoms

14 Problem 2: The malignant lymphoplasmacytic cell Lymphoplasmacytic lymphoma involving either the bone marrow or extramedullary sites Cytologic spectrum - small lymphocytes to well-formed plasma cells High levels of surface CD19, CD20, and immunoglobulin light chain expression

15 What causes the increased production of IgM in Waldenström macroglobulinemia?

16 Cytokines are elevated in WM Responsible for cell communication Cytokines are proteins to allow cells to communicate They are secreted after stimulation They play a role in many cell responses They often affect the actions of other cytokines

17 Cytokines are elevated in WM

18 B-lymphocyte stimulator (BLyS) Critical for maintaining normal B-cells and for immunoglobulin production Too little BLyS results in absence of B- lymphocytes and low immunoglobulin levels Too much BLyS in mice causes lymphoma

19 BLyS expression in WM

20 BLyS increases IgM in WM cells

21 Where does BLyS come from? Autocrine Paracrine BAFF-R BCMA TACI BLyS APRIL APRIL NF-kB Bcl-2 Bcl-xL Bax Bim BLyS Tumor Environment Malignant B cell

22 BLyS collaborates with other cytokines including IL-6 and IL-21 to produce IgM

23 IL-6 expression increased in WM Inflammatory cytokine Causes B-lymphocyte proliferation and differentiation Stimulates T-cell proliferation Serum levels are elevated in WM patients

24 IL-6 increases IgM levels in WM Increasing amounts of IL-6 increases IgM production IL-6 is controlled by a different cytokine - CCL5

25 IL-21 expression increased in WM IL-21 produced by T-cells and NK cells Promotes plasma cell growth Prevents death of cancer cells

26 IL-21 controls plasmacytic differentiation and IL-6 production

27 CCL5 (Rantes) controls IL-6 in WM CCL5 levels are very high in patients with high IgM levels CCL5 is produced by WM cells Signals through a intracellular protein GLI2

28 MYD88 Mutations amplify the communication

29 The role of cytokines in controlling IgM levels in WM

30 WM cells send messages to surrounding cells to prevent themselves from being killed by the immune system

31 Waldenstrom cells send messages to immune cells to protect themselves

32 The role of cytokines in controlling escape from the immune system 0h 24h 72h IL-21 increases the expression of PD-1

33 PD-1 expressing T cells do not function properly

34 PD-L1 and PD-L2 that activate PD-1 are highly expressed in WM Normal Marrow WM Marrow PD-L1 PD-L2

35 Ways to Pull the Plug on Waldenstrom Cell Communication Suppressing cytokine production in general Lenalidomide, JAK/STAT inhibitors, ibrutinib Blocking specific cytokines antibodies to BLyS, IL-6 Blocking suppression of the immune system antibodies to PD-1 and PD-L1

36 Summary Waldenström macroglobulinemia is a disease with two problems the cancerous cell in the bone marrow or lymph nodes and the protein in the blood. Cytokines made by cells in the tumor microenvironment support the growth of the cancer cell, the production of IgM, and help the cells hide from the immune system. Interfering with cell communication is a new treatment option.

37 Acknowledgements Anne Novak Denny Grote Steve Ziesmer Grant funding:

Waldenström Macroglobulinemia: The Burning Questions. IWMF Ed Forum May 18 2014 Morie Gertz MD, MACP

Waldenström Macroglobulinemia: The Burning Questions IWMF Ed Forum May 18 2014 Morie Gertz MD, MACP Are my kids going to get this? Familial seen in approximately 5 10% of all CLL patients and can be associated