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Jan Burger, MD PhD Department of Leukemia MD Anderson Cancer Center

The “outside ” (microenvironment) of the CLL cell: new insights into disease biology and new therapeutic targets. Conventional therapies. Stromal cell. protect. Jan Burger, MD PhD Department of Leukemia MD Anderson Cancer Center. CLL. Versteckspiel im Wald

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Jan Burger, MD PhD Department of Leukemia MD Anderson Cancer Center

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  1. The “outside” (microenvironment) of the CLL cell: new insights into disease biology and new therapeutic targets Conventional therapies Stromal cell protect Jan Burger, MD PhD Department of Leukemia MD Anderson Cancer Center CLL Versteckspiel im Wald by Friedrich Eduard Meyerheim (1808-1879)

  2. Microenvironment in CLL • Larger proliferating CLL cells form proliferation centers (pseudofollicles), a hallmark finding in CLL • Within pseudofollicles, CLL cells are in close contact with accessory cell (stomal cells, T cells) From: Soma LA et al, Human Pathology. 2006;37:152-159 From: PE Patten et al. Blood. 2008;111:5173-81 Messmer BT, et al. J Clin Invest. 115(3): 755-764, 03/2005

  3. Microenvironment in CLL: a-SMA and CD14/68+ cells CLL#1 CLL#2 Bhattacharya and Mertens et al., Leukemia (2011) 25, 722–726 CLL#3 normal tonsil From: J Rual et al. Clinical Cancer Research 12, 5622-31, 2006

  4. CLL in vitro model: BMSC co-cultures • Standardized CLL-stroma co-culture conditions for drug testing • Ideal for testing drug combinations

  5. From: Sivina et al., Leukemia 26:1812-20, 08/2012

  6. In vitro model : Nurselike cells BAFF-R, BCMA, TACI* BAFF, APRIL CXCR5¶ CXCL13 CXCL12 ?antigen CD31, plexin-B1 BCR# CXCR4† CD38, CD100‡ * Nishio M et al. Blood 106:1012-20, 2005 ¶ Burkle A et al. Blood 110:3316-25, 2007 † Burger JA et al. Blood 96, 2655-63, 2000 ‡ Deaglio S et al. Blood 105(8):3042-50, 2005 #Burger JA et al. Blood. 113:3050-8, 2009

  7. The lymph node microenvironment promotes BCR signaling CCL4 CCL3 • CLL cells isolated from lymph nodes showed upregulation of CCL3 and CCL4 • LN signature GEPs have a remarkable similarity to GEP of CLL cells after co-cultured with nurselike cells, including upregulation of CCL3, CCL4, EGR2, EGR3, and MYC From: Y Herishanu et al., Blood. 2011 Jan 13;117(2):563-74

  8. Summary: molecular interactions in the CLL microenvironment • The moleculoar interactions between CLL cells and their microenvironment are complex • Soluble factors, BCR signaling and cell-cell interactions are important • Chemokine receptors and BCR-associated kinases are current drug targets From: Burger JA et al., Blood. 2009 Oct 15;114(16):3367-75

  9. Targeting the microenvironment in CLL: Plerixafor (AMD3100) • Plerixafor is a CXCR4 antagonist and blocks HIV-1 entry into T cells • Plerixafor is a bicyclam • Plerixafor binds to Asp171 in TM-IV and Asp262 in TM-VI of CXCR4 From: Gerlach LE et al., J. Biol. Chem. 276:14153, 2001

  10. Results: Best Confirmed Response* * Responses were assessed based on definitions provided by the National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia. Cheson BD, et al; Blood. 1996 Jun 15;87(12):4990-7.

  11. Targeting of BCR signaling in CLL • BCR-associated kinases are targets of new drugs in preclinical and clinical development • SYK (Spleen tyrosine kinase) inhibitors: fostamatinib (R788) • BTK (Bruton’s tyrosine kinase) inhibitors: ibrutinib (formerly: PCI-32765) • PI3 kinases: Isoform-Selective Inhibitor of PI 3-Kinases, GS-110 (formerly: CAL-101) From: Nat Rev Immunol 2:945

  12. Pattern of Response: Blood Lymphocytes vs Lymph Nodes ALC SPD Mean % Change from Baseline SCR(61) 1(60) 2(57) 3(52) 4(50) 5(51) 6(47) 7(46) 8(48) 9(43) 10(38) 11(31) Cycle SPD- sum of products of lymph node dimension

  13. Inhibition of chemotaxis CXCL12 CXCL13 * * * * Migrated cells(% of input) + chemokine + chemokine Ctrl Ctrl Medium Medium AMD3100 PCI-32765 (10 nM) PCI-32765 (10 nM) PCI-32765 (100 nM) PCI-32765 (100 nM) PCI-32765 (1000 nM) PCI-32765 (1000 nM) S. Ponader et al., Blood 119: 1182-9, 2012 means of 6 patients ± SEM, *p≤0.05 compared to Medium

  14. GS-1101 (CAL-101) inhibits CLL cell chemotaxis towards CXCL12 and CXCL13 Hoellenriegel J et al.; Blood 118(13):3603-12, 09/2011

  15. GS-1101 (CAL-101) antagonizes CLL cell migration beneath marrow stroma cells (pseudoemperipolesis) Hoellenriegel J et al.; Blood 118(13):3603-12, 09/2011

  16. PCI-32765: effects on adhesion and migration VCAM-1 adhesion assay Chemotaxis assay From: Rooijet al., Blood 119: 2590-2594, 2012

  17. Tcl1 MOUSE model of cll Effects of Btk inhibitor ibrutinib + Ibrutinib Control Vehicle control Ibrutinib25mg/kg/day 2.5 mg/kg/d 25mg/kg/day 1.6 P=0.64 P=0.137 P=0.028 30 1.4 P=0.356 1.2 20 P=0.05 1.0 Body weight (g) P=0.01 10 0.8 Spleen weight (g) 0.6 0 0.4 Ibrutinib(mg/kg/day) Ctrl(n=4) 0.2 0 2.5(n=3) 25(n=4) 25(n=4)Outliers Ibrutinib(mg/kg/day) Ctrl(n=4) 2.5(n=3) 25(n=4) 25(n=4)Outliers S. Ponader et al., Blood 119: 1182-9, 2012

  18. BCR-related Biomarker: CCL3, CCL4 (MIP-1α,β) Ibrutinib trial GS-1101 trial pre-treatment CCL3 pre-treatment CCL4 pg/mL time (days) S. Ponader et al., Blood 119: 1182-9, 2012 Hoellenriegel J et al.; Blood 118(13):3603-12, 09/2011

  19. Key effects of inhibitors of BCR-associated kinases Btk, Syk, PI3Kδ • Inhibitors of BCR signaling and block survival and proliferation, • but also homing and tissue retention of CLL cells • Effects on either pathway differ between patients Adapted after: Burger JA et al., Blood. 2009 Oct 15;114(16):3367-75

  20. Summary and outlook • Chemokine receptors and adhesion molecules are essential for tissue homing and migration of CLL cells • CXCR4 and BCR-associated kinases (SYK, BTK, PI3Kδ) are targeted in clinical trials in CLL • These therapies “mobilize” CLL cells from the tissues into the blood • There is promising clinical activity of these new therapeutic approaches

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