Novel Approaches to CAR-T Cell Platform
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1 Novel Approaches to CAR-T Cell Platform Vita Golubovskaya, Ph.D. Director, R&D Promab Biotechnologies 3 rd CAR-TCR Summit 2017 S E P T E M B E R 5-7 B O S T O N
2 Novel Approaches To CAR-T Cell Platform Promab s CAR-T Platform is based on 12 patent applications and Includes 3000 hybridoma, mouse, rabbit and human Ab platforms CAR-T cells Tumor Antigen Peptide
3 Promab Strategies For CAR-T Platform Bi-specific scfv Extracellular tag for purification and in vivo Monitoring scfv-enzyme Complex to modulate tumor microenvironment Novel or Mutant co-stimulatory domain to modulate CAR-T cell activity Safety switch Combination therapy: CAR-T + sdrna to block checkpoint Inhibitors, Gene editing Modified from Nature Reviews Clinical Oncology, 13, (2016)
4 Promab s CAR-T Platform includes Several Validated Approaches I. CAR-T cells with Decreased Cytokines II. Novel CAR co-activation domains III. CD47 and humanized CD47-CAR-T cells Safer CAR-T cells for clinic
5 I. CAR-T cells with Decreased Cytokines I. Flag-tag for CAR-T monitoring and Imaging CD19-Flag-CD28-CD3 zeta CAR CD19 ScFv Membrane h TM Flag T cell CD28 CD3 zeta
6 Flag-tagged CD19-CAR are effectively detected by Flag antibody Berahovich et al, Frontiers in Bioscience, 2017, June 1
7 CD19-Flag CAR-T Similarly Kill CD19-Positive Rajileukemia Cells and Hela-CD19 + Positive Cells But Do Not Kill CD19 - Negative Cells Berahovich et al, Frontiers in Bioscience, 2017, June 1
8 CD19-Flag CAR-T cells secrete 30% less Cytokines IFN-g, IL-2 and IL-6 compared to CD19-CAR-T cells K562/Raji cells Hela/Hela-CD19 cells IFN-g IL-2 IL-6 Berahovich et al, Frontiers in Bioscience, 2017, June 1
9 CD19-Flag-CAR-T cells significantly block Hela-CD19 xenograft tumor growth Berahovich et al, Frontiers in Bioscience, 2017, June 1
10 CD19-Flag CAR-T Cells Significantly Prolong Survival of Mice in Raji Leukemia Model CD19-Flag CAR-T cells block Raji tumor growth Similarly to CD19-CAR-T Cells CD19-Flag CAR-T cells prolong mice survival CD19-CAR-T cells prolong mice survival Berahovich et al, Frontiers in Bioscience, 2017, June 1
11 CD19-CAR-T Cells Target Cancer Stem Cells CD-19-CAR-T Cells Target Cancer and Cancer Stem Cells Hela cells Hela-CD19 cells
12 II. Novel CAR Co-activation Domains: GITR; Mutant CD28 Domain Collaboration with Dr. Marcela Maus, Massachusetts General Hospital, Harvard Medical School, Boston, USA GITR Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR, TNFRSF18, and CD357) CD19-(-/+Flag); EGFR; Meso-GITR-CD3-CAR GITRL GITR Inhibit T reg suppressive function ScFv TRAF1 Siva TRAF3 TRAF2 NF-k B Induce CD8+ Effector function Membrane TM Caspases Apoptosis Survival Proliferation T cell GITR NFkB CD3 zeta
13 GITR Co-activation Domain Activates CAR-T Cells Similarly to CD28 and 4-1BB Domains BxPC3 Cells Pancreatic Cancer Cells Hela-CD19 Target Cells Hela-CD19 cancer cells Target Cells Non-transduced T cells CD19-GITR-z (1) CD19-GITR-z (2) E:T=10:1
14 CD19-GITR-CD3z CAR-T Cells Decrease Raji-luc + Xenograft Tumor Growth CD19-GITR-CD3 z ZCAR-T cells (mice # 1-3) T cells (mouse #4) Days after Raji-luc+ injection Control - 1xPBS CAR-T injected day 12 1x10 7 CAR-T iv 1x10 6 cells Raji-luc subcutaneously CD19-GITR-CD3 z CAR-T CAR-T cells #4-T cells
15 Mutant CD28 Co-activation Domain APC CD80 CD86 CD28 T cell CD28 p110 p85 Grb2 ** _ * Itk Lck Grb2 Filamin A Meso-CD28DD-CD3-CAR; EGFR-CD28DD-CD3-CAR ScFv IL-2 Membrane TM CD28 DD (double mutant domain) CD28 * Duplication of protein-binding T cell motifs-mutation, IL-2 regulationmutation #1; 28DD plus addition of point mutation- #2-T195Paffecting binding CD3 zeta partners
16 Mesothelin-CD28DD Mutant CAR-T Cells Express Same or Higher Cytotoxic Activity Cells Against Ovarian A1847 Cancer Cells and reduce > 4-5-fold IL-2 and IFN-g production A1847 cells Target cells T cells Mock CAR-T cells IL-2 IFN-g * * * * * Meso28DD has higher cytolytic activity at earlier time points after adding CAR-T cells E:T=10:1 Meso- CD28WT-CD3z Meso-Flag-28DD- CD3z Meso-28DD-CD3z
17 EGFR 28-Mutant CAR-T Cells Express Same Cytotoxic Activity as EGFR 28-Wild Type CAR-T Cells and secrete less IFN-g but > IL-2 SKOV3 Ovarian Cancer Target Cells Target cells T cells Mock CAR-T cells IFN-g BxPC3 cells * * p=0.004 EGFRwt vs T cells 32% * ** *** ** p=0.02 EGFR DD T195P vs T cells *** p=0.014 EGFR DD T195P vs EGFR wt EGFR-28 DD-Z EGFR-28 DDT195PZ EGFR-28 WT Z Effector:Target cells=10:1 BxPC3 Pancreatic Cancer Target Cells Target cells T cells Mock CAR-T cells IL-2 ** 30% 30% p= EGFR WT vs T cells ** p=0.003 EGFRDDT195P vs T cells *** ***p=0.01 EGFR DDT195P vs EGFR WT * EGFR-28 DD Z EGFR28 WT Z EGFR=28DDT195P-Z Effector::Target cells =10:1
18 Effector and Memory Functions of T Cells Are Important for CAR-T Cell Efficacy Memory function APC Proliferation TN T SCM T CM T EM T EFF (L-selectin) Naive T cell T Stem cell memory T central memory cell T effector memory cell CD62L (CD-197) Differentiation CCR CD45RA CD45RO Golubovskaya, Wu, Cancers, 8(3), 2016 T effector cell Effector function
19 CD45RO CD45RO Mutations in CD28 Co-activation Domain Increase % of Tcm, Tem Memory Cells CD45RA CD45RA CD45RA CD45RA EGFR-CAR-T cells with mutant CD28 domain increase % of Tcm and Tem-memory cells 37% Tcm, 4% Tem EGFR-28 WT-Z CAR-T cells CAR-T with wild-type CD28 domain are 55% Tint1 and 37% Tcm, with 4% Tem and <1% naïve Tem & Tce Tint1 & Tcm Tes & Tce Tint1 & Tn Tn Tint1 & Tce CD27 Tes Tn 4% Tcm Tem 37.4% CD27 CD45RO EGFR-28DD*-Z CAR-T cells Tcm & Tem 14% Tem 45.8% Tcm CAR-T with DD * CD28 domain are 13% Tn, 45% Tcm, 14% Tem vs 0.3 Tn, 37% Tcm and 4% Tem in 28WT CD27 CD27 CD45RO 46% Tcm, 14% Tem
20 III. CD47 and Humanized CD47 CAR-T Cells Macrophage Don t eat me signaling CD47 SIRP-a Phagocytosis Tumor TSP-1 VEGFR-2 EGFR Angiogenesis Motility Metastasis Survival CSC signaling Proliferation Tumor growth
21 R a tio M F I C D 4 7 /is o ty p e (fo ld ) CD47 CD47 Ab and scfv bind CD47 CD47 scfv A Isotype CD FT A431 A549 Cancer Cancer cell Cancer cell lines lines lines A1847 BxPC3 Gastric tumor C33A CHO HCT116 Hela-CD19 Hep3B Membrane TM MCF-7 OC3-VGH PANC-1 PC-3 SKOV-3 T cell CD28 B CD Binding of CD47 scfv to CD47 Ag B6H12 CD3 zeta F T A A A B x P C 3 C 3 3 A C H O C a n c e r C e ll L in e s H C T H e L a -C D 1 9 H e p 3 B M C F 7 O C 3 -V G H P a n c 1 P C -3 S K O V 3
22 CD47-CAR-T Cells Kill CD47-Positive Target Cancer Cells and secrete cytokines Ovarian cancer: SKOV-3 cells Pancreatic cancer: BxPC3 cells Target cells Mock-CAR-T cells T cells Target cells + T cells + Mock CAR-T cells 10:1=E:T CD47-CAR-T cells Pancreatic cancer: BxPC3 cells E:T=10:1 IFN-g IL-2 IL-6 CD47-CAR-T cells
23 CD47-CAR-T Cells Significantly Decrease BxPC3 Pancreatic Xenograft Tumor Growth Mice Body weight (g) Intratumoral CAR-T cell delivery Control 1xPBS CD47- CAR-T cells 0 D7 D11 D14 D18 D21 D24 D28 D32 D35 D39 D41 * * * p=0.004 vs 1xPBS Control Control 1xPBS T1 T2 T3 T4 T5 Days after BxPC3 pancreatic cancer cell injection Human CD3 zeta PBS CD47-CAR-T Isotype Control CD47-CAR-T cells T1 T2 T3 T4
24 Humanized CD47 ScFv Detects Better CD47 in Tumor than in Normal Tissues and Than Mouse CD47 scfv Humanized CD47 ScFv Mouse CD47 ScFv Lymphoma 0218 Lymphoma 0218 Humanized CD47 ScFv Mouse CD47 ScFv Tonsil 0046 Tonsil 0046
25 Humanized CD47-CAR-T Cells Effectively and specifically Kill CD47 + Cancer Cells SKOV-3 ovarian cancer cells A1847 ovarian cancer cells Mock-CAR-T cells Target cells alone A1847 ovarian cancer target cells Mock-CAR-T cells Humanized CD47-CAR-T cells Humanized CD47-4-CAR-T E:T=20:1 BxPC3 pancreatic cancer cells BxPC3 target cells E:T=10:1 Hela-CD19 cells Mock-CAR-T cells Hela-CD19 cells Humanized CD47 -CAR-T cells T cells Humanized CD47-4-CAR-T CD19-CAR-T cells E:T=10:1 E:T=10:1
26 Different Approaches to Increase CAR-T Cell Therapy Targeting T cell metabolism Inhibition of checkpoints Glycolysis TEFF scfv Fatty acid oxidation TEM T cell subsets Cytokine Combinations TEM IL-7+IL-15 IL-15+IL-21 Inhibition of Treg number CAR structure T reg EFF PD-1 CTLA-4 CD28 4-1BB CAR-T T EM Individualized T cell profiling CAR-T immunotherapy Golubovskaya, Wu, Cancers, 8(3), 2016
27 differentiation proliferation differentiation AKT1/2 Inhibitor Increases T Effector Memory Subset: Tem IL-15 and IL-15+IL7 Increase Tn, Tcm Subsets T Cells Grown with FBS have >Tn and Tcm Subsets vs T Cells Grown with Human AKT1/2 inhibitor increases population of T effector memory subset: Tem IL-15 Serum and IL-15+IL7 that increase Correlated Tn, Tcm subsets with important Increased for proliferation Proliferation and memory functions T cells grown on FBS have >Tn and Tcm subsets vs T cells grown with hu serum that correlated with increased proliferation AKT ½ inh d a y 9 p h e n o ty p e s IL-15 IL-15+IL-7 T e s e n d -s ta g e e ffe c to r T c e c e n tra l e ffe c to r 5 0 T e m e ffe c to r m e m o ry T c m c e n tra l m e m o ry T in t1 in te rm e d ia te T n n a iv e h u s e r u m, n o r m a l IL -2, n o v ir u s h u s e r u m, n o r m a l IL -2, C D 1 9 -F L A G 0 h u s e ru m, lo w IL -2, C D 1 9 -F L A G h u s e ru m, lo w IL -2 + A k ti-1 /2, C D 1 9 -F L A G h u s e r u m, lo w IL -2 + IL -1 5, C D 1 9 -F L A G h u s e r u m, lo w IL -2 + IL IL -7, C D 1 9 -F L A G F B S, lo w IL -2, C D 1 9 -F L A G F B S, lo w IL -2 + A k ti-1 /2, C D 1 9 -F L A G h u s e ru m, IL IL -7, C D 1 9 -F L A G F B S, n o rm a l IL -2, n o v iru s F B S, n o rm a l IL -2, C D 1 9 -F L A G Hu Serum FBS % Tn: % CD27 + CD45RO % Tcm: % CD27 + CD45RA % Tem: % CD27 CD45RA % Tes: % CD27 CD45RO % Tint1: % CD27 + CD45RA + minus % CD27 + CD45RO % Tce: % CD27 CD45RO + minus % CD27 CD45RA
28 Conclusion Pipeline of safer CAR-T cells is developed for future clinical trials: 1. CAR-T cells with decreased cytokine production 2. CAR-T cells with novel co-activation domains 3. Novel CD47-CAR-T cells - as an example of >100 CAR-T cells validated both in vitro and in vivo based on Promab s monoclonal, humanized or human antibodies
29 Promab s Collaborations Academic Collaborators Stanford University Dana-Farber Harvard Cancer Center Massachusetts General Hospital UF Shands Cancer Center Mayo Clinic Oxford University Roswell Park Cancer Institute City of Hope China Hospitals Companies TCR 2 Therapeutics C4 Therapeutics Avidbiotics Helix Biopharma SRI International Rxi Pharmaceuticals Ziopharm Oncology, other
30 THANK YOU ProMab Biotechnologies, Inc Hilltop Drive Building B, Suite C320 Richmond, CA Tel: Fax:
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