Novel Immunologic Therapies for Multiple Myeloma Hearn Jay

Novel Immunologic Therapies for Multiple Myeloma Hearn Jay Cho MD, Ph. D Mt. Sinai School of Medicine

Disclosures • Clinical research support – Ludwig Institute for Cancer Research • Laboratory research support – Cancer Research Institute • I will discuss investigational applications of Elotuzumab, Engineered adoptive T cell therapy, and rec. MAGEA 3 + AS 15 ASCI

Rationale for Immunotherapy • Durable complete remissions reported for allogeneic bone marrow transplant – Immunologic therapy, “graft-versus-tumor effect” • Donor lymphocyte infusion rescues patients who relapse after allo-transplant – T cell-mediated anti-tumor immunity • Humoral immune responses against myeloma-associated antigens detected in patients – Pre- and post-treatment, allo transplant

Immunotherapeutic Strategies • Monoclonal antibodies • Adoptive cell therapies • Vaccines

Monoclonal antibodies Monoclonal antibody Antigenic target Elotuzumab CS-1 Daratumumab CD 38 Siltuximab IL-6 Dacetuzumab CD 40 MA 5 MUC-1 BT-062* CD 138 CT-0118† PD-1 IPH-2101† KIR * Immunotoxin conjugate † NK cell immunomodulator

Elotuzumab • Humanized m. Ab against CS-1 – CS-1 highly expressed on MM cells, normal plasma cells, and NK/T cells • Pre-clinical data suggests ADCC as primary mechanism – NK cell-dependent • Laboratory evidence that CS-1 mediates NK cell activation

Elotuzumab • Activity reported in phase I trials in combination with Rev/dex or Vel/dex – Lonial et al, 2012. JCO 30: 1953 – Jakubowiak et al, 2012. JCO 30: 1960

Myeloma-associated Antigens • Idiotype – Myeloma-specific – Poor results in clinical trials • Tumor-associated Antigens – MUC-1 – h. TERT • Cancer-Testis Antigens – Expressed in many cancers – Restricted expression in normal tissue – Type I MAGE (MAGE-A 3 and CT 7) and NY-ESO -1 expressed in myeloma

Adoptive Cellular Therapy • TIL and LAK cells • Expanded Ag-specific T cells • Gene-modified T cell therapy – Ag-specific T cell receptor (TCR) – Chimeric Antigen Receptor (CAR) gene transfer • NK and/or g/d T cells – Autologous – Haploidentical SCT

Gene-modified T cell strategies

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

MAGE-A 3 protein + AS 15 ASCI as consolidation for multiple myeloma patients undergoing autologous stem cell transplantation Protein = MAGE-A 3 Gene = MAGE-A 3 ASCI = Antigen Specific Cancer Immunotherapy Gene cloning Recombinant MAGE-A 3 protein Immunostimulant AS 15 Plasmid ASCI Production in microorganisms Production Purification Formulation AS 15 = MPL, QS 21, Cp. G DNA oligo Courtesy of Glaxo Smith Kline

MAGE-A 3 protein + AS 15 ASCI as consolidation for multiple myeloma patients undergoing autologous stem cell transplantation

MAGE-A 3 protein + AS 15 ASCI as consolidation for multiple myeloma patients undergoing autologous stem cell transplantation

Future Directions • Combination immuno- and targeted therapy – Cytotoxic + immuno – Immune modulation + immuno • Consolidation for non-auto-SCT candidates • Immunotherapy for MGUS/ smoldering MM

Acknowledgements • Sagar Lonial MD, Emory Winship Cancer Institute • Aaron Rapoport MD, Univ. of Maryland School of Medicine • LGS 2009 -005 team • Nikoletta Lendvai MD, Ph. D, MSKCC • Adam Cohen MD, Fox Chase Cancer Center • Ludwig Institute for Cancer Research – – Sacha Gnjatic Ph. D Achim Jungbluth MD Stephane Bertolini Linda Pan

Lloyd J. Old MD 1933 - 2011