Multiple Myeloma Immunotherapy Updates Rafat Abonour, M.D. Edward Stadtmauer, M.D. International Myeloma Foundation
What is Immunotherapy? • Using the immune system to help fight myeloma. • The immune system is 2 parts – Humoral immunity mediated by antibodies – Cellular immunity mediated by cytotoxic lymphocytes and natural killer cells. International Myeloma Foundation 2
Antibodies Mediated Immunotherapy • Using genetically engineered antibodies to bind to the myeloma cells and kills them. • Either by bringing on – Proteins that kills the myeloma cells (complement) – Cells that kills the myeloma cells like cytotoxic lymphocytes or natural killer cells. International Myeloma Foundation 3
MAb-Based Targeting of Myeloma Antibody-dependent Complement-dependent Apoptosis/growth cellular cytotoxicity (ADCC) cytotoxicity (CDC) arrest via targeting C1q signaling pathways Effector C1q CDC cells: MM MM FcR Daratumumab (CD38) Lorvotuzumab mertansine (CD56) nBT062-maytansinoid (CD138) ADCC 1339 (IL-6) MM BHQ880 (DKK1) RAP-011 (activin A) Lucatumumab or dacetuzumab (CD40) Daratumumab (CD38) Elotuzumab (SLAM 7) Daratumumab (CD38) Tai YT, et al. Bone Marrow Res. 2011;2011:924058. MOR208 (HM1.24) International Myeloma Foundation 4
Targets on the Myeloma Cell Surface CD38 SLAMF7 International Myeloma Foundation 5 15
Daratumumab Efficacy in Combined Analysis PR VGPR CR sCR 35 ORR = 31% 30 2% 3% 1% CR or better 13% 25 VGPR or 10% better 20 ORR, % 15 10 18% 5 0 16 mg/kg N = 148 • ORR was consistent in subgroups including age, number of prior lines of therapy, refractory status, or renal function International Myeloma Foundation 6
Progression-free Survival 100 Responders MR (Minimal Response)/SD (Stable Disease) Patients progression-free and alive, % PD (Progressive Disease)/NE (Non-Evaluable) 75 Responders (Median ~7.4 months) 50 25 MR/SD: 3.2 (2.8-3.7) months 0 PD (median ~0.9 months) 0 2 4 6 8 10 12 14 16 18 20 Time from first dose, months Patients at risk Responders 46 46 41 35 27 14 13 5 3 3 0 MR/SD 77 45 21 13 3 2 1 0 0 0 0 PD/NE 25 0 0 0 0 0 0 0 0 0 0 International Myeloma Foundation 7
Overall Survival 100 75 Responders Patients alive, % 50 8 MR/SD 25 PD Responders MR/SD 0 PD/NE 0 2 4 6 8 10 12 14 16 18 20 22 Time from first dose, months Patients at risk Responders 46 46 46 45 44 43 42 29 15 13 3 0 MR/SD 77 74 67 63 57 53 47 37 10 5 1 0 PD/NE 25 16 12 11 7 7 5 4 1 1 0 0 International Myeloma Foundation For the combined analysis, median OS = 19.9 months 1-year overall survival rate = 69% (95% CI, 60.4-75.6) 7
Elotuzumab Elotuzumab (HuLuc63) is an IV CD16 humanized monoclonal antibody targeting human SLAMF7, a cell surface glycoprotein. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784. Tai YT et al. Blood. Elotuzumab 2008;112:1329-1337. van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624. Lonial S et al. Blood. 2009;114:432. Richardson PG, et al. ASH 2014. Abstract 302 International Myeloma Foundation 8
Elotuzumab is an IV humanized monoclonal antibody targeting human SLAMF7 • Elotuzumab it may not work on its own • Original study with elo only in 35 pts, doses ranging from 0.5-20 mg/kg every two weeks demonstrated no responses but stable disease in 27% of pts • However combined with revlimid and dex in relapsed pts, response rate was 82% (expected would be about 60%) International Myeloma Foundation 10
ELOQUENT-2: Elotuzumab With Lenalidomide/Dexamethasone R/R MM • Randomized, open-label, multicenter phase III trial Elotuzumab 10 mg/kg IV QW cycles 1, 2 then Q2W + Lenalidomide 25 mg PO D1-21 + Dexamethasone 40 mg PO QW Pts with Until (n = 321) relapsed MM Progression or 28-day cycles and 1-3 prior unacceptable treatments toxicity Lenalidomide 25 mg PO D1-21 + (N = 646) Dexamethasone 40 mg PO QW (n = 325) • Primary endpoints: Progression Free time (PFS), Overall Response • Secondary endpoints: Overall Survival, safety, health-related Quality of Life Dimopoulos MA, et al. ASH 2015. Abstract 28. International Myeloma Foundation 6 11
ELOQUENT-2 Results E-Rd Rd (n=321) (n=325) HR P Value Median PFS, mos 19.4 14.9 0.70 <0.001 ─ ORR, % 79 66 <0.001 ─ ─ ≥VGPR, % 33 28 AEs, % ─ ─ ≥G3 cardiac failure 4 6 ─ ─ ≥G3 acute renal failure 4 4 No benefit observed in patients who were previously exposed to immunomodulatory agent. Patients with Del17p, 1q21 amplifications and t(4;14) faired as well as standard risk. International Myeloma Foundation Lonial S et al. N Engl J Med . 2015;373:621. 12
Cellular Mediated Immunotherapy • Off the shelf: not custom made to attack myeloma but turns on the immune system to recognize myeloma cells and destroy it. The classic drugs are call checkpoint inhibitors. • Custom made patients T cells to recognize myeloma cells and kill it. The porotype called CAR-T cells. International Myeloma Foundation 13
Checkpoint Inhibitors The old: Lenalidomide enhances checkpoint blockade and induces the destruction of myeloma cells by cytotoxic lymphocytes. The new: Anti PDL-1 and anti PD-1. First in class is the drug Pembrolizumab. Not approved yet in myeloma abut many clinical trials are ongoing and some has shown great efficacy with other drugs such as Lenalidomide. International Myeloma Foundation 14
CAR –T Immune Therapy International Myeloma Foundation 15
Chimeric antigen receptors (CARs) help T-cells recognize and destroy cancer cells T cells are white blood cells that attack and kill viruses and cancer cells Chimeric antigen receptors (CARs) help T-cells recognize and destroy cancer cells 1. T cells are collected from the patient. A machine removes the desired cells from the blood, then returns the rest back to the patient . International Myeloma Foundation 16
CAR-BCMA T Cells in Myeloma: Background • T cells can be genetically modified to express chimeric antigen receptors (CARs) specific for T Cell malignancy-associated antigens AntiBCMA • B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma T Cell T Cell cells. AntiBCMA AntiBCMA T Cell – BCMA is a potential target for CAR T-cell AntiBCMA therapy for MM • The patient’s own T-cells were stimulated, transduced with CAR-BCMA retroviruses, and cultured for 9 days before infusion. • Study presented ASH 2015 evaluated CAR- BCMA T cell infusion for treatment of advanced MM International Myeloma Foundation 17 1. Carpenter RO, et al. Clin Cancer Res. 2013;19:2048-2060. Ali SA, et al. ASH 2015. Abstract LBA-1.
CAR-BCMA T Cells in Myeloma: Study Design • First-in-human phase I trial Pts with advanced Cyclophosphamide 300 mg/m 2 relapsed/ refractory CAR-BCMA T cells* Fludarabine 30 mg/m 2 MM Single infusion QD for 3 days More than 3 prior lines of therapy; *Dose escalation of BCMA expression CAR+ T cells/kg on myeloma cells 0.3 x 10 6 12 patients enrolled 1.0 x 10 6 3.0 x 10 6 9.0 x 10 6 Ali SA, et al. ASH 2015. Abstract LBA-1 . International Myeloma Foundation 18
CAR-BCMA T Cells in Myeloma: Response to therapy Response to Therapy Number of Patients (total 12 treated) Stringent complete 1 response(sCR ) Very good partial response 1 VGPR Partial response 2 Stable disease 8 Ali SA et al. Proc ASH 2015; Abstract LBA1. International Myeloma Foundation 19
Conclusions: • Immunotherapy has come a long way. • Treatment with monoclonal antibodies has resulted in remarkable results. • Checkipoint inhibitors are showing great promise and may lead to the eradication of residual myeloma. • Engineered T cells are very promising. International Myeloma Foundation 20
Cellular Immunotherapy Against CD19 for Myeloma September 22, 2016 Edward A. Stadtmauer, MD Chief, Hematologic Malignancies Section Professor of Medicine Abramson Cancer Center University of Pennsylvania Philadelphia, Pa International Myeloma Foundation 21
Rationale for Cellular Immunotherapy in Myeloma “Novel agents” (-imid’s, proteasome inhibitors) 1. Novel agents and autoSCT extend survival but progression is common ASCT 2. T and NK cells from myeloma patients can kill autologous myeloma cells ex vivo 3. Allogeneic SCT may “cure” myeloma by a T-cell mediated graft vs tumor effect • high morbidity and mortality • usually associated with GVHD 4. Perhaps if we could engineer our own immune cells to specifically attack myeloma we would get the good graft vs myeloma effect without the GVHD. Barlogie et al. J Clin Oncol 2006; Kroger N, Blood 2004; Crawley, Blood 2005; International Myeloma Foundation Spisek R et al. J Exp Med. 2007; Noonan K et al, Cancer Res 2005; Krishnan A et al Lancet Oncology 2013 ) 22
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