GENE EDITED CAR-T THERAPIES THE PARADIGM IN ONCOLOGY

Transcription

1 GENE EDITED CAR-T THERAPIES THE PARADIGM IN ONCOLOGY Cellectis, March 2018

2 2 FORWARD-LOOKING STATEMENTS THIS PRESENTATION CONTAINS FORWARD- LOOKING STATEMENTS THAT ARE BASED ON OUR MANAGEMENT S CURRENT EXPECTATIONS AND ASSUMPTIONS AND ON INFORMATION CURRENTLY AVAILABLE TO MANAGEMENT. FORWARD- LOOKING STATEMENTS INVOLVE KNOWN AND UNKNOWN RISKS, UNCERTAINTIES AND OTHER FACTORS THAT MAY CAUSE OUR ACTUAL RESULTS, PERFORMANCE OR ACHIEVEMENTS TO BE MATERIALLY DIFFERENT FROM ANY FUTURE RESULTS, PERFORMANCE OR ACHIEVEMENTS EXPRESSED OR IMPLIED BY THE FORWARD- LOOKING STATEMENTS. THE RISKS AND UNCERTAINTIES INCLUDE, BUT ARE NOT LIMITED TO THE RISK THAT THE PRELIMINARY RESULTS FROM OUR PRODUCT CANDIDATES WILL NOT CONTINUE OR BE REPEATED, THE RISK OF NOT OBTAINING REGULATORY APPROVAL TO COMMENCE CLINICAL TRIALS ON THE UCART PRODUCT CANDIDATES, THE RISK THAT ANY ONE OR MORE OF OUR PRODUCT CANDIDATES WILL NOT BE SUCCESSFULLY DEVELOPED AND COMMERCIALIZED. FURTHER INFORMATION ON THE RISK FACTORS THAT MAY AFFECT COMPANY BUSINESS AND FINANCIAL PERFORMANCE, IS INCLUDED IN FILINGS CELLECTIS MAKES WITH THE SECURITY EXCHANGE COMMISSION FROM TIME TO TIME AND ITS FINANCIAL REPORTS. EXCEPT AS REQUIRED BY LAW, WE ASSUME NO OBLIGATION TO UPDATE THESE FORWARD- LOOKING STATEMENTS PUBLICLY, OR TO UPDATE THE REASONS ACTUAL RESULTS COULD DIFFER MATERIALLY FROM THOSE ANTICIPATED IN THE FORWARD- LOOKING STATEMENTS, EVEN IF NEW INFORMATION BECOMES AVAILABLE IN THE FUTURE. CELLECTIS PROPRIETARY INFORMATION. NOT TO BE COPIED, DISTRIBUTED OR USED WITHOUT CELLECTIS PRIOR WRITTEN CONSENT.

3 Dual Platform to Enhance the power of the Immune System against cancer Ag Chimeric Antigen Receptor Tumors recognition Gene Editing TALEN Nuclease 3

4 Engineered Off-The-Shelf CAR T-Cells CS1 or UCART Attributes CAR expression to redirect T-cells to tumor antigens Suicide gene (RQR8) for safety Inactivation of the TCRa constant gene (TRAC) Donor blood cells TALEN Product TALEN mediated gene editing to enable an allogenic approach eliminates the TCR and minimizes risk of GvHD Additional gene editing to Facilitate continued lymphodepletion (CD52,dCK) Prevent CAR T-cell cross-reactivity (CS1/SLAMF7) To Checkpoint pathways inhibition (PD1,Lag3, ) To delay rejection by T-cells (MCH-I inactivation) 4

5 5 Allogeneic CAR T GMP Manufacturing n n GMP manufacturing in place for UCART19, UCART123, UCART22 Full QC system, cleared for clinical trials

6 Rich Allogeneic CAR T Pipeline Addressing unmet medical need with proven targets Program Indication Product development Preclinical Manufacturing IND Filing* Phase I Ph II Ph III UCART19** ALL (PALL) ALL (CALM) UCART123 AML BPDCN UCART22 B-ALL B-NHL UCARTCS1 MULTIPLE MYELOMA n n n 2 UCART in clinic: UCART19 & UCART123 Rich pipeline, with proven targets Potential quick wins in next 3 years with several IND filings * or European equivalent ** UCART19 is exclusively licensed to Servier and under a joint clinical development program between Servier and Pfizer 6

7 UCART19* Initial Proof of Concept in ALL 1 st patient dosed in June 2015 (compassionate) Phase I trials (US/EU) started in June 2016 Tumor cell 4 recruiting centers (EU and US) 14 patients treated disclosed (7 adults and 7 pediatric)** Results in line with early autologous CAR-T Phase I results published in past years UCART19 Patients failed >5 lines of treatment, including autologous CAR-T Ph1b expansion at U Penn and MD Anderson * UCART19 is exclusively licensed to Servier and under a joint clinical development program between Servier and Pfizer ** Including compassionate 7

8 8 Early Clinical Data UCART19* in Pediatric ALL patients (ASH 2017) Lymphodepletion & patient age Disease status before treatment Dose level (CAR-T Cells/kg) MRD- CR/CRi Adverse event > Grade 3 Relapse follow up SERVIER & KCL (PALL) ASH 2017 CFA 6 m to 17 y All patients were ineligible for or had failed autologous CAR T treatment 1.1 to 2.3x % (7/7)* CR or CRi CRS 14% (1/7) NT 0% (0/7) 29% (2/7) - 6 m 1 CD19- and 1 CD19+ KITE & NCI ASCO 2013 CF 1 to 30 y Relapse or refractory 1x % (2/2) CR CRS 50% (1/2) JUNO & SCH (PLAT- 02) ASH 2014 C or CF 4 m to 3 y 4 pts MRD+, 2 pts MRD Relapse after allo-sct 5x % (5/6) CR CRS 33% (2/6) NT 50% (3/6) JUNO & FHCRC AACR 2015 C or CF or CE 18 to 60y Relapse or refractory 1x % (20/22) CR CRS 36% (8/22) 18% (4/22) 3 CD19- and 1 CD19+ NOVARTIS (ELIANA) ASH 2016 CF or other 3 to 21 y All patients with morphologic disease: primary refractory, chemorefractory after first relapse, relapsed after second line therapy or ineligible for allo- SCT 0.2 to 4x % (24/29) CR or CRi CRS 52% (15/29) NT 21% (6/29) NOVARTIS & UPENN (PEDI CART19) N Engl J Med /- CE 7 & 10 y All 2 pts MRD+ Chemorefractory after second relapse or second relapse after allo-sct or 100% (2/2) CR CRS 50% (1/2) NT 0% (0/2) 50% (1/2) - 2 m MSKCC & DFCI ASH to 22 y 3/4 pts with morphologic disease Relapse 0.3 to 1x % (2/4) CR or CRi CRS 50% (2/4) * Including 2 patients in compassionate use C: cyclophosphamide; CF: cyclophosphamide and fludarabine; CFA: cyclophosphamide, fludarabine and Alemtuzumab; CE: cyclophosphamide and etoposide; CEVD: cyclophosphamide, etoposide, vincristine, dexamethasone; CDVP: cyclophosphamide, daunorubicin, vincristine, prednisone Minimal disease < 5% blasts, morphologic disease 5% blasts CRi: complete remission with incomplete hematopoietic recovery

9 9 UCART123 Targeting AML and BPDCN Hematologic malignancies Healthy tissues Expression in a subset of hematopoietic cells - Plasmacytoid dendritic cells - Basophils - Monocytes - Subsets of hematopoietic progenitors Overexpressed in myeloid leukemias. - In the majority of acute myeloid leukemia (AML) blasts - Associated with leukemia stem cells (LSCs) - In almost all patients with blastic plasmacytoid dendritic cell - neoplasm (BPDCN) Encouraging results with CD123 target in autologous CAR-T approaches (ASH 2017 Budde LE) UCART123 Attributes Anti-CD123 CAR expression to redirect T-cells to tumor antigens Suicide gene for safety TCR disruption 1 to avoid GvHD

10 10 UCART123 in AML and BPDCN Efficacy Data Significant improvement compared to Cytarabine standard-of-care (Ara-C) Peripheral Blood Evaluation Overall Survival Ara-C UCART M TCRa/b KO UCART123 1M UCART M Ara-C UCART123 1M Treatments Started Day 24 TCRa/b KO In collaboration with Dr. Monica Guzman, Cornell-Weill

11 11 UCART123 in AML Encouraging Safety Profile UCART123 preferentially eliminates AML cells over normal hematopoietic cells Day 2 Peripheral Blood Primary AML Cells Bone Marrow Day 8 Normal BM Day 16 or UCART123 TCRa/b KO Day 24 Day 36 In collaboration with Dr. Monica Guzman, Cornell-Weill

12 12 UCART123 in AML and BPDCN Development plan Preclinical Proof of Concept UCART123 In vitro and in vivo development finalized Manufacturing UCART123 High yield, high potency cgmp batches Q Q IND for both indications AML Cornell-Weill BPDCN MD Anderson Phase 1 First patient enrollment, clinical hold lifted after 2 months Study resumed November 2017 with protocol changes Q Q2-Q Interim Data Update on first AML patients Expansion Phase Phase 1b in RR and 1 st line AML and BPDCN patients Expected in 2018 Expected in 2019

13 13 UCARTCS1 Targeting Multiple Myeloma Unmet Medical Need > 30,000 patients / year in the US High relapse rate, median OS of 9 months Target Antigen Well proven target with Elotuzumab (BMS/Abbvie) as PoC CS1 (SLAMF7) is highly expressed on MM cancer cells CS1 is expressed on CD8 T-cells UCARTCS1 Attributes Pre-clinical data shows high efficacy of re-dosing strategies Suicide gene is included for safety TCR gene disruption using TALEN to avoid GvHD CS1 gene is disabled by TALEN to prevent CAR-T Cell cross-reactivity (CS1 is naturally expressed on CD8+ T Cells) CD8 CD8

14 14 UCARTCS1 Increased activity of CAR T-cells following CS1 inactivation Increased yield of CD8 + cells (day 18) Less differentiated T-cell phenotype Higher in vitro anti-tumor activity (4h)

15 15 UCARTCS1 In vivo activity against primary myeloma tumor cells PDX-MM models Establishment of NSG-hu microenvironment (4-6 weeks) Weekly M-protein Monitoring Start ~3 to 4 weeks post MM injection Establishing primary MM in NSG-hu mice MM cells were injected into bone chip Treatment of MM-bearing NSG-hu mice w/ UCARTCS1 Single i.v. injection U C A R T C S 1 Patient s cells from: w / C t r l T - C e l l s w / U C A R T C S 1 M - p r o t e i n ( µ g / m L ) U n t r e a t e d M M T r e a t e d M M P l a s m a C e l l L e u k e m i a M - p r o t e i n ( µ g / m L ) M-Protein (ug/ml w / U C A R T C S 1 w / U C A R T C S 1 U C A R T C S D a y s a f t e r C a r - T i n j e c t i o n D a y s a f t e r C a r - T i n j e c t i o n Jin He, Jing Yang, and Sattva Neelapu UCART CS1 exhibits durable in vivo efficacy in high-risk MM in PDX-MM models

16 16 UCARTCS1 Anti-tumor activity: high performance with re-dosing Percent survival Vehicle UCARTCS1 3E6 UCARTCS1 3E6 redosing UCARTCS1 10E6 UCARTCS1 10E6 redosing Times (days) Day 0 Treatment 1 Day 25 Treatment 2

17 17 UCARTCS1 Development Plan Proof of Concept Increased cytotoxic activity compared to non-edited T Cells Q In vivo studies Ongoing Preclinical studies ongoing in collaboration with MD Anderson Cancer Center (Dr. Jing Yang and Dr. Sattva Neelapu) Manufacturing Development of a modified GMP compatible manufacturing process (inversion of transduction/electroporation steps) Expected in 2018 IND Filing Expected in 2019

18 18 TALEN efficiency and specificity Clinical grade CAR T-Cells Recent tremendous improvements of gene-editing platforms. Boosted academic studies Promising perspectives for therapeutic needs but stringent specificity to control risks of genomic toxicity A mean of mutation frequency of ~ 80% at several loci in primary T cells No off-site mutagenesis detected for TRAC x CD52 double KO ( 60% double KO) 100 Mutation frequency (%) DcK HPRT CTLA4 PD1 TIM3 LAG3 TRAC Modified TALEN active on methylated CpG Genome editing platform established in different species (mouse, cyno) for preclinical studies TALEN also amenable for genome wide analysis of cleavage by Guide-Seq

19 19 Tuning TALEN specificity non-conventional RVDs Non-conventional RVDs display different specificity patterns

20 20 Tuning TALEN specificity non-conventional RVDs Cell count In d e ls fr e q u e n c y T 3 v 1 P D -1 / T R A C T 3 v 2 P D -1 / T R A C T 3 v 3 P D -1 / T R A C T 3 v 4 P D -1 / T R A C T 3 v 1 P D -1 / T R T 3 v 2 P D -1 / T R T 3 v 3 P D -1 / T R T 3 v 4 P D -1 / T R b a c k g r o u n d (N T ) v 1 O S 9 b a c k g r o u n d (N T ) v 2 O S 3 PD P D 1 T R A C v 2 O S3 v 1 O S9 PD1T3v4 maintain high efficiency of gene editing v1os9 and v2os3 are not mutated by PD1T3v4

21 TALEN gene editing for allogeneic CAR T Consistent efficiencies of over 95% of single KOs MOCK TRAC TALEN TCRab Ø Single KO > 95% Ø Recovery > 90% MOCK TRAC TALEN 21

22 Towards next generation CAR T-cells Synthetic biology for high performance UCART Example of targeted integration at CD25 locus CD25 expression upon tumor engagement IL12 contributes to anti tumor activity (Th1, NK, CD8) I.V. IL12 shows systemic adverse effects (BM, Liver, mucus membranes) Local On-Target IL12 secretion may avoid systemic toxicity CAR TALEN TCR STOP Tumor cells Engineered IL-12 follows CD25 expression pattern upon tumor engagement. TCR CAR STOP CAR TALEN CD25 CD25 IL12 STOP 2A IL12 STOP 22 T-cells +++ CD25 CD25 2A IL12 STOP Engineered IL12 Tumor dependent expression of engineered IL-12 under the control of CD25 promoter significantly improves tumor eradication. 22

23 23 Persistence of allogeneic CAR T-cells Double targeted integration

24 Persistence of allogeneic CAR T-cells Combining B2M KO and NK inhibition Gated on TCR-/HLA I- cells > 88% double KO >68 % targeted integration at each locus simultaneously 24

25 TALEN gene editing for allogeneic CAR T Simultaneous TRAC and b2m TALEN AAV6 donor templates targeting CAR at TRAC locus and NK inhibitor at b2m locus HLA-ABC NK B2M TCRab TRAC NK B2M TRAC 96% TCR KO 87% double KO 80/72 % targeted integration at each locus 60% double KI 25

26 TALEN gene editing for allogeneic CAR T High performance cell programming TALEN gene editing allows GMP production of allogeneic CAR T-cells with initial efficacy data on par with autologous CAR T-cells TALEN displays high level of specificity, adequate for clinical use : UCART19 and UCART123 already in the clinic (1 st patient dosed in June 2015 with UCART19) Specificity of a given TALEN can be tuned to eliminate remaining off-target cleavage to lower risk of genotoxicity Highly efficient multiple KO /KI allows a vast array of possibilities to improve clinical benefit of CAR T-cells Rich pipeline of more sophisticated products to enter the clinic in the coming year with expanding clinical data 26

27 THANK YOU