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

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

4. Changes in survival patterns
1. Pulte, Leuk & Lymph 2014

5. But most of our patients still
relapse…

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

8. 1. Binsfield, Biochim Biophys Acta, 2014

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. 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. 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. Examples of RIC allo SCT for MM
1. Binsfield, Biochim Biophys Acta, 2014

13. Trials comparing tandem auto SCT
with auto-allo SCT
• Biological randomization

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. Vaccination strategies
• MAGE
• Idiotype vaccine
• DC-MM fusion vaccine

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. 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. Trial Design
1. Rapoport, Clin Cancer Res 2013

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. Results
1. Rapoport, Clin Cancer Res 2013

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. 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. 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. BMT CTN 1401

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. 1. Ocio, Leukemia 201

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. 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. Chimeric Antigen Receptor (CAR)
Effector Cells

30. Chimeric antigen receptor
• Extracellular domain: antigen specific
• Endodomain: signals cells cytotoxic
functioning
– CD28/CD3ζ
– 41BB
• T cells
• NK cells
hinge

31. 1. Binsfeld, Biochimica et Biophysica Acta, 2014

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. NK cells: one paradigm for
adoptive cellular therapy

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. 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. Shah et al, PLoS One, 2013

37. Shah et al, PLoS One, 2013

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. 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. Thank you!
Khop khun!