Immunotherapy for Myeloma: with highlights from ASH 2015

Transcription

1 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

2 Outline Monoclonal antibodies Vaccines Cellular therapies

3 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

4 Phase 2 study of Pembrolizumab/pom/dex for rel./ref. MM Pts with R/R MM with 2 prior therapies including PI and IMiD (n = 33) Pembrolizumab 200 mg IV D1,14* Pomalidomide 4 mg PO D1-21 Dexamethasone 40 mg PO D1,7,14,21 28-day cycles until PD After 24 mos responding pts can continue pomalidomide/ dexamethasone until PD *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

5 Phase I Pembrolizumab/Len/dex in rel./ref. MM R/R MM pts with 2 prior treatments including a PI and IMiD Dose Determination (n = 9) Fixed Dose Confirmation (n = 8) (N = 50) Final MTD: Pembrolizumab 200 mg IV Q2W Lenalidomide 25 mg Dexamethasone 40 mg Dose Expansion (n = 33) Median 4 priors, 76% Len-refractory, 64% Bortrefractory 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

6 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)

7 Daratumumab may have immunomodulatory activity n=148 R/R MM, on dara 16 mg/kg Serial samples from PB and BM for T cell phenotype, cytokine production, Treg activity Increased T cell counts on tx 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

8 Elotuzumab mechanisms Activation of NK cell CD16 (FcγRIII) Degranulation (Cytotoxicity) Tumor cell lysis by ADCC 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)

9 CD16 MFI CD56low CD16 MFI CD56 dim NK cells %CD107a+ PBL+MM1R+Elo CD56 dim NK cells CD107a % CD107a+ CD56 dim NK cells PBL+MM1R+Elo %CD107a+ CD56 dim NK cells NK cell phenotype and ex vivo response to elotuzumab 40 PBL+MM1R PBL+MM1R +Elo 30 XY Data: Correlation of Corr SLAMF7 CD16 LAMP1_RR 30 r = 0.63 p = CD HD ND R/R HD ND RR CD16 CD16 MFI MFI CD56 CD56low dim NK cells XY Data: Correlation of Corr SLAMF7 CD16 LAMP1_RR XY Data: Correlation of Corr SLAMF7 CD16 LAMP1_RR r = r = 0.42 p = p = SLAMF7 MFI expression CD56 dim CD56low NK cells SLAMF7 MFI expression CD56 dim CD56low NK cells UPCC 16414: Elotuzumab + urelumab (anti-cd137) or lirilumab (anti-kir) for R/R or post-sct MM Pazina et al. ASH 2015, #3024

10 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.

11 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

12 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

13 BCMA (B-cell maturation antigen) On normal and malignant plasma cells Promotes MM cell proliferation, survival, drug resistance Anti-BCMA-MMAF antibodydrug conjugate (GSK ) 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 1 Novak et al, Blood 2004; 2 Moreaux et al, Blood 2004; 3 Bellucci et al, Blood 2005; 4 Tai et al, Blood 2014; 5 Carpenter et al, Clin Can Res 2013;

14 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 Cyclophosphamide 300 mg/m 2 Fludarabine 30 mg/m 2 QD for 3 days CAR-BCMA T cells* Single infusion *Dose escalation of CAR+ T cells/kg 0.3 x x x x 10 6 Ali et al, ASH 2015, LBA #1

15 BCMA-specific CAR in rel/ref MM Pt Myeloma Type CAR-BCMA Dose (T cells/kg) Response Response Duration, Wks 1 κ light chain only 0.3 x 10 6 PR 2 2 IgA λ 0.3 x 10 6 SD 6 3 κ light chain only 0.3 x 10 6 SD 6 4 κ light chain only 1.0 x 10 6 SD 12 5 IgG κ 1.0 x 10 6 SD 4 6 IgG λ 1.0 x 10 6 SD 2 7 IgG λ 3.0 x 10 6 SD 7 8 κ light chain only 3.0 x 10 6 VGPR 8 9 κ light chain only 3.0 x 10 6 SD IgA λ 9.0 x 10 6 scr IgG λ 9.0 x 10 6 PR IgA λ 3.0 x 10 6 SD 2 Ali et al, ASH 2015, LBA #1

16 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

17 UPCC study design/schema Pilot, first-in-human, 3+3 dose-escalation study 2 nd generation, CD3/41BB-based CAR n=12-18 rel/ref MM patients, 3 prior therapies PI: A. Cohen

18 Screening / eligibility Leukopheresis (Cytoxan) CAR T cell Infusion UPCC study design/schema BCMA lenticar T cell manufacture/cryopreserve * 30% 10% 60% Clinical/lab assessments: Screening, pretx***, D0, +1, 2, 4, 7, 10, 14, 21, 28** MM assessments: Screening, pre-tx***, D+14, 28** BM aspirate/bx: Pre-tx***, D+28, 90 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

19 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

20 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

21 Extra slides

22 Rationale for immunotherapy 1. Novel agents and autosct extend survival but are not curative 2. T and NK cells from myeloma patients can kill autologous myeloma cells ex vivo SWOG S 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

23 Designing a Myeloma CAR: candidate targets The classics: CD138 CD38 CD56 kappa light chain The new models: Lewis Y CD44v6 CS1/SLAMF7 BCMA

24 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

25 Types of tumor immunotherapy Antibodies Immune cell-targeting Antagonists: CTLA-4, PD-1, PD-L1, KIR, Tim- 3, LAG-3 Agonists: CD137/4-1BB, OX40, GITR, CD40 Tumor-targeting Naked Antibody-drug conjugates BiTEs / BiKE s Vaccines tumor cell/lysate protein peptide DNA viral ganglioside dendritic cell Cellular allosct/dli Autologous cells PBL TIL (MIL) T cell lines NK cells Gene-modified T cells Transgenic TCR Chimeric antigen receptors (CAR) Other Cytokines TLR agonists Adjuvants Chemotherapy Radiation Biologics