cellular therapy for multiple myeloma
TRANSCRIPT
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Cellular Therapy for Multiple MyelomaNina Shah M.D.
Assistant ProfessorDepartment of Stem Cell Transplantation
and Cellular TherapyM.D. Anderson Cancer Center
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Objectives
• Myeloma therapy: general principles• Immunotherapy: general principles• Allogeneic stem cell transplantation (SCT)• Cellular therapies in development
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Myeloma: We’ve come a long way
• Proteosome inhibitors• Immunomodulatory agents• Triple therapy• High dose chemotherapy and autologous stem
cell transplantation• Maintenance
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Changes in survival patterns
1. Pulte, Leuk & Lymph 2014
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But most of our patients still relapse…
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Immunotherapy
• Allogeneic stem cell transplantation• Vaccine strategies• CAR T and NK cells• Monoclonal antibodies• NK cells
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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 20132. Andrade, Cancer Immun, 2008
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1. Binsfield, Biochim Biophys Acta, 2014
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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 20053. LeBlanc, BMT 20014. Krishnan, Lancet Oncol 20115. Bruno, NEJM 20076. Barlogie JCO 2006
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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 19962. Gharton, Br J Hematol, 2001
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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 effect1. Kroger, BBMT 20042. Crawley, Bloodl, 2007
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Examples of RIC allo SCT for MM
1. Binsfield, Biochim Biophys Acta, 2014
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Trials comparing tandem auto SCT with auto-allo SCT
• Biological randomization
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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)
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Vaccination strategies
• MAGE• Idiotype vaccine• DC-MM fusion vaccine
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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 20132. Andrade, Cancer Immun, 2008
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Clinical trial of MAGE-A3/Poly-ICLC immunizationsFollowed 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
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Trial Design
1. Rapoport, Clin Cancer Res 2013
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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
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Results
1. Rapoport, Clin Cancer Res 2013
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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
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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
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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 trial1. Dabadghao, Blr J Hematol 19982. Gong, Blood, 2002
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BMT CTN 1401
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Chimeric Antigen Receptor (CAR) Effector Cells
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Chimeric antigen receptor
• Extracellular domain: antigen specific• Endodomain: signals cells cytotoxic
functioning – CD28/CD3ζ– 41BB
• T cells• NK cells
hinge
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1. Binsfeld, Biochimica et Biophysica Acta, 2014
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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 cells71. Mihara, Leukemia, 20122. Chu, Leukemia, 20133. Jiang, Mol Oncol, 20144. Chu, Clin Cancer Research, 20145. Benjamin, AACR, 20126. Barber, Genee Ther, 20117. Mastaglio, ASH 2014
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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
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NK cells: one paradigm for adoptive cellular therapy
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NK Cells for Multiple Myeloma
• MM cell lines and primary cells appear susceptible to NK cytotoxicity1
• Infusion of activated NK cells prolongs survival in a murine model of MM2
• Expanded NK cells kill MM in murine MM model3
1. Frohn et al, Br J of Haematology, 2002
2. Alilci et al, Expt Hematology, 2007
3. Garg et al, Haematologica, 2012
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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, 20122. Veuillen, JCI, 2012 3. Gibson, Hum Pathol, 20114. Reiners, Blood, 20135. Benson, Blood, 20106. Carbone, Blood, 2005
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Peripheral Blood NK cells for MM• Phase 2 study of autologous or haplo-identical NK cells1
• Relapsed/ refractory MM (n=8)• NK cells expanded with feeder cells• Preparative regimen:
– Bortezomib– Bortezomib +Flu/Cy/Dex– IL-2
• Cells detectable 7 days out• 1 PR• No SAEs
1. Szmania, J Immunotherapy, 2015
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Frozen cordBlood unit
Ficoll
MNC
Culture condition: 2(γ-irradiated)APC : 1 cord TNC
IL-2 100u/ml
GP500 bioreactor
Day 7CD3 depletion (CliniMACS)
CD3-depleted NK cells
Culture condition: 2(γ-irradiated)APC : 1 CD3 - cell
IL-2 100u/mlFor another 7 days
Day 14CD3 depletion (CliniMACS)
CD3-depleted NK cells
CD3 + cells
CD3 + cells
Flow cytometry on day7 & 14
CD56CD16CD3
CD19 CD14 CD45
Clinical NK Expansion Experimental Design
Thaw
Day 0
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Shah et al, PLoS One, 2013
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Shah et al, PLoS One, 2013
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-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
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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
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Thank you!Khop khun!