Immunotherapy 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)• Immunotherapies 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

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

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)• 41BB

1. Ocio, Leukemia 2014

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 progress2. Lonial, EHA June 2013

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)

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

CD38

• SAR650984 (humanized IgG1 monoclonal antibody)1

• Daratumumab (humanized mo-antibody) 2

• ADCC, CDC, direct apoptosis without steric hindrance of CD38 enzymatic activity

1. Martin, ASH 20142. Plesner, ASCO 2014

• 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

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)

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)

KIR

• Inhibitory receptor on NK cells• Blocking this receptor is though to “activate”

autologous NK cells• IPH2101 (Lirilumab)

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

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

CD138-targetting CAR NK Cells1

• CAR-scFv (4B3)-CD3ζ• NK-92 cell line transduced

1. Jiang, Molec Oncology, 2014

CD38-specifc CAR T cells

1. Mihara, Leukemia, 2012

CS1-specific CAR T cells1

• CS1-scFv-CD28-CD3ζ • Retroviral vector

1. Chu, CCR, 2014

CS1-specific CAR-NK cells1

• CS1-scFv-CD28-CD3ζ• NK-92 cell line

1. Chu, Leukemia, 2014

CS1-specific CAR-NK cells1

1. Chu, Leukemia, 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

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

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!