Understanding the Immune System in Myeloma

Transcription

1 Brian GM Durie Understanding the Immune System in Myeloma Living Well with Myeloma Teleconference Series Thursday, March 19 th

2 The Immune System is Like a Swiss Watch B Cell T Cell Plasma Cell Changing one thing affects all the others! NK Cell 2

3 Parts of the Immune System B Cell Plasma Cell T Cell Dendritic Cells Natural Killer (NK) Cell Stromal Cell/ Fibroblast Monocyte/Macrophage 3

4 Normal vs. Myeloma Normal After Infection Pneumonia B Cells Plasma Cells Memory Cells Myeloma Persistence/Build up of Myeloma Cells Antigen Trigger Idiotypic B Cells Idiotypic Plasma Cells Myeloma 4

5 How Myeloma Evolves 5

6 How Myeloma Messes Up the Normal Immune System Reduced Ig IgG IgA IgM Normal Plasma Cells + Macrophage + + Normal B Cells Myeloma Stromal Cell 6

7 Bone Marrow Microenvironment: Wow! A Lot Going On! 7

8 Why Myeloma Grows Block 2 Idiotypic T Cells Myeloma Cells Persist and Grow Block 1 NK Cells Abnormal B Cells Fed By Myeloma Fed By Stromal Cell Macrophage 8

9 Immune Impact of Myeloma Many Effects Normal Ig reduced Suppressive T regs over reactive Lack of specific cytotoxic T 8 cells (TILs) Helper T cells blocked Natural killer (NK) cells reduced/blocked 9

10 How to Recover Immune Function? Very complex, multiple factors NOT easy Treat the myeloma Enhance/reconstitute immune cell numbers and/or functions 10

11 Types of Immune Therapy Direct antibody attack on myeloma Enhance good immune cell activity NK cells T cells Dendritic cells e.g. with vaccines Macrophages Infuse T, Dendritic, or NK cells engineer/grow in laboratory 11

12 6 Ways Anti-CD38 Attacks Myeloma* *Daratumumab SAR MOR202 12

13 Anti CD38 MoAB: Daratumumab PD Response with higher doses 13

14 Using Your Own Natural Killer (NK) Cells to Attack with Elotuzumab (Anti-SLAM F7) activation NK Cell CD16 SLAM F7 SLAM F7 Myeloma Cell Elotuzumab Trigger Elotuzumab Linkage 14

15 Examples Role of Combinations IMiDs (e.g. Revlimid) enhance NK cell killing Proteasome inhibitors (e.g. Velcade) increase dendritic cell activated T-cell cytotoxicity 15

16 What IMiDs Do IMiDs = Immune Modulatory Drugs Trigger IL-2 + NK Cell IL-6 Block IFN γ Trigger + Myeloma Cell IMiDs Enhanced NK Cell Killing 16

17 Synergy from Combinations: Elotuzumab (SLAMF7 Antibody) + Len/Dex* Dramatic benefit PR 92% VGPR 17 CR/sCR 5 *Richardson P, et al. ASH Abstract

18 Elotuzumab + Len + LoDex Proportion of Progression Free Patients (%) Median time to progression/death: 10 mg/kg (n=36): not yet reached 20 mg/kg (n=37): 18.6 mos (95% CI ) Prolonged PFS 20 mg/kg 10 mg/kg Time (months) Richardson PG, et al. ASH Abstract

19 What about Velcade? Another immunomodulatory pathway: Myeloma Ag Vaccine can enhance T8 + IFN γ T Cell + Dendritic Cell HSP60 Velcade HSP90 Myeloma Cell Enhanced T8 + mediated cytotocicity 19

20 Value of Combinations Many drugs have immune effects So combinations make sense! 20

21 Possible Role for Anti-PD 1 21

22 Current Options for MoAb Therapy Antibody Therapies Ulocuplumab Dacetuzumab Lorvotuzumab Lucatumumab Elotuzumab Daratumumab SAR MOR202 Antibody Therapies BI-505 Ravtansine Indatuximab Pidilzumab Rivolumab Pembrolizumab Milatuzumab 22

23 Impact of Successful Treatment At Diagnosis Excellent Response Survival 10 Years high normal Immunosuppresive T Regs Oligoclonal Spikes Reconstitution T4+T8; T H : IL-17 NK Cells Normal B Cells Plasma Cells Macrophages Dendritic Cells low Unique Immune Signature 23

24 What Does All This Mean in 2015? The immune system matters! Immune attack is largely independent of underlying mutations/high risk features (e.g. 17p-; t(4;14) 1q+) We must learn how to sequence and combine immune and other therapies! 24

25 Key Opportunities Immune modulation early Combinations to achieve best initial results Use immune approaches to achieve/enhance MRD status 25

26 MRD Sensitivity and Treatment Outcomes SERUM TOOLS IMMUNOPHENOTYPE RQ-PCR NEXT-GENERATION FLOW NEXT-GENERATION SEQUENCE CURE Years 26

27 Black Swan 3-Step Approach 1 Early Diagnosis Add immune Rx to primary therapy 2 MRD Assessment of Response Study MRD myeloma and immune cells 3 Clinical Trials To eradicate MRD 27

28 Details of 3-Step Plan Immune Maintenance Develop specific Rx Monitor If negative If positive Study Residual MRD Assess Relapse/ Resistant Disease MRD Assessment Immune Rx Alternate Rx 28

29 Bottom Line Immune therapy matters Can be key to better and longer remissions and lead to cure 29

30 30