Immunotherapy for Myeloma: with highlights from ASH 2015
Adam D. Cohen, MD Assistant Professor Division of Hematology/Oncology Abramson Cancer Center University of Pennsylvania
January 22, 2016 Outline
Monoclonal antibodies Vaccines Cellular therapies PD-1/PD-L1 inhibition in myeloma
T and NK cells from MM patients have functional defects • increased PD-1 expression c/w healthy donors PD-L1 expressed on MM cells (maybe) Blockade of PD-1/PD-L1 axis: • induces tumor immunity in MM murine models • enhances MM patient T and NK cell responses ex vivo
Single agent Nivolumab (anti-PD-1) • No objective responses (n=27) in R/R MM • SD in 67%
Lesokhin et al, ASH 2014, #291 Phase 2 study of Pembrolizumab/pom/dex for rel./ref. MM
After 24 mos Pts with R/R MM Pembrolizumab 200 mg IV D1,14* responding pts can with ≥ 2 prior Pomalidomide 4 mg PO D1-21 continue therapies † Dexamethasone 40 mg PO D1,7,14,21 pomalidomide/ including 28-day cycles until PD dexamethasone PI and IMiD until PD (n = 33) *First 6 pts treated on D1 only. †20 mg for pts older than 70 yrs of age.
Median 3 priors, 70% double-refractory (?pom exposure) Tox: cytopenias, dyspnea, hyperglycemia • 15% gr 3-4 pneumonia, 1 infectious death • Autoimmune: pneumonitis (10%), hypothyroid, hepatitis (<5%) Responses (n=27) • ORR 59% (1 sCR, 4 VGPR, 11 PR) – 55% in double-refractory Median PFS, OS not reached at 7.4 mos. IHC for PD-L1 expression variable, hard to standardize
Badros AZ, et al. ASH 2015, #506 Phase I Pembrolizumab/Len/dex in rel./ref. MM
R/R MM pts Dose with ≥ 2 prior Fixed Dose Dose Determination treatments Confirmation Expansion 3 + 3 including a (n = 8) (n = 33) (n = 9) PI and IMiD (N = 50) Final MTD: Pembrolizumab 200 mg IV Q2W Lenalidomide 25 mg Dexamethasone 40 mg
Median 4 priors, 76% Len-refractory, 64% Bort- refractory Tox: 6 irAE’s (thyroid, adrenal) • No pneumonitis Responses (n=17) • ORR 76% (4 VGPR, 9 PR) – Med DOR: 9.7 mos • 56% in Len-refractory (n=9)
San Miguel et al. ASH 2015, #505 PD-1/PD-L1 antibody trials in myeloma
Nivolumab (anti-PD1) • + ipilumumab or lirilumab (anti-KIR) in rel/ref MM and NHL (Ph 1) Pembrolizumab (anti-PD1) • as consolidation after autoSCT (ph 2) • as consolidation for VGPR pts. post-treatment (ph 2) • + pom/dex vs. pom/dex in R/R MM (ph 3) • + len/dex vs. len/dex in newly-diagnosed MM (ph 3) Pidilizumab (CT-011, anti-PD1) • + len in R/R MM (ph 1/2) • + DC-MM fusion vaccine post-autoSCT (ph 1/2) Atezolizumab (MPDL3280A, anti-PDL1) • + len in R/R MM and post-autoSCT (ph 1)
Durvalumab (MEDI4736, anti-PDL1) • alone, +pom, or +pom/dex in R/R MM (ph 1b) Daratumumab may have immunomodulatory activity Increased T cell counts on tx n=148 R/R MM, on dara 16 mg/kg Serial samples from PB and BM for T cell phenotype, cytokine production, Treg activity
T cell counts increased over time Subsets of Tregs, Bregs, MDSC’s express CD38 • Depleted by Dara Increased CD8:CD4 and CD8:Treg ratios Increased TCR clonality • Correlated with CD8 increase and response
Krejcik et al. ASH 2015, #3037 2. Elotuzumab mechanisms Tumor cell lysis by ADCC Degranulation Activation of (Cytotoxicity) NK cell
1.
CD16 (FcγRIII)
NK cell Fc
- SLAMF7 MM cell
- Elotuzumab (Elo)
Hypothesis: Elotuzumab promotes killing of multiple myeloma cells through two mechanisms 1. NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC)
2. Direct NK cell activation (Collins/Benson Cancer Immunol Immunother, 2013) NK cell phenotype and ex vivo response to elotuzumab
40
PBL+MM1R
PBL+MM1R +Elo XY Data: Correlation of Corr SLAMF7 CD16 LAMP1_RR
30 30 r = 0.63
p = 0.0068
NK cells NK
NK cells NK
o
l
E
dim +
dim 20
20 R
1
CD107a
M
M +
L 10 B CD56 10 P
% CD56 CD107a+ % 0 0 20000 40000 60000 80000 100000
0 CD56 %CD107a+ dim HD ND R/R CD16CD1 MFI6 MCD56FI CD56lo w NK cells
HD ND RR
XY Data: Correlation of Corr SLAMF7 CD16 LAMXYP1 _DRaRta : Correlation of Corr SLAMF7 CD16 LAMP1_RR r = 0.42 100000 r = 0.75 30 p = 0.09
NK cells NK p = 0.0003
w o
o 80000
l
l
NK cells NK
6
dim
E
5
+ 20 D
60000 R
dim
C
1
I
F M
M 40000
M
6
+ 1
L 10 D
20000 B
C P
0
CD16 MFI MFI CD56 CD16 0 20000 40000 60000 0 SLAMF7SLAMF 7MFI exp CD56ressiodimn C DNK56 locellsw 0 20000 40000 60000 %CD107a+ CD56 %CD107a+ SLAMF7SLAMF7 MFIexpr eCD56ssion dimCD 5 NK6low cells
UPCC 16414: Elotuzumab + urelumab (anti-CD137) or lirilumab (anti-KIR) for R/R or post-SCT MM
Pazina et al. ASH 2015, #3024 Myeloma vaccines
DC/MM fusion vaccine + anti-PD1 post-ASCT (Rosenblatt et al, #4218) • Vax + pidilizumab q6wks x 3 (starting d+60-90) (n=22) • ⬆ MM-reactive CD8+ (1.8%9%), ⬇Tregs • Gr 1-2 arthralgias, LFT, cytopenias • 3 response conversions to CR
• RP2 of DC/MM vax + len vs. len post-ASCT (BMT-CTN 1401)
Others • recMAGE-A3 protein s/p autoSCT • PVX-410 peptide vaccine for SMM • GVAX + Len as maintenance • Idiotype vax s/p autoSCT • Patient-specific, mutation-derived neo-antigens Avigan et al, Semin Oncol 2012
Cohen et al, ASH 2014, #1184; Nooka et al, ASH 2015, #4246; Borrello et al, ASH 2015, #4238; Perumal et al, ASH 2015, #1851. Chimeric antigen receptors - background Combines recognition domain of antibody with signaling domain of T cell Uses gene transfer (eg. lentiviral vector) to stably express CAR on T cells confers novel antigen specificity Addition of co-stimulatory domains (CD28, 4-1BB/CD137) augments proliferation and survival CART19 cells active in B-ALL, CLL, and NHL
Garfall et al, Discovery Med 2014 CART19 s/p salvage autoSCT in MM
CD19 expressed on minor subset of MM plasma cells, but potentially on MM stem cell Hypothesis: Targeting CD19+ fraction post-high-dose melphalan may delay or prevent relapse
Garfall et al, NEJM 2015 BCMA (B-cell maturation antigen)
On normal and malignant plasma cells Promotes MM cell proliferation, survival, drug resistance
Anti-BCMA-MMAF antibody- drug conjugate (GSK2857916) In vitro and in vivo activity against MM Phase I trial open late 2014 BCMA-CAR • Transduced MM pt. T cells • Active in vitro and in vivo
1Novak et al, Blood 2004; 2Moreaux et al, Blood 2004; 3Bellucci et al, Blood 2005; 4Tai et al, Blood 2014; 5Carpenter et al, Clin Can Res 2013; BCMA-specific CAR in rel/ref MM
first in human, dose-escalation n=12 R/R MM pts, ≥ 3 prior lines Screen for BCMA expression by IHC or flow
*Dose escalation of Cyclophosphamide 300 mg/m2 CAR+ T cells/kg CAR-BCMA T cells* 0.3 x 106 Fludarabine 30 mg/m2 Single infusion 1.0 x 106 QD for 3 days 3.0 x 106 9.0 x 106
Ali et al, ASH 2015, LBA #1 BCMA-specific CAR in rel/ref MM
Pt Myeloma CAR-BCMA Dose Response Response Duration, Type (T cells/kg) Wks 1 κ light chain only 0.3 x 106 PR 2 2 IgA λ 0.3 x 106 SD 6 3 κ light chain only 0.3 x 106 SD 6 4 κ light chain only 1.0 x 106 SD 12 5 IgG κ 1.0 x 106 SD 4 6 IgG λ 1.0 x 106 SD 2 7 IgG λ 3.0 x 106 SD 7 8 κ light chain only 3.0 x 106 VGPR 8 9 κ light chain only 3.0 x 106 SD 16 10 IgA λ 9.0 x 106 sCR 12+ 11 IgG λ 9.0 x 106 PR 6+ 12 IgA λ 3.0 x 106 SD 2
Ali et al, ASH 2015, LBA #1 BCMA-specific CAR in rel/ref MM At 3 lower dose levels: mild fevers, cytopenias, 1 CRS (VGPR)
At highest dose level: • Pt 10: relapsed 3 mos. post-auto, 90% MM cells pre-tx ongoing sCR at 14 weeks – Severe CRS, prolonged pancytopenia – Myositis/elevated CPK, AKI • Pt 11: 5 priors, 80% MM cells pre-tx ongoing PR at 6 weeks, BM neg. – Severe CRS, delirium, coagulopathy
Responses associated with CAR-T expansion, CRS, and IL-6 levels
soluble BCMA levels decreased in responding patients
Ali et al, ASH 2015, LBA #1 UPCC 14415 study design/schema
Pilot, first-in-human, 3+3 dose-escalation study 2nd generation, CD3/41BB-based CAR n=12-18 rel/ref MM patients, ≥3 prior therapies
PI: A. Cohen
UPCC 14415 study design/schema
BCMA lentiCAR T cell manufacture/cryopreserve
60% Clinical/lab assessments: Screening, pre-
tx***, D0, +1, 2, 4, 7, 10, 14, 21, 28**
30% MM assessments: Screening, pre-tx***, D+14, * 10% 28**
BM aspirate/bx: Pre-tx***, D+28, 90
Screening Screening eligibility /
Leukopheresis
T cell cell T
CAR Infusion (Cytoxan) F/u q4wks** Wk -4 D -3 D0 D1 D2 D28 * Patients may receive therapy during manufacturing to maintain disease control ** After first 28 days, follow-up is q4 wks up to 6 mos., then q3 mos. up to 2 years *** Pre-tx = pre-treatment, 3 to 7 days before CAR T cell infusion Multiple other CARs, TCR Tg, BiTEs for MM
BCMA-CAR • Chekmasova et al, ASH 2015, #3094 SLAMF7-CAR • Chu et al, Clin Can Res 2014 • Danhof, ASH 2015, #115; Galetto, ASH 2015, #116 NY-ESO1 TCR Transgenic • Rapoport, Stadtmauer et al, Nature Med 2015
BCMA BiTE • Hipp, ASH 2015, #2999 CD38 BiTE • Moore, ASH 2015, #1798
Trials set to open in 2016 Take home points
PD-1 blockade + IMiD/dex active in rel/ref MM • role of steroids? • Risk of irAEs (eg pneumonitis)? • Blocking PD-1 vs. PD-L1?
Tumor-targeted Abs (Dara, Elo) may have immune-modulatory activity
Several vaccines in early development • BMT-CTN randomized DC/MM fusion vax post-SCT trial to open
BCMA validated as CAR target in MM • Proof of principle responses in chemo-refractory patients • Significant toxicity at higher doses
Multiple novel immunotherapy trials to open in 2016 • Vaccines, CARs, mAbs, BiTEs Extra slides
Rationale for immunotherapy 1. Novel agents and SWOG S9321 autoSCT extend survival but are not curative 2. T and NK cells from myeloma patients can kill autologous myeloma cells ex vivo 3. DLI (donor lymphocyte infusion) demonstrates graft-versus-myeloma (GVM) effect • usually associated with GVHD 4. Allogeneic SCT may “cure” myeloma • high mortality with full myeloablation
Barlogie et al. J Clin Oncol 2006; Kroger N, Blood 2004; Crawley, Blood 2005; Spisek R et al. J Exp Med. 2007; Noonan K et al, Cancer Res 2005
Designing a Myeloma CAR: candidate targets
The classics: The new models: • CD138 • Lewis Y • CD38 • CD44v6 • CD56 • CS1/SLAMF7 • kappa light chain • BCMA
BCMA (B-cell maturation antigen)
TNFRSF17, CD269 Receptor for BAFF (Blys) and APRIL Expressed on mature B cell subsets, PC’s, and plasmacytoid DC’s Maintains plasma cell homeostasis • BCMA-/- mice have normal B cell #s, impaired PC survival BAFF-APRIL system implicated in autoimmunity
Rickert et al, Immunol Rev 2011; Maus, June, Clin Can Res 2013 Types of tumor immunotherapy
Antibodies Vaccines Cellular Immune cell-targeting tumor cell/lysate • alloSCT/DLI • Antagonists: protein • Autologous cells – CTLA-4, PD-1, peptide PD-L1, KIR, Tim- DNA • PBL 3, LAG-3 • TIL (MIL) • Agonists: viral • T cell lines – CD137/4-1BB, ganglioside OX40, GITR, dendritic cell • NK cells CD40 • Gene-modified T cells Tumor-targeting • Transgenic TCR • Naked • Chimeric antigen • Antibody-drug receptors (CAR) conjugates BiTEs / BiKE’s
Other Cytokines TLR agonists Adjuvants Chemotherapy Radiation Biologics