Cellular Therapy for Multiple MyelomaNina Shah M.D.

Assistant ProfessorDepartment of Stem Cell Transplantation

and Cellular TherapyM.D. Anderson Cancer Center

Objectives

• Myeloma therapy: general principles• Immunotherapy: general principles• Allogeneic stem cell transplantation (SCT)• Cellular therapies in development

Myeloma: We’ve come a long way

• Proteosome inhibitors• Immunomodulatory agents• Triple therapy• High dose chemotherapy and autologous stem

cell transplantation• Maintenance

Changes in survival patterns

1. Pulte, Leuk & Lymph 2014

But most of our patients still relapse…

Immunotherapy

• Allogeneic stem cell transplantation• Vaccine strategies• CAR T and NK cells• Monoclonal antibodies• NK cells

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

1. Binsfield, Biochim Biophys Acta, 2014

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

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

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

Examples of RIC allo SCT for MM

1. Binsfield, Biochim Biophys Acta, 2014

Trials comparing tandem auto SCT with auto-allo SCT

• Biological randomization

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)

Vaccination strategies

• MAGE• Idiotype vaccine• DC-MM fusion vaccine

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

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

Trial Design

1. Rapoport, Clin Cancer Res 2013

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

Results

1. Rapoport, Clin Cancer Res 2013

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

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

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

BMT CTN 1401

Chimeric Antigen Receptor (CAR) Effector Cells

Chimeric antigen receptor

• Extracellular domain: antigen specific• Endodomain: signals cells cytotoxic

functioning – CD28/CD3ζ– 41BB

• T cells• NK cells

hinge

1. Binsfeld, Biochimica et Biophysica Acta, 2014

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

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

NK cells: one paradigm for adoptive cellular therapy

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

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

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

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

Shah et al, PLoS One, 2013

Shah et al, PLoS One, 2013

-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

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

Thank you!Khop khun!