Understanding the Immune System in Myeloma

Transcription

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
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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
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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:
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10 mg/kg (n=36): not yet reached
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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)
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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
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Bottom Line
Immune therapy matters
Can be key to better and longer
remissions…
…and lead to cure
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