Strategic Research Road Map for WM. May 2015 Lee Greenberger PhD Chief Scientific Officer

Transcription

1 Strategic Research Road Map for WM May 2015 Lee Greenberger PhD Chief Scientific Officer 1

2 Agenda Who is LLS Our interest in WM The Road Ahead Funding the Future KEY MESSAGE 2

3 3 Who are we?

4 LLS is the 3rd largest cancer foundation LLS is the 3 rd largest cancer foundation All blood cancer focus: largest voluntary health agency within the field Research at the cutting edge Invested ~ $70 in research every year for the last 8 years >300 active grants; 25 therapeutic assets in clinical trials Over 500 new grant application /yr Exceptionally large, direct patient contact: 58 chapters across in US & Canada 2.2 million social network contacts;2.6 million subscribers; Over 10 million volunteers and donors 60,000 patient calls into national call center Best in Class fundraising: Team In Training; Light The Night Walk; School & Youth; Man & Woman of the Year; Major gifts; Corporate Partners 4

5 LLS brings entire blood cancer ecosystem together Goal: - Cures - Patient Access Clinical Trials Patients Research Patient Programs and Support Health Care Professionals LLS Academic Research Therapy Acceleration Third-Party Payors Biopharma Advocacy Government Access 5

6 Why so much interest in Waldenstrom s Macroglobulinema? All blood cancer in the US: % 34% 51% 156,420 cases/yr T-cell leukemia lymphoma myeloma EXMZL (MALT) 8% SMZL 2% PMBCL MCL 2% 6% HL 12% LPL (WM) 2% NMZL 2% BL 2% NLPHL 1% THRLBCL 1% HCL 1% FL 25% 1500 new cases/yr US DLBCL 36% 6 Sources: SEER data, Scott and Gascoyne.2014.Nature Cancer Rev 14: B-cell Lymphomas: cases/yr

7 Why so much interest in Waldenstrom s Macroglobulinema? Medical need: standard of therapy still evolving and no cures Huge opportunity - Signal transduction pathways that drive growth leads to a new therapeutic - Understanding of genomics suggests unique targets for therapies - Role of the environment surrounding WM cells beginning to be understood - Knowledge and know-how in immunotherapies could be applied to WM - Application of knowledge of other cancers (e.g. CLL) to WM Knowledge gap unique to WM still substantial but approachable

8 Signal Transduction: Cancer uses different tracks for growth and survival ibrutinib NYC idelalisib ABT-199 8

9 The Road Ahead: Signal Transduction in WM MYD 88 90% of WM have mutated MYD88 FDA approved January Ibrutinib From Rossi.2014.ASH Educational Program Can we develop inhibitor of the MYD88 pathway? What other signaling pathway may be involved? Are in vivo / in vitro models in place to evaluate in WM? Will combination therapy be appropriate? What are the resistance mechanisms? 9 1 See Treon et al NEJM. 372:

10 New therapies approved in CLL (a B-cell disease) sets the stage for WM CLL / yr 10.0 years 3 years?? Approved by FDA November 2013 Rituximab Ofatumumab Obinituzumab Ibrutinib Idelalisib Combinations ABT-199 CAR T Approved by FDA February 2014 Approved by FDA July 23, 2014 New monotherapies for WM; what about combinations? 1. Kumar et al., 2008; Kantarjian et al.,

11 The Microenvironment CXCR4 mutated in 30% of WM pts 1 Regulates B-cell homing to the bone marrow CXCR4+ cells more aggressive disease and poor clinical outcome 2 Mediates resistance to ibrutinib but sensitivity to other therapies, including anti-cxcr4 antibody 3 Much more to learn about supporting microenvironment for WM 1. Hunter et al Blood 13: ; 2. Treon et al Blood 123: ; 3. Roccaro et al Blood.123:

12 MLL2 TP53 MLL3 PIM1 B2M PRDM1 BCL2 MEF2B MYD88 KDM2B CD58 EZH2 AKAP8 CCND3 DUSP27 TLL2 EP300 DPYD KLF2 MTMR8 TSC22D1 TBL1XR1 BCL2L10 CAMTA1 DUSP9 GRB2 MYO1G RASGEF1A SERPINA1 ZNF521 NOTCH1 % of mutated cases Omics in WM epigenetics Genomics: Mutations in MYD88, CXCR Lessons learned from diffuse large B-cell lymphoma Mutational analysis Have we described all the genomic markers (what is the tail)? What do we know about epigenetic regulators and are they important in WM? Can personalized therapies be designed based on omic analysis?

13 Immunotherapies for WM Release the brake: Immunocheckpoint inhibition Step on the gas: Immunoactivation (CAR T)

14 Immunoactivation via Chimeric Antigen Receptor (CAR) T Therapy Genetic engineering Carl June, MD U. Pennsylvania David Porter, MD U. Pennsylvania B-cell Tumor cell Tumorkilling T-cell 90% CR in ALL 50% CR in CLL >50% CR in DLBCL Stephan Grupp, MD, PhD Children s Hospital of Philadelphia Coming Soon CART-CS1 CART-CD123 CART-ROR1 CART-BCMA CART-CD138 others LLS has invested over $20 M in CAR T since 1998

15 Immune checkpoint inhibitors : lessons from the treatment of Hodgkin s lymphoma New Findings in 2014 Therapy: anti PD-1 antibodies Extraordinary response in patients with relapsed/refractory disease 1,2 Well tolerated Why it s important: New therapeutic modality with marked efficacy Safety profile may be superior to cytotoxics currently in use Utility for other blood cancer types (e.g. DLBCL 3, WM 4?) How did LLS help? LLS funded investigators who found very high expression of PD-1 in HL Multiple new grant awards in progress to expand utility to other lympyhomas X Anti-PD-1 antibody 1. Ansell et al., 2015.NEJM 372: 311-9; Moskowitz et al ASH 2014 abstract 290; Lesokhiin et al., ASH 2014 abstract 291; Ansell, ASH 2014 abstract 3015

16 LLS contributions to WM in the future On-going research grants and therapeutic opportunities: WM specific: Dr. Steve Treon (DFCI), Irene Ghobrial (DFCI) Target related : Dr. Ari Melnick (Cornell), Dr. Eduardo Davila (U Maryland), Dr. Jennifer Brown (DFCI), Dr. John Byrd (Ohio State), Dr. Jerry Adams (Walter and Eliza Hall Institute of Medical Research), Dr. Carl June (U Penn) ArGEN-X CD79 mab for WM LLS and IWMF holding Road Map session for WM: May 16-17, 2015 in NYC Additional grant money in 2016 partnered with IWMF: $125,000 / year for the next two years Co-Pay for Waldenstrom s available from LLS qualified applications costs related to treatment contact LLS at

17 Summary New therapies are emerging for WM There is still much to learn about WM LLS is committed to gaining a better understanding of the disease, developing new therapies, and providing patient access to treatments for WM Thank You 17

18 EXTRA