immunotherapy for multiple myeloma

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Update on immunologic approaches: monoclonal antibodies - MAGE, CAR-T and allogeneic transplant
Nina Shah, MD

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  • Mayo data
  • Alimitation of this study was that MAGE-A3 expression in
    the myeloma cells was not required for study entry, thus
    reducing our ability to evaluate the clinical impact of
    vaccine-specific T- and B-cell responses
  • 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. Overview of findings • EBMT retrospective analysis of MA conditioning allo SCT versus auto SCT showed better OS in auto groups (34 vs 18 months) but lower relapse rate in allo group (50% vs 70% at 4 years). Results likely due to increased TRM1 • EBMT analysis shows decreased NRM from 46% to 30% from 1983-1993 vs 1994-1998 2 1. Bjorkstrand, Blood 1996 2. Gharton, Br J Hematol, 2001
    11. 11. Myeloablative (MA) vs reduced intensity conditioning (RIC) • MA allo SCT associated with 50% TRM but some long term survivors (30-40%) • Outcomes may be improved with better modern supportive care measures • RIC: mel 100-140 +/- flu or bu or TBI – 11-22% NRM – 21% severe GVH – 50% CR1 • RIC may improved NRM but possibly at expense of efficacy2 • Idea is to allow immunosuppression to facilitate engraftment and GVM effect 1. Kroger, BBMT 2004 2. Crawley, Bloodl, 2007
    12. 12. Examples of RIC allo SCT for MM 1. Binsfield, Biochim Biophys Acta, 2014
    13. 13. Trials comparing tandem auto SCT with auto-allo SCT • Biological randomization
    14. 14. When should we use allo SCT? • Probably not for refractory or aggressively relapsed disease – But a subset of patients with relapsed disease can achieve CR/ long term survival – One study showed that these patients may actually do better with MA conditioning and lenalidomide maintenance (Kroger, BMT, 2013) • Perhaps upfront in high risk disease (17p deletion, PCL) • MDACC data with allo SCT shows that patients do better if they have allo as 1st remission consolidation, standard risk cytogenetics (Bashir, Am J of Hematol 2012) • Clinical trials pending (BMT CTN 1301)
    15. 15. Vaccination strategies • MAGE • Idiotype vaccine • DC-MM fusion vaccine
    16. 16. 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
    17. 17. 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
    18. 18. Trial Design 1. Rapoport, Clin Cancer Res 2013
    19. 19. 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
    20. 20. Results 1. Rapoport, Clin Cancer Res 2013
    21. 21. 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
    22. 22. 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
    23. 23. 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
    24. 24. BMT CTN 1401
    25. 25. 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)
    26. 26. 1. Ocio, Leukemia 201
    27. 27. 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
    28. 28. CD38 • SAR650984 (humanized IgG1 monoclonal antibody)1 – ADCC, CDC, direct apoptosis without steric hindrance of CD38 enzymatic activity – Phase 1b trial with len/dexl 3, 5, 10 mg/kg – Well-tolerated – 58% ORR – Single agent activity with ORR of 24% • Daratumumab (humanized mo-antibody) 2 – So far, acceptable safety profile in combo with len/dex – Phase 1-2 study with Dara at 2-16 mg/kg recently reported – 72% ORR 1. Martin, ASCO 2014 2. Plesner, ASCO 2014
    29. 29. Chimeric Antigen Receptor (CAR) Effector Cells
    30. 30. Chimeric antigen receptor • Extracellular domain: antigen specific • Endodomain: signals cells cytotoxic functioning – CD28/CD3ζ – 41BB • T cells • NK cells hinge
    31. 31. 1. Binsfeld, Biochimica et Biophysica Acta, 2014
    32. 32. 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 1. Mihara, Leukemia, 2012 2. Chu, Leukemia, 2013 3. Jiang, Mol Oncol, 2014 4. Chu, Clin Cancer Research, 2014 5. Benjamin, AACR, 2012
    33. 33. NK cells: one paradigm for adoptive cellular therapy
    34. 34. 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
    35. 35. Frozen cord Blood unit Ficoll GP500 bioreactor MNC Culture condition: 2(γ-irradiated)APC : 1 cord TNC IL-2 100u/ml 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 + cells CD3-depleted NK cells CD3 + cells Flow cytometry on day7 & 14 CD56 CD16 CD3 CD19 CD14 CD45 Clinical NK Expansion Experimental Design Thaw Day 0
    36. 36. Shah et al, PLoS One, 2013
    37. 37. Shah et al, PLoS One, 2013
    38. 38. 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 High dose melphalan, 200 mg/m2 Low dose lenalidomide -8 -7 -5 0 CB NK cells Autologous graft patients with multiple myeloma -2 10 e6 cells/kg: no DLTs thus far
    39. 39. 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
    40. 40. Thank you! Khop khun!

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