Enhancing the IQ of CAR T Cells
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1 SITC 2014 Enhancing the IQ of CAR T Cells Michael Jensen, MD Sinegal Endowed Professor of Pediatrics, UWSOM Director, Ben Towne Center for Childhood Cancer Research
2 Jensen COI Disclosure: -scientific co-founder of Juno Therapeutics, Inc. (JTI) -equity holder in JTI -inventor of IP licensed to JTI -SAB/consultant to JTI
3 Limited Engineering Of Optimized Binding Domain/Spacer Tuning CAR T Cell Therapy Version 1.1- Empiric Designs, Trial and Error, Luck Sadelain et al Vector Transduction Variable Efficiency, Expression Levels, Unregulated Constitutive Promoter Variable Cell Product Composition/ Differentiation Status
4 Synthetic Biology: -The re-design of existing, natural biological systems for useful purposes. or -The design and construction of new orthogonal biological parts, devices, and systems. (from SyntheticBiology.org)
5 Synthetic Biology s (Genetic) Engineering Approach- Designing new molecular parts, device modules, circuits, and networks: - modeling the designed systems & predicting their properties - making & testing the designs - updating our understanding from the model/test agreement
6 Vocabulary of Synthetic Biologists- PARTS- DNA sequences encoding some component of the genetic machinery. (e.g. promoter, cdna, riboswitch, transcription regulator, IRES, etc) DEVICES- A group of parts that work together to perform a specific function. (exp. small molecule regulated promoter for controlled transgene expression) CHASSIS- Organism (host) containing the device (s)
7 Current State: Polyclonal T Cells/ Constitutively Expressed CAR/No Suicide Mechanism Cell Mass in Patient Leukemia Normal B Cells CAR T Cells Time
8 T Cells Fail to Engraft to Therapeutic Levels / Engrafted T Cells Fail To Retain Anti-tumor Functional Outputs Cell Mass in Patient Leukemia Normal B Cells CAR T Cells Time
9 SynBio- Chassis Refinement I. FORMULATING CAR T CELL PRODUCTS OF DEFINED COMPOSITION FOR IMPROVED REPRODUCIBLE ENGRAFTMENT, EFFICACY, AND SAFETY
10 PLAT-02 Defined Product Composition: PBMC FORMULATED CAR T CELL PRODUCT Immunomagnetic Selection Lentivirus Transduction Expansion Formulation 100% CAR + CD8 + 1 : 100% CAR + CD4 + 1
11 MANUFACTURING CAR T CELL PRODUCTS OF DEFINED COMPOSITION: DAY 1 LEUKAPHERESIS/PBMC ISOLATION ACTIVATION OF T CELLS (ANTI-CD3/CD28 BEADS) DAY2 LENTIVIRUS TRANSDUCTION EXPANSION IN CYTOKINES Mid-Process Bead Removal/ EGFRt Positive Selection DAY 1 PURIFICATION OF CD4 and CD8 SUBSETS DAY CRYOPRESERVATION
12 Defined Composition CAR T Cell Product Uniformity Compared to Unformulated Products Product CD4+ Product EGFRt+ % % of CD4+ cells % of EGFRt+ cells _S _S _S _S _S _S03 CD3 CD4 CD8 PLAT-01 PLAT
13 Phenotype of Expanded Defined Composition CD19CAR T Cell Products At Time of Cryopreservation (Day 11-18): CD19CAR/EGFRt+ CD4+ CD8+ CD62L/CD28+ CD27+
14 Superior In Vivo Anti-tumor Activity of Defined Composition CD19CAR T Cell Products (1:1 CD4/CD8 Cell Dose, 100% CAR+) (Compared to Undefined or Single Parameter Selected Products)
15 CURRENT STATE: Version 2.0 (SCRI PLAT-02) Parts List- EF1α-promoter T2A Linker 4-1BB CD3zeta FMC63 scfv Devices- G3 SIN Lenti Chassis- Defined combinations of T cell subsets
16 Pediatric Leukemia CD19CAR Adoptive Therapy Trials Site Defined Cells Vector scfv ECD Spacer Co-stim Selection/ Suicide MSKCC No Retro SJ251 CD28partial CD28 No/No CHOP No Lenti FMC63 CD8hinge 4-1BB No/No NCI No Retro FMC63 CD28 No/No Baylor EBV Retro FMC63 Full IgG1 CD28 No/No SCRI CD4:CD8 Lenti FMC63 IgG4hinge 4-1BB Yes/Yes
17 PLAT-02: A Phase 1/2 Trial of Defined Composition CD19CAR T Cell Adoptive Therapy For Refractory Relapsed and Post-HSCT Recurrent Pediatric ALL
18 PLAT-02: Post allohsctpatient Profile Update : 15 pts enrolled, 11 pts infused S09 and S10 Infused S09 PR after first dose, received second dose, no response. S10/S11 MRD- CR
19 PLAT-02:Post-alloHSCT ALL Relapse/Pt Derived Donor Origin T Cells CD4/CD8 1:1 AntiCD19CAR(4-1BBzeta)-EGFRt Dose 250,000 cells/kg of CD4 product and CD8 product Peripheral Blood Day +14: CD3+CD8+ EGFRt+ CD45RO CD3+CD4+ DAY + 14 CSF: CD3+CD8+ EGFRt+ 78.8% CD3+CD % EGFRt+ CD62L+
20 Dose Level 3 (5.0x10 6 /kg) PLAT-02: Day +7 Tumor Burden vs Response Marrow Dz Burden Response Dose Level 2 (1.0x10 6 /kg) Dose Level 1 (0.5x10 6 /kg) Dex 100% 75% 50% 25% PD PR CR
21 PLAT-02: Remission Duration (Intent to Treat/Post-HSCT Relapse) Complete Response (MRD-neg by MPF) Dose Level 3 (5.0x10 6 /kg) Dose Level 2 (1.0x10 6 /kg) Ongoing Ongoing Ongoing Dose Level 1 (0.5x10 6 /kg) Relapse Ongoing Ongoing Ongoing Ongoing Ongoing (Months)
22 PLAT-02: Day +7 Tumor Burden vs Engraftment Dose Level 2 (1.0x10 6 /kg) Dose Level 1 (0.5x10 6 /kg) Marrow Dz Burden Peak EGFRt + T Cells in PB (cells/μl) <1 (Dex) 1, Pend % 75% 50% 25%
23 PLAT-02: Magnitude and Duration of CAR/EGFRt + T Cell Persistence
24 Dose Level 3 (5.0x10 6 /kg) Dose Level 2 (1.0x10 6 /kg) PLAT-02: Duration of B Cell Aplasia Complete Response//B Cell Aplasia Toci Dose Level 1 (0.5x10 6 /kg) Toci+ Dex Pred. (Months)
25 Summary I: 1. Feasible (100% based on intent to treat) to manufacture defined composition products. 2. Bioactive against ALL, high peak engraftment, duration of engraftment is heterogeneous. 3. Products have high frequencies of CD62L/CD28/CD27 + T Cells.
26 LIFE THREATENING TOXICITIES ARISING FROM UNREGULATED CAR T CELL FUNCTIONAL OUPUTS Cell Mass in Patient Leukemia Normal B Cells CAR T Cells Time
27 CURRENT STATE: Version 2.0 (JCAR14, 17) Parts List- EF1α-promoter T2A Linker 4-1BB CD3zeta FMC63 scfv Devices- G3 SIN Lenti Chassis- Defined combinations of T cell subsets
28 CAR T Cells Are Constitutively ON - S02 CAR T Cell Engraftment- PB CSF Severe Sx s/pressors, Toci, Dex
29 II.CLINICAN CONTROLLED CAR T CELLS THROUGH REGULATED TRANSGENE EXPRESSION
30
31 biodevice ASSEMBLY: Transgene Expression Rheostats For Regulated TgX Expression: TamR Transcriptional Regulatory System
32 TamR-Transcription Platform- Parts I Human Estrogen Receptor LBD Tuned For Tamoxifen Binding Human RelA Transactivation Domain TamR-TF Human Hepatocyte Nuclear Factor-1α DNA Binding Domain 7X hualb promoter HNF-1α Binding Motif TamR-TF Responsive Synthetic Promoter Adenovirus E1b mp/tata Prototype described by Rosciliet al., 2002
33 TamRTranscriptional Control System
34 TamR-Transcription Platform- LV Device LV Transfer Plasmid #1 LV Transfer Plasmid #2 TamR-TF LV Transfer Plasmid #1 LV Transfer Plasmid #2 Dual Packaged LV >15Kb Payload Capacity
35 TamR-Transcription Platform- Parts II Cell Surface Barcoding Tags
36 TamR-LV Transcription Platform- Performance in Primary Human T Cells
37 TamR-LV CAR Functional Outputs % Specific Lysis OFF ON (+Tam)
38 TamR-LV tftuning For High Versus Low Regulated Outputs TamR-tf high TamR-tf low 4-OHT nm
39 T Cell Activation Amplifies Tam-Dependent TamRLV Transgene Expression Outputs
40 T Cell Activation Amplifies Tam-Dependent CAR Expression K562p K562 CD19+ CD4 Mock transduced CD4+TamR CD19CAR +Vehicle CD4 + TamR CD19CAR +4OHT HER2T
41 TamR-LV Formats For Regulated Expression of TransgeneX by CAR T Cells TgX
42 Summary II: 1. TamR-LV transgene expression regulation system displays favorable attributes for clinical application. 2. System has tunable features for output states (4-OHT sensitivity). 3. System exhibits context specific (T cell activation) positive feedback.
43 Selection of Antigen Loss Tumor Escape Variants Cell Mass in Patient Time
44 III. Multiplexing CAR T Cell Target Antigen Recognition Aggregate data from CHOP, NCI, Seattle suggest CD19 epitope escape loss as etiology of treatment failure in approx. 10% of relapsing patients.
45 STRATEGIES TO GENERATE CAR T CELL PRODUCTS WITH 2X SPECIFICITIES
46 Dual CAR LV s ( Adding ) CD19CAR/HER2t CD20CAR/EGFRt GMCSFRss GMCSFRss Stop GMCSFRss GMCSFRss Stop EF1p CD19CAR HER2t EF1p CD20CAR EGFRt T2A T2A EGFRt/HER2t Expression by Transduced Human CD8 + CTLs EGFRt HER2t Redirected CD19 and/or CD20 Cytolysis by Human CD8 + CTLs
47 BiSpecific CAR ( Combining )
48
49 Summary III: 1. Multiplexed antigen specificity is feasible and can be accomplished in a single LV vector. 2. Targeting 2 antigens on tumor cells expected to diminish antigen escape as etiology of treatment failure.
50 Cell Mass in Patient Complications of Prolonged B Cell Aplasia & Chronic Activation of CAR + T Cells Time
51 IV. Control of CAR T Cell Persistence
52 Construction of truncated human EGFR (huegfrt) with retention of Cetuximab binding epitope AA: LP D III D IV TM 3 GMCSFRss huegfr domains Signal sequence
53 huegfrt can be incorporated into lenti-viral vector for co-expression with CD19 chimeric antigen receptor(cd19car) GCSFRss GCSFRss Stop 5 3 EF1p CD19CAR huegfrt T2A CD19CAR (anti-fc-bio+sa-pe) EGFRt (Ctxmb-Bio+SA-PE)
54 huegfrt sensitizes huegfrt + human T cells to Cetuximab mediated ADCC % 51 Cr-Release No Ab Rituxan Rituximab Erbitux 50:1 25:1 5:1 1:1 E:T 96.3 EGFRt Targets: 51 Cr-labeled huegfrt+ T cells; Effectors: GM-CSF stimulated hupbmc Mixed with 1ug/mL Cetuximab or Rituxan (anti-cd20) for 4hr Rituximab
55 In vivo: Depletion of EGFRt+ cells Frequency of transferred cells in blood (FACS analysis) 24h post Erbitux 24h post Rituxan Rituximab e EGFR mab + SA-PE Number of tegfr+ cells from spleen 1.5 cell number (x10 6 ) Erbitux Rituxan control Rituximab
56 Summary IV: 1. EGFRt can serve as a suicide construct based on in vitro and murine models. 2. The efficacy of cetuximab mediated ablation of EGFRt + T cells in humans is unknown.
57 SynBio T Cells FUTURE STATE: Version 3.0 Parts List- Devices- Expression Rheostats, Sensors, Logic Gated Bio-Circuits Chassis- Defined combinations of T cell subsets
58
59 Stephen Forman, MD David DiGiusto, PhD Leslie Popplewell, MD Michael Hudechek, MD Stanley Riddell, MD Behnam Badie, MD Rebecca Gardner, MD (PLAT-01/-02 PI)) Julie Park, MD (ENCIT-01 PI) Annette Kuenkele, MD (L1-CAM CAR) Kaileen Rohr (TamR-Tg) Anne Silva, MD (spacer/bispecific) Cindy Chang (mouse models) Paulina Paszkiewicz (Busch Lab) (EGFRt/Erbitux ablation) Xiuli Wang, MD,PhD (human Tcm/EGFRt) Hao Hong PhD L1CAM Stephen Forman, MD - Supported by: RO1 CA COH Lymphoma SPORE SU2C/St. Baldrick s Dream Team LSDF Opportunity Grant
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