immunotherapy for multiple myeloma
DESCRIPTION
Immunotherapy for Multiple Myeloma. Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine. Disclosures. Clinical research support Ludwig Institute for Cancer Research Laboratory research support Cancer Research Institute NIH/NCI - PowerPoint PPT PresentationTRANSCRIPT
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Immunotherapy for Multiple Myeloma
Hearn Jay Cho MD, PhD
Mt. Sinai School of Medicine
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Disclosures
• Clinical research support– Ludwig Institute for Cancer Research
• Laboratory research support– Cancer Research Institute– NIH/NCI
• I will discuss investigational applications of FDA-approved and investigational agents
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Rationale for Immunotherapy
• Durable complete remissions reported for allogeneic stem cell transplantation– Immunologic therapy, “graft-versus-tumor
effect”• Donor lymphocyte infusion rescues patients
who relapse after allo-transplant– T cell-mediated anti-tumor immunity
• Humoral and cellular immune responses against myeloma-associated antigens detected in patients– Pre- and post-treatment, allo transplant
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Immunotherapeutic Strategies
• “Targeting” monoclonal antibodies (mAbs)
• Immune checkpoint inhibitors• Adoptive cell therapies
– Transgenic T cell receptor (TCR)– Chimeric antigen receptors (CAR)
• Therapeutic tumor vaccines
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“Targeting” mAbs
Monoclonal antibody Antigenic target
Elotuzumab SLAMF7 (CS-1)
Daratumumab SAR650984
CD38
Siltuximab IL-6
Tocilizumab IL-6R
Dacetuzumab CD40
MA5 MUC-1
BT-062* CD138
IPH-2101† KIR
* Immunotoxin conjugate
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Targeting mAbs
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Targeting mAbs
• Elotuzumab– Elo Len Dex Ph 2 relapse, PFS 33 months,
ASCO 2013– FDA Breakthrough Therapy 2014
• Daratumumab– Dara ± Len Dex Ph1/2 relapse, high
response rate, ASH 2013– FDA Breakthrough Therapy/ Fast Track
2014
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Targeting mAbs Mechanisms
• Elotuzumab– Activates NK cells, renders them capable
of killing SLAMF7(-) tumor cells. Cancer Immunol Immunother 62:1831
• Daratumumab– CD38 ectoenzyme catalyzes critical step in
NADAdenosine metabolism, modulates TCR signaling. J Mol Med 91:165
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Immune Checkpoint Inhibitors
Antibody Target
Ipilimumab*Tremelimumab
CTLA-4
Pembrolizumab*NivolumabPidilizumab
PD-1
MPDL3280A**MEDI4736
PD-L1
* FDA approved** Breakthrough Therapy
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Immune Checkpoint Inhibitors
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Checkpoint Inhibitors Trials
• Basket trials– Ipilimumab + Nivolumab heme malignancy– MPDL3280A in solid tumors and heme
malignancy
• Combination– Pembrolizumab + len/dex– Pidilizumab + DC fusion vaccine
• Post-allo-SCT– Ipilimumab
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Vaccine Immunotherapy
• Cell-based vaccines– Dendritic cell vaccines– Tumor cell vaccines
• Autologous or cell lines
• MHC-restricted peptide vaccines• “Universal” vaccines
– Recombinant proteins– Synthetic long peptides– Plasmid DNA vaccines
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Myeloma-associated Antigens
• Idiotype– Myeloma-specific
– Poor results in clinical trials
• Tumor-associated Antigens– WT1
– Muc1
– hTERT
• Cancer-Testis Antigens– Expressed in many cancers
– Restricted expression in normal tissue
– Type I MAGE (MAGE-A3 and CT7), NY-ESO-1, SSX2 expressed in myeloma
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LGS2009-005: Summary (overlay) by clinical site for MAGEA3 O/L Peptides
d0 auto-SCT + d3 PBL reinfusion
Event1
Event2 4
Event 8 9 10
Event11 12
Event13 14
Event15 16
Event18
daysdays
Days from auto-stem cell transplant
Cohen et al, ASH 2013
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Future Directions
• Combination immuno- and targeted therapy– Cytotoxic + immuno/ Auto-SCT + immuno– ImiDs + immunotherapy– Polyvalent vaccines
• Consolidation for non-auto-SCT candidates
• MGUS/ smoldering MM