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Immunotherapy for Multiple Myeloma

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

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Immunotherapy for Multiple Myeloma

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  1. Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine

  2. 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

  3. 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

  4. Immunotherapeutic Strategies • “Targeting” monoclonal antibodies (mAbs) • Immune checkpoint inhibitors • Adoptive cell therapies • Transgenic T cell receptor (TCR) • Chimeric antigen receptors (CAR) • Therapeutic tumor vaccines

  5. “Targeting” mAbs * Immunotoxin conjugate

  6. Targeting mAbs

  7. 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

  8. Targeting mAbs Mechanisms • Elotuzumab • Activates NK cells, renders them capable of killing SLAMF7(-) tumor cells. Cancer ImmunolImmunother 62:1831 • Daratumumab • CD38 ectoenzyme catalyzes critical step in NADAdenosine metabolism, modulates TCR signaling. J Mol Med 91:165

  9. Immune Checkpoint Inhibitors * FDA approved ** Breakthrough Therapy

  10. Immune Checkpoint Inhibitors

  11. Checkpoint Inhibitors Trials • Basket trials • Ipilimumab + Nivolumabheme malignancy • MPDL3280A in solid tumors and heme malignancy • Combination • Pembrolizumab + len/dex • Pidilizumab + DC fusion vaccine • Post-allo-SCT • Ipilimumab

  12. 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

  13. 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

  14. LGS2009-005: Summary (overlay) by clinical site for MAGEA3 O/L Peptides Event 1 Event 2 4 Event 8 9 10 Event 11 12 Event 13 14 Event 15 16 Event 18 days days Days from auto-stem cell transplant d0 auto-SCT + d3 PBL reinfusion Cohen et al, ASH 2013

  15. 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

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