BCMA-specific CAR T cells for Myeloma

Transcription

1 BCMA-specific CAR T cells for Myeloma Adam D. Cohen, MD Abramson Cancer Center University of Pennsylvania October 14, 2017

2 Chimeric antigen receptors - background w Combines recognition domain of antibody with signaling domain of T cell w Uses gene transfer (eg. lentiviral vector) to stably express CAR on T cells à confers novel antigen specificity w Addition of co-stimulatory domains (CD28, 4-1BB/CD137) augments proliferation and survival Garfall et al, Discovery Med 2014

3 Building CAR T cells T cell CTL019 cell Lentiviral vector 1. Cytotoxicity 2. Cytokine production 3. Long-term memory Native TCR Anti-CD19 CAR construct CD19 Dead tumor cell Tumor cell

4 CD19-targeted CAR T cells for B cell malignancies w Responses seen in heavily-pretreated CLL, ALL, and B-cell NHL ORR 40-50% in CLL and NHL 80% in ALL FDA approved 2017 some durable CRs > 5 years w Toxicities: Tumor lysis syndrome B cell aplasia / hypogammaglobulinemia Cytokine release syndrome very high IL6, also IFN-gamma, TNF tocilizumab (anti-il6 receptor mab) can abrogate CRS Neurotoxicity/encephalopathy Headache, delirium, obtundation, seizure, aphasia Rare cerebral edema Davila et al, Science Trans Med 2014; Porter et al, Sci Trans Med 2015; Maude et al, NEJM 2014

5 Designing a Myeloma CAR: candidate targets wthe classics: CD138 CD38 CD56 kappa light chain CD19 wthe new models: Lewis Y CD44v6 CS1/SLAMF7 BCMA

6 BCMA (B-cell maturation antigen) w TNFRSF17, CD269 w Receptor for BAFF (Blys) and APRIL w Expressed on mature B cell subsets, PC s, and plasmacytoid DC s w Maintains plasma cell homeostasis BCMA -/- mice have normal B cell #s, impaired PC survival w BAFF-APRIL system implicated in autoimmunity Rickert et al, Immunol Rev 2011; Maus, June, Clin Can Res 2013

7 BCMA is highly expressed in MM cells Frigyesi et al, Blood 2014; Tai et al, Blood 2014; Carpenter et al, Clin Can Res 2013

8 BCMA signaling and myeloma pathogenesis w BAFF and APRIL enhance MM cell growth, resistance to apoptosis w BCMA co-immunoprecipitates with IRF4 w BCMA loss reduces viability w BCMA overexpression enhances MM growth Novak et al, Blood 2004; Moreaux et al, Blood 2004; Shaffer et al, Nature 2008; Tai et al, Blood 2016

9 BCMA-specific CAR T cells can kill MM cells w 2 nd gen (CD3/CD28) CAR using scfv from mouse anti-human BCMA w Lentiviral vector Carpenter et al, Clin Cancer Res 2013

10 NCI BCMA-specific CAR in rel/ref MM Cyclophosphamide 300 mg/m2 Fludarabine 30 mg/m2 QD for 3 days CAR-BCMA T cells* Single infusion w Responses in 4/12 pts. PR (2wks), VGPR (8wks), scr (17wks), VGPR (26+ wks) w Associated with CART expansion w Severe CRS and delirium Ali et al, ASH 2015, LBA #1; Blood *Dose escalation of CAR+ T cells/kg 0.3 x x x x 106

11 Penn/Novartis human BCMA CAR Anti-BCMA scfv Signal seq. VH Linker VL CD8a Hinge and TM 4-1BB CD3z w BCMA-binding scfv clones identified from human B cell antibody libraries Lentiviral vector, CD3/41BB domains w Lead candidate selected based on in vitro and in vivo activity P B S B L I (P h o to n s /s e c ) (M e a n ± S E M ) U TD B C M A -4 B C M A -9 B C M A -1 0 B C M A -1 3 B C M A D a y s P o s t Im p la n t Richardson et al, submitted

12 Study design Cohort x 10 8 CAR+ T cells (n=3-6) Cohort 2 Cytox 1.5 g/m x 10 7 CAR+ T cells (n=3-6) Cohort 3 Cytox 1.5 g/m x 10 8 CAR+ T cells (n=3-6) 4 week delay between subjects Up to n=9 Up to n=9 Up to n=9 w Primary objective Safety w Secondary Feasibility Efficacy (response rates, PFS, OS, MRD) w Exploratory: CART-BCMA expansion, persistence, phenotype Impact on normal B cell and PC compartments BCMA expression pre- and post-treatment Cytokine/chemokine levels Soluble BCMA, BAFF, APRIL levels Assess for anti-car immune responses Impact on tumor microenvironment 1) Flow BCMA-CAR Pre Day 7 CD8 2) qpcr

13 Study design Lenti Transduction, Expansion & Cryopreservation Screening & Eligibility Apheresis Wk-4 * +/- Cytoxan CART-BCMA 10% 30% 60% D-7 D0 D1 D2 {D-3 Pre-Tx BM asp/bx Clinical/Lab Assessments: Screening, pre-tx***, D0,+1,2,4,7,10,14,21,28** MM Assessments: Screening, pre-tx***,d14, D28** D28 BM asp/bx D90 BM asp/bx * 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

14 Patient characteristics Cohort 1 (n=9) Cohen et al, ASH 2016, #1147 Characteristic Median (range) or % Age 57 (44 70) Gender 67% male; 33% female Isotype IgG (33%), IgA (44%), LC (22%) Prior lines of therapy 9 (4-11) Lenalidomide 100% (refractory: 78%) Bortezomib 100% (refr: 89%) Pomalidomide 100% (refr: 89%) Carfilzomib 100% (refr: 89%) Autologous SCT 78% Cyclophosphamide 100% (refr: 67%) High-risk genetics -17p or TP53 mutation Daratumumab 44% (refr: 44%) Anti-PD1 33% (refr: 33%) 100% 67% Extramedullary dz 33% % BM plasma cells 80 (15 95) Day 0 absolute CD3 258/µL ( )

15 Safety (n=9) w Cytokine release syndrome in 8/9 (89%) Grade 1 (n=1); Grade 2 (n=4); Grade 3 (n=2); Grade 4 (n=1) 4/9 received tocilizumab Median hospital stay = 9 days (range 3 40) w Dose-limiting toxicity (pt. 03): Grade 4 PRES (posterior reversible encephalopathy syndrome) Recurrent seizures, obtundation MRI brain: diffuse enhancement w/ swelling and sulcal effacement. Rapid peripheral CART expansion Solumedrol 1 g/d x 3àCytoxan 1.5 g/m2 day 17 Rapid improvement, resolution of MRI changes and neuro deficits Garfall et al, ASH 2016, #5702 Cohen et al, ASH 2016, #1147

16 CART-BCMA for MM: Cohort 1 (CART cells alone) w 4/9 (44%) with response, 1 with scr>12 months Associated with CART expansion, sbcma Pt 01 Pt 03 Enrollment ongoing in cohorts using Cytoxan conditioning Pre-tx Day 42 Cohen et al, ASH 2016, #1147

17 CART-BCMA expansion: Quantitative PCR scr MR VGPR SD PD MR PR PD VGPR

18 CART-BCMA expansion correlates with response Peak expansion AUC-28d * c o p ie s /µ g D N A * c o p ie s *d a y s /µ g D N A ³ P R < P R ³ P R < P R

19 Soluble BCMA declines correlate with response

20 CD4/CD8 ratio and in vitro growth may predict in vivo expansion

21 BCMA expression on MM cells BCMA FMO control

22 BCMA-CAR T cell trials for Myeloma NCI Penn (cohort 1) Bluebird Legend Sites Single Single Multi-center Multi-center scfv Murine Human Murine?? Vector Gammaretroviral Lentiviral Lentiviral?? Domains CD3/CD28 CD3/41BB CD3/41BB CD3/41BB BCMA+ required Dosing Condition ing Med # priors Yes (IHC) (52/85 (62%) 0.3 9x10 6 /kg 1 day No 5 x days Yes (??) x day Yes (??) 0.6 7x10 6 /kg 3 days Flu/Cy - Flu/Cy Cy 7* *includes XRT Ali et al, Blood 2016; Cohen et al, ASH 2016; Lin et al, EHA 2017; Fan et al, ASCO 2017

23 Hermanson et al, ASH 2016, #383; Qasim et al, Sci Trans Med 2017; Boldajipour et al, ASH 2016, #381; Other CART-BCMA approaches w CART-BCMA w Henan University (China) w MSKCC w Southwest Hospital (China) w Kite w CARTyrin Novel antigen-binding domain Transposon-based manufacturing Suicide gene w Allogeneic universal CART cells Off-the-shelf product KO of TCRa (limits GVHD risk) and CD52 (resists lymphodepletion) Expression of CD20 Can deplete with rituxan

24 BCMA-specific ADCs and BiTEs GSK (anti-bcma ADC) AMG 420 (BCMAxCD3 bispecific Ab) Cohen et al, ASH 2016; Hipp et al, Leukemia 2016

25 Conclusions w CART-BCMA manufacturing feasible in heavily pretreated MM patients w Significant expansion, clinical activity seen 4/9 (44%) ORR with CART-BCMA alone, can be durable x 2 years Higher responses with lymphodepletion Responses associated with dose, CART expansion w Toxicity CRS and neurotoxicity, can be severe No other off-target or off-tumor toxicities w Loss/downregulation of BCMA may be escape mechanism w Many studies ongoing or soon to open

26 Questions/Challenges w Level of BCMA expression on MM cells w Optimal constructs, conditioning, manufacturing, dosing w Mechanisms of escape/resistance w Correlates of expansion/response w Toxicity management/prevention w Optimal patients, combinations w Cost

27 Acknowledgments Co-investigators Ed Stadtmauer Al Garfall Dan Vogl Brendan Weiss Eric Lancaster (neurology) TCSL/PDCS Jos Melenhorst Simon Lacey David Ambrose Farzana Nazimuddin Vanessa Gonzalez Fang Chen CVPF Bruce Levine Zoe Zheng Don Siegel Center for Cellular Immunotherapeutics Karen Dengel Regina Ferthio Tenesia Carey Naseem Kerr Lee Dengel Gabriela Plesa Les Lledo Wei-Ting Hwang Jamella Knots-Miller Cynthia Desir Amy Marshall Laurel Caffee Jane Anderson Desire Fenderson Mary Truran Annemarie Nelson Laura O Keefe Carl June Office of Clinical Research (Sponsor) Emma Meagher David Vaughn (Medical Director) Penn MM CAR Working Group Regina Young Marco Ruella John Scholler Selene Nunez-Cruz Michael Milone (scientific advisor) Novartis Celeste Richardson Keith Mansfield Reshma Singh Eugene Choi Jennifer Brogdon Heather Huet Greg Motz Randi Isaacs Ewelina Morawa

28 Extra slides

29 Immunotherapy for MM: Targets and Tools ADCs GSK Neri et al, Clin Can Res 2016