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