immunotherapy for multiple myeloma hearn jay cho md, phd mt. sinai school of medicine
TRANSCRIPT
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
• I will discuss investigational applications of FDA-approved and investigational agents
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
Immunotherapeutic Strategies
• “Targeting” monoclonal antibodies (mAbs)
• Immune checkpoint inhibitors• Adoptive cell therapies
– Transgenic T cell receptor (TCR)– Chimeric antigen receptors (CAR)
• Therapeutic tumor vaccines
“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
Targeting mAbs
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
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
Immune Checkpoint Inhibitors
Antibody Target
Ipilimumab*Tremelimumab
CTLA-4
Pembrolizumab*NivolumabPidilizumab
PD-1
MPDL3280A**MEDI4736
PD-L1
* FDA approved** Breakthrough Therapy
Immune Checkpoint Inhibitors
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
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
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
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
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