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. Objectives
• Myeloma therapy: general principles
• Immunotherapy: general principles
• Allogeneic stem cell transplantation (SCT)
• Immunotherapies in development
3. Myeloma: We’ve come a long way
• Proteosome inhibitors
• Immunomodulatory agents
• Triple therapy
• High dose chemotherapy and autologous stem
cell transplantation
• Maintenance
6. Immunotherapy
• Allogeneic stem cell transplantation
• Vaccine strategies
• CAR T and NK cells
• Monoclonal antibodies
• NK cells
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
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
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. 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
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
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. 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. 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
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. 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. 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
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. 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. 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. KIR
• Inhibitory receptor on NK cells
• Blocking this receptor is though to “activate”
autologous NK cells
• IPH2101 (Lirilumab)
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
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. CD138-targetting CAR NK Cells1
• CAR-scFv (4B3)-CD3ζ
• NK-92 cell line transduced
1. Jiang, Molec Oncology, 2014
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. NK cells: one paradigm for
adoptive cellular therapy
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. 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
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. 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
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
