Understanding the Immune System in Myeloma

Brian GM Durie
Understanding the Immune System in Myeloma
Living Well with Myeloma Teleconference Series
Thursday, March 19th 2015
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The Immune System is Like a Swiss Watch
T Cell
Plasma Cell
Changing
one thing
affects all
the others!
B Cell
NK Cell
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Parts of the Immune System
B Cell
T Cell
Natural Killer (NK) Cell
Plasma Cell
Dendritic Cells
Stromal Cell/
Fibroblast
Monocyte/Macrophage
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Normal vs. Myeloma
Normal
Pneumonia
After Infection
B Cells
Plasma Cells
Myeloma
Antigen Trigger
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Memory Cells
Persistence/Build up of
Myeloma Cells
Idiotypic
B Cells
Idiotypic
Plasma Cells
Myeloma
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How Myeloma Evolves
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How Myeloma Messes Up the Normal
Immune System
Reduced Ig
Macrophage
–
IgG
IgA
IgM
+
Normal
Plasma Cells
–
+
Normal
B Cells
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Myeloma
Stromal Cell
6
Bone Marrow Microenvironment:
Wow! A Lot Going On!
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Why Myeloma Grows
Block 2
Idiotypic
T Cells
Myeloma
Cells Persist
and Grow
–
–
Fed By
Myeloma
NK Cells
Block 1
Fed By
Abnormal
B Cells
Macrophage
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Stromal Cell
8
Immune Impact of Myeloma
Many Effects
•
•
•
•
•
Normal Ig reduced
Suppressive Tregs over reactive
Lack of specific cytotoxic T8 cells (TILs)
Helper T cells blocked
Natural killer (NK) cells reduced/blocked
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How to Recover Immune Function?
Very complex, multiple factors…
…NOT easy
• Treat the myeloma
• Enhance/reconstitute immune cell
numbers and/or functions
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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
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6 Ways Anti-CD38 Attacks Myeloma*
1
6
2
5
3
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*Daratumumab
SAR650984
MOR202
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Anti CD38 MoAB: Daratumumab
PD
Response
with higher
doses
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Using Your Own Natural Killer (NK)
Cells to Attack with Elotuzumab (Anti-SLAM F7)
NK
Cell
CD16
SLAM F7
activation
Myeloma
Cell
SLAM F7
Elotuzumab
Trigger
Elotuzumab
Linkage
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Role of Combinations
Examples
• IMiDs (e.g. Revlimid) enhance NK cell
killing
• Proteasome inhibitors (e.g. Velcade)
increase dendritic cell activated T-cell
cytotoxicity
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What IMiDs Do
IMiDs = Immune Modulatory Drugs
IL-6
Trigger
IL-2
Trigger
IMiDs
NK
Cell
+
IFN γ
Block
+
Myeloma
Cell
Enhanced NK Cell Killing
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Synergy from Combinations:
Elotuzumab (SLAMF7 Antibody) + Len/Dex*
Dramatic benefit
≥ PR 92%
• VGPR 17
• CR/sCR 5
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*Richardson P, et al. ASH 2012. Abstract 202.
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Elotuzumab + Len + LoDex
Proportion of
Progression Free Patients (%)
100
Prolonged
PFS
90
80
70
10 mg/kg
60
50
40
30
20 mg/kg
Median time to progression/death:
20
10 mg/kg (n=36): not yet reached
10
20 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7)
0
0
3
6
9
12
15
18
21
24
27
30
Time (months)
International Myeloma Foundation
Richardson PG, et al. ASH 2012. Abstract 202
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What about Velcade?
Another immunomodulatory pathway:
Myeloma Ag
T8 +
IFN γ
+
Vaccine can
enhance
Dendritic Cell
T Cell
HSP60
–
HSP90
Velcade
Myeloma Cell
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Enhanced T8+ mediated cytotocicity
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Value of Combinations
• Many drugs have immune effects
So combinations make sense!
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Possible Role for Anti-PD 1
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Current Options for MoAb Therapy
Antibody
Therapies
Antibody
Therapies
Ulocuplumab
BI-505
Dacetuzumab
Lorvotuzumab
Ravtansine
Indatuximab
Lucatumumab
Pidilzumab
Rivolumab
Pembrolizumab
Elotuzumab
Daratumumab
SAR650984
MOR202
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Milatuzumab
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Impact of Successful Treatment
At Diagnosis
high
Excellent
Response
Immunosuppresive
T Regs
Oligoclonal
Spikes
normal
low
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Survival ≥
10 Years
Reconstitution
T4+T8; TH: IL-17
NK Cells
Normal B Cells
Plasma Cells
Macrophages
Dendritic Cells
Unique
Immune
Signature
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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!
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Key Opportunities
• Immune modulation early
• Combinations to achieve best initial
results
• Use immune approaches to
achieve/enhance MRD status
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MRD Sensitivity and Treatment Outcomes
SERUM TOOLS
IMMUNOPHENOTYPE
RQ-PCR
NEXT-GENERATION FLOW
NEXT-GENERATION SEQUENCE
CURE
Years
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Black Swan 3-Step Approach
3 Clinical Trials
2
1 Early Diagnosis
•Add immune Rx to
primary therapy
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MRD Assessment
of Response
•To eradicate MRD
•Study MRD myeloma
and immune cells
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Details of 3-Step Plan
Develop
specific Rx
Immune
Maintenance
Monitor
If negative
If positive
MRD Assessment
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Study Residual
MRD
Assess
Relapse/
Resistant
Disease
Immune Rx
Alternate Rx
28
Bottom Line
Immune therapy matters
Can be key to better and longer
remissions…
…and lead to cure
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