Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine.
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Transcript of Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine.
![Page 1: Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine.](https://reader036.fdocuments.in/reader036/viewer/2022062308/56649d705503460f94a5286d/html5/thumbnails/1.jpg)
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
![Page 4: Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine.](https://reader036.fdocuments.in/reader036/viewer/2022062308/56649d705503460f94a5286d/html5/thumbnails/4.jpg)
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
![Page 7: Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine.](https://reader036.fdocuments.in/reader036/viewer/2022062308/56649d705503460f94a5286d/html5/thumbnails/7.jpg)
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
![Page 11: Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine.](https://reader036.fdocuments.in/reader036/viewer/2022062308/56649d705503460f94a5286d/html5/thumbnails/11.jpg)
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