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Immunotherapy for Multiple Myeloma

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Immunotherapy for Multiple Myeloma. Nina Shah.

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Immunotherapy for Multiple Myeloma

  1. 1. Immunotherapy for Multiple Myeloma Nina Shah M.D. Assistant Professor Department of Stem Cell Transplantation and Cellular Therapy M.D. Anderson Cancer Center
  2. 2. Objectives • Myeloma therapy: general principles • Immunotherapy: general principles • Allogeneic stem cell transplantation (SCT) • Immunotherapies in development
  3. 3. Myeloma: We’ve come a long way • Proteosome inhibitors • Immunomodulatory agents • Triple therapy • High dose chemotherapy and autologous stem cell transplantation • Maintenance
  4. 4. Changes in survival patterns 1. Pulte, Leuk & Lymph 2014
  5. 5. But most of our patients still relapse…
  6. 6. Immunotherapy • Allogeneic stem cell transplantation • Vaccine strategies • CAR T and NK cells • Monoclonal antibodies • NK cells
  7. 7. Immune system alterations in MM • BM infiltration by plasma cells • Interaction between MM cells and BM microenvironment immunosuppression • Decrease in number and functional activity of immune cells • Recruitment of immunosuppressive cells • Deficient antigen processing/ presentation • Expression of co-inhibitory molecules by tumor cells 1. De Carvalho, Cancer Immunol Immunother 2013 2. Andrade, Cancer Immun, 2008
  8. 8. 1. Binsfield, Biochim Biophys Acta, 2014
  9. 9. Allogeneic stem cell transplantation: controversies remain • Exploit the graft vs myeloma affect • DLI’s have been used1 • Chronic GVH may predict for long term disease control2,3 but this data has not been consistent • Conflicting data in randomized studies comparing tandem auto SCT vs auto- allo SCT4,5 • But true effect of allo SCT may take longer than 5 years to emerge • Myeloablative (MA) allo SCT associated with 50% TRM but some long term survivors (30-40%) 6 • Outcomes may be improved with better modern supportive care measures 1. Tricot, Blood 1996 2. Crawley, Blood 2005 3. LeBlanc, BMT 2001 4. Krishnan, Lancet Oncol 2011 5. Bruno, NEJM 2007 6. Barlogie JCO 2006
  10. 10. Vaccination strategies • MAGE • Idiotype vaccine • DC-MM fusion vaccine
  11. 11. MAGE • MAGE-C1/CT7 and MAGE-C2/CT10: genes that appear to be expressed in MM, solitary plasmacytomas and MGUS1 • Function yet unknown • MAGEC1/ CT7 gene frequently expressed in advanced MM and is associated with worse overall survival (OS) 2 • Resultant protein is immunogenic • Thus potential cancer/testis antigen (CTA) /target for immunotherapy 1. De Carvalho, Cancer Immunol Immunother 2013 2. Andrade, Cancer Immun, 2008
  12. 12. Clinical trial of MAGE-A3/Poly-ICLC immunizations Followed by Adoptive Transfer of Vaccine-Primed and Costimulated Autologous T Cells • Phase 2 trial, 27 pts undergoing auto SCT for MM • MAGE-A3 cancer-testis antigen (CTAg) vaccine • Injected with TLR-3 agonist Poly-ICLC (Hiltonol) adjuvant GM-CSF to enhance T-cell priming/ boosting • Co-injection of Prevnar vaccine • The protein also contains the HIV-1-TAT membrane translocation sequence to facilitate formation of MHC class I complexes • Lenalidomide maintenance was started at day 100 1. Rapoport, Clin Cancer Res 2013
  13. 13. Trial Design 1. Rapoport, Clin Cancer Res 2013
  14. 14. Results • T-cell infusions were well tolerated • Vaccine injection site reactions occurred in >90 pts • 2/9 pts developed sterile abscesses • MAGE-A3–specific CD8 T cells seen in 7 of 8 evaluable HLA-A2 pts (88%) • Vaccine-specific cytokine producing T cells generated in 19 of 25 patients (76%) • Antibody responses developed in 7/9 patients (78%) who received montanide and only weakly in 2/18 patients (11%) who did not • 2-year OS was 74% and 2-year EFS was 56% 1. Rapoport, Clin Cancer Res 2013
  15. 15. Results 1. Rapoport, Clin Cancer Res 2013
  16. 16. Results Limitation: MAGE-A3 expression in the myeloma cells was not required for study entry; thus reducing ability to evaluate vaccine-specific T- and B-cell responses Double positive vaccine-directed IFN-gamma responses on CD4 and CD8 T cells together was possibly associated with better EFS 1. Rapoport, Clin Cancer Res 2013
  17. 17. Idiotype Vaccine • Targets the variable Ig on surface of plasma cell • Idiotype-specific T cells at a low frequency have been detected in 90% of patients with MM or MGUS1 • Induction of CTL activity against autologous myeloma cells also shown after stimulation with idiotype-loaded DCs • Hypothesis that idiotype-specific response diminishes MM progresses • Thus far clinical trials have shown safety and some T cell responses but no definitive clinical response. 1. Yi, Blood 1995
  18. 18. Dendritic cell-based vaccines • DC’s from MM pts can present idiotype determinants to autologous T cells1 • DC-tumor cell fusions – Protection against MM in murine model2 • Vaccination with DC-fusion induces tumor immunity and may work best in post-SCT setting when minimal T regs • Most efficient strategy may be vaccination with lenalidomide on board as there may be decrease in T cell PD-1 expression and inhibition of T regs • Basis for upcoming BMT CTN 1401 trial 1. Dabadghao, Blr J Hematol 1998 2. Gong, Blood, 2002
  19. 19. BMT CTN 1401
  20. 20. Monoclonal antibody targets • CS1 – cell surface glycoprotein involved in cell-cell interactions, adhesion to BM stroma – role in MM unknown – Co-localizes with CD138 • CD38 – Involved in cell adhesion – Regulation of intracellular metabolism • CD138 • CD74 • CD40 • CD162 • B2 microglobulin • KIR (IPH 2101) • 41BB
  21. 21. 1. Ocio, Leukemia 2014
  22. 22. Elotuzumab • Humanized monoclonal antibody against CS1 • Phase 1b/2 trial with bortezomib: ORR of 48% and PFS 9.5 months • Randomized phase 2, open label study in patients with previously treated MM • 2 doses evaluated: 10 mg/kg (n=36) and 20 mg/kg (n= 37) in combination with lenalidomide and low dose dexamethasone. • 10 mg/kg: PFS of 33 months, ORR of 92% • 20 mg/kg: PFS of 18 months, ORR of 76% • 10 mg/kg is being evaluated in the phase 3 studies – ELOQUENT 1 (newly diagnosed MM patients) – ELOQUENT 2 (relapsed MM patients) 1. Jakubowiak et al, in progress 2. Lonial, EHA June 2013
  23. 23. Relapsed/refractory myeloma • Lonial et al, NEJM August 2015 • ELOQUENT-2: A phase III, randomized study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) • PFS: ELd 19.4 (16.6, 22.2) months, Ld 14.9 (12.1, 17.2) months (HR [95% CI] 0.70 [0.57, 0.85]; p = 0.0004 • ORR (95% CI) was 79% (74, 83) ELd, 66% (60, 71) Ld (p = 0.0002)
  24. 24. CD38 • Cell adhesion molecule • Regulates calcium flux and signal transduction • On MM cells but also low level on CD4, CDD8, sometimes BCs, NK cells • But overall a good tumoe-specific candidate
  25. 25. CD38 • SAR650984 (humanized IgG1 monoclonal antibody)1 • Daratumumab (humanized mo-antibody) 2 • ADCC, CDC, direct apoptosis without steric hindrance of CD38 enzymatic activity 1. Martin, ASH 2014 2. Plesner, ASCO 2014
  26. 26. • Phase Ib dose escalation trial (Martin et al, ASH 2014) • SAR + len/dex • N= 31, relapsed/ refractory MM • No DLTs • ORR 64.5% • CBR 71% • PFS 7.2 months • Single agent activity with ORR of 24% SAR 658094 Anti-CD38 MoAb
  27. 27. SAR 658094 Anti-CD38 MoAb • SAR decreases MM cell adhesion to BM accessory cells via blockage of CD31-CD38 interaction (An et al, ASH 2014) • KIR3DL1, HLA-B Bw4-80Ile genotype predictive of correlated with increased ORR and PFS among patients treated with SAR/LEN/Dex (Marra, ASH, 2014)
  28. 28. Daratumumab • Combination with: – VD or VTD (Newly dx) – VMP (newly Dx and transplant inelligible) – Pom/dex (relapsed/refractory) • Well-tolerated • Survival and response data pending (Lockhost, ASH 2014) • Given with len/dex in R/R MM: – ORR = 75% (Plesner ASH 2014)
  29. 29. KIR • Inhibitory receptor on NK cells • Blocking this receptor is though to “activate” autologous NK cells • IPH2101 (Lirilumab)
  30. 30. IPH21011 • Phase I study • N=32 • 7 dose levels • Ex vivo enhancement of NK activity against MM • 1 SAE (AKI) • No responses 1. Benson, Blood, 2102
  31. 31. Chimeric Antigen Receptor (CAR) Effector Cells
  32. 32. Chimeric antigen receptor • Extracellular domain: antigen specific • Endodomain: signals cells cytotoxic functioning – CD28/CD3ζ – 41BB • T cells • NK cells hinge
  33. 33. 1. Binsfeld, Biochimica et Biophysica Acta, 2014
  34. 34. Pre-Clinical data with CAR therapy for MM • In vitro activity of CAR cells – CD38-specific CAR T cells1 • In vivo activity of CAR-NK cells in murine models – CS1-specific CAR-NK2 – CD138-specific CAR-NK3 • In vivo activity of CAR-T cells in murine models – CS1-specific CAR-T cells4 – CD56-specific CAR-T cells5 – NKG2D-expressing CAR-T cells6 – NY-ESO-1-specific TCR- transduced T cells7 1. Mihara, Leukemia, 2012 2. Chu, Leukemia, 2013 3. Jiang, Mol Oncol, 2014 4. Chu, Clin Cancer Research, 2014 5. Benjamin, AACR, 2012 6. Barber, Genee Ther, 2011 7. Mastaglio, ASH 2014
  35. 35. CD138-targetting CAR NK Cells1 • CAR-scFv (4B3)-CD3ζ • NK-92 cell line transduced 1. Jiang, Molec Oncology, 2014
  36. 36. CD38-specifc CAR T cells 1. Mihara, Leukemia, 2012
  37. 37. CS1-specific CAR T cells1 • CS1-scFv-CD28-CD3ζ • Retroviral vector 1. Chu, CCR, 2014
  38. 38. CS1-specific CAR-NK cells1 • CS1-scFv-CD28-CD3ζ • NK-92 cell line 1. Chu, Leukemia, 2014
  39. 39. CS1-specific CAR-NK cells1 1. Chu, Leukemia, 2014
  40. 40. Clinical trial of CD19 CAR-T cells • Garfall et al, ASCO 2015 • Relapsed MM pts • 1-5x107CTL019 cells infused 12-14 days after high-dose melphalan + ASCT • N=4 • hypogammaglobulinemia (4/4) and grade 1 cytokine release syndrome (1/4) • Cells detectable in the 3 evaluable pts • 2 CRs, 1 progression
  41. 41. NK cells: one paradigm for adoptive cellular therapy
  42. 42. Why don’t autologous NK cells work? • Altered balance of inhibitory and activating receptors on autologous NK cells1 • Altered ligands on tumor cells - requiring more active NK cells than at baseline2 • Change in distribution of NK cell subpopulations (LN, PB) 3 • Direct immunosuppression by tumor cell –produced soluble factors (cytokines, ligands) 1, 4 • NK cells from MM patients express PD-15 • Increased Class I on MM cells in advanced disease6 1. Lion, Leukemia, 2012 2. Veuillen, JCI, 2012 3. Gibson, Hum Pathol, 2011 4. Reiners, Blood, 2013 5. Benson, Blood, 2010 6. Carbone, Blood, 2005
  43. 43. Frozen cord Blood unit Ficoll MNC Culture condition: 2(γ-irradiated)APC : 1 cord TNC IL-2 100u/ml GP500 bioreactor Day 7 CD3 depletion (CliniMACS) CD3-depleted NK cells Culture condition: 2(γ-irradiated)APC : 1 CD3 - cell IL-2 100u/ml For another 7 days Day 14 CD3 depletion (CliniMACS) CD3-depleted NK cells CD3 + cells CD3 + cells Flow cytometry on day7 & 14 CD56 CD16 CD3 CD19 CD14 CD45 Clinical NK Expansion Experimental Design Thaw Day 0
  44. 44. Shah et al, PLoS One, 2013
  45. 45. Shah et al, PLoS One, 2013
  46. 46. -8 -7 -5 0 Low dose lenalidomide High dose melphalan, 200 mg/m2 CB NK cells Autologous graft Protocol 2011-0379: Phase I/II study of umbilical cord blood- derived natural killer cells in conjunction with high dose chemotherapy and autologous stem cell transplant for patients with multiple myeloma -2 1 x 108 cells/kg: no infusion reactions or GVH thus far
  47. 47. Conclusions • Though the timeline for patients with myeloma has changed a definitive cure is still needed • Myeloma is a malignancy of immune dysregulation and likely immune exhaustion • Therefore immunotherapies likely have an important role in the treatment paradigm • Fine tuning of antibody, cellular and vaccine therapy will eventually lead us to the ideal partners for the recently developed novel therapies
  48. 48. Thank you! Khop khun!

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