CAR T-CELLS: ENGINEERING IMMUNE CELLS TO TREAT CANCER. Roman GALETTO, PhD 17 th Club Phase 1 Annual Meeting April 5 th Paris

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1 CAR T-CELLS: ENGINEERING IMMUNE CELLS TO TREAT CANCER Roman GALETTO, PhD 17 th Club Phase 1 Annual Meeting April 5 th Paris Cellectis, 05-APR-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 CAR Structure and Mechanisms of Action CAR T-cell Production Targeted Antigens, Preclinical Models and Toxicity Studies CAR T-cells in current Clinical Development Next Generation of CAR T-cells

4 CAR Structure and Mechanisms of Action CAR T-cell Production Targeted Antigens, Preclinical Models and Toxicity Studies CAR T-cells in current Clinical Development Next Generation of CAR T-cells

5 5 CAR T-cells Chimeric Antigen Receptors TUMOR CELL Lymphocytes are engineered in order to recognize specific tumor antigens and drive killing of the cancer cells Clinical trials with CARTs targeting CD19 in patients with B-cell leukemia have shown impressive results, with unprecedented remission rates

6 6 CAR T-cells Living Drugs in Immuno-Oncology CARs: Cell membrane bound mabs Allows MHC-independent antigen recognition - only antigens expressed at the cell surface are recognized - resistant to one of the known immune recognition evasion mechanisms shown in tumors (MHC downregulation by tumor cells) T-cells replicate in response to contact with antigen in vivo CAR domains are derived from different human proteins, each conferring a particular function to the chimeric protein

7 7 CAR T-cells Structure and Mechanism of Action from The Scientist, April 1 st 2015 TCR derived signalling domain (CD3ζ) TCR derived signalling domain (CD3ζ) Co-stimulatory domain derived from CD28 or 41BB TCR derived signalling domain (CD3ζ) Co-stimulatory domain derived from CD28 or 41BB Supplementary Costimulatory domain (derived from CD27, CD134 or other) CD3ζ : transduction of initial activation signals (proliferation and cytotoxic activity) Co-stimulatory domains: enhance cell proliferation and persistence

8 8 CAR T-cells Structure and Mechanism of Action CART cell activation upon antigen recognition mediates direct killing of tumor cells

9 CAR Structure and Mechanisms of Action CAR T-cell Production Targeted Antigens, Preclinical Models and Toxicity Studies CAR T-cells in current Clinical Development Next Generation of CAR T-cells

10 10 CAR T-cells Production of Autologous CART cells T-cell enrichment/purification Polyclonal activation of T-cells Transduction with lentiviral vector (insertion of CAR coding sequence) Infusion to the patient Expansion ex-vivo in closed culture systems (Bioreactors) Purification, Formulation and Cryopreservation of CAR T-cells QC and product release

11 CAR Structure and Mechanisms of Action CAR T-cell Production Targeted Antigens, Preclinical Models and Toxicity Studies CAR T-cells in current Clinical Development Next Generation of CAR T-cells

12 12 CAR T-cells Targeted antigens Uniform expression in tumor cells - in all cells and at comparable levels Minimal/null expression in normal cells - avoid "on-target/off-tumor" toxicity Tumor accessibility by CARTs (route of administration) Potential activity in the context of tumor microenvironment

13 13 CAR T-cells B-cell lymphomas and anti-cd19 CART cells Unprecedented clinical responses in R/R B-ALL and LBCL Uniform expression in B-cell lymphomas (and normal B-cells) - acceptable on-target/off-tumor activity (B-cell aplasia compensated by Immunoglobulin infusion) Malignant B-cells (present in PB, LS and BM) are easily accessible by CART cells upon IV administration Permissive tumor microenvironment in comparison to solid tumors Two products approuved by FDA in 2017: 30AUG2017 (Novartis): R/R B-ALL patients (at least two prior relapses) 18OCT2017 (Kite/Gilead): Large B-cell lymphoma after two previous lines of treatment

14 14 CAR T-cells B-cell lymphomas and anti-cd19 CART cells Long-term survival based on approximations of the reported event-free survival curves

15 15 CAR T-cells Beyond B-cell lymphomas Target selection 1) Target and scfv validation - assessment of potential off-target binding (specificity) Tissue Cross Reactivity, Cell microarray - on-target/off-tumor toxicity Expression levels in healthy vs. tumor cells metastatic colon cancer patient (lung and liver) - Respiratory distress 15 min after infusion - Massive organ failure HER2 expression in healthy tissues (including lung) was responsible of pulmonary distress and CRS

16 16 CAR T-cells Beyond B-cell lymphomas - on-target/off-tumor toxicity Expression levels in healthy vs. tumor cells Modulation of scfv/car affinity Modification of CAR architecture in order to modulate expansion, survival and persistence of CART cells in vivo CAR transient expression Pharmacological Immunosuppression or incorporation of suicide mechanisms to limit CART cell activity Alternative routes of administration: ensure lymphocyte homing and accessibility to the tumor (and limit systemic spread of CARTs)

17 17 CAR T-cells Beyond B-cell lymphomas Target selection 2) Development of preclinical models - mouse and/or cynomologous models to assess activity and toxicity Inter-species reactivity of the scfv Development of syngeneic models

18 CAR T-cells Beyond B-cell lymphomas Target selection 3) Possibility to adapt therapeutic doses according to tumor burden Minimize the risk/intensity of CRS and its consequences (multi-organ failure and neurotoxicity) Factors associated to CRS: - Tumor burden - CART cell doses - CART cell expansion - Lymphodepleting regimen? - Cytokine levels reached after infiusion (mainly IL-6) Lee et al. Blood,

19 19 CAR T-cells Beyond B-cell lymphomas Target selection 3) Possibility to adapt therapeutic doses according to tumor burden Minimize the risk/intensity of CRS and its consequences (multi-organ failure and neurotoxicity) CD4/CAR+ CD8/CAR+ T Albumin IL-6 IFNγ Gust et al. Cancer Discovery Dec.2017

20 CAR Structure and Mechanisms of Action CAR T-cell Production Targeted Antigens, Preclinical Models and Toxicity Studies CAR T-cells in current Clinical Development Next Generation of CAR T-cells

21 21 CAR T-cells CARTs in clinical development Hartmann et al; EMBO Mol Med, 2017

22 CAR T-cells CARTs in clinical development Hartmann et al; EMBO Mol Med,

23 23 CAR T-cells CARTs in clinical development Solid Tumors (completed trials) Completed CAR solid tumor clinical trials Johnson and June; Cell Research. 2017

24 CAR Structure and Mechanisms of Action CAR T-cell Production Targeted Antigens, Preclinical Models and Toxicity Studies CAR T-cells in current Clinical Development Next Generation of CAR T-cells

25 CAR T-cells Next generation CART cells Selected cell population as staring material - T-cells SCM/CM - ratios CD4/CD8 Self renewal Proliferative Capacity Vectorization strategies - random integration of viral vectors - targeted integration* - transient expression Effector functions Cytotoxic activity Short lifespan Improved trafficking and tumor infiltration (in solid tumors) - intra-tumor injection - CAR co-expression with chemokine receptors * Using gene-editing technologies 25

26 CAR T-cells Next generation CART cells CART cells compatible with SOC for a defined indication or with lymphodepleting regimens - Cells resistant to PNAs* - Cells resistant to MAbs* Bypass evasion mechanisms developed by tumors - target more than one TAA to avoid development of "resistance" (CD19/CD20) - Cells resistant to the immunosuppressive tumor microenvironment combination with anti-ctla4 or anti-pd1 MAbs CARTs KO* for CTLA4 or PD1 * Using gene-editing technologies 26

27 27 CAR T-cells Next generation CART cells Improve safety profile - control CAR activity AND NOT Srivastava and Ridell; Trends in Immunology. 2015

28 28 CAR T-cells Next generation CART cells Off-the-shelf allogeneic CART cells

29 29 CAR T-cells Next generation CART cells Off-the-shelf allogeneic CART cells Cellules CART autologues.. Cellules CART allogéniques (off-the-shelf) TCR KO Allogeneic T-cells that are genetically engineered: - to target a tumor-associated antigen and - to minimize the risk of GvHD by knocking out the TCR

30 30 Allogeneic UCART cells GMP Manufacturing As any off-the-shelf product, UCARTs are manufactured and controlled ahead of time. UCARTs are stored as frozen vials in defined dosage forms, shipped to be readily available at the clinical sites, to be directly administered upon thawing.

31 UCART123 cells Targeting AML and BPDCN UCART123 Attributes Anti-CD123 CAR expression to redirect T-cells to tumor cells Suicide gene for safety TALEN mediated TCR disruption to avoid GvHD Preclinical efficacy data in AML Peripheral Blood Evaluation Overall Survival Ara-C UCART M TCRα/β KO UCART123 1M UCART M Ara-C UCART123 1M Treatments Started Day 24 TCRα/β KO Significant improvement compared to Cytarabine standard-of-care (Ara-C) In collaboration with Dr. Monica Guzman,Weill Cornell 31

32 32 UCART123 cells Preclinical efficacy data in AML Animals treated with UCART123 achieve lasting molecular remission In collaboration with Dr. Monica Guzman,Weill Cornell

33 UCART123 cells Encouraging safety profile UCART123 preferentially eliminates AML cells over normal hematopoietic cells Peripheral Blood Day 2 Primary AML Cells Bone Marrow Day 8 Normal BM Day 16 or UCART123 TCRα/β KO Day 24 Day 36 In collaboration with Dr. Monica Guzman,Weill Cornell 33

34 34 UCARTCS1 cells Targeting MM UCARTCS1 Attributes Anti-CS1 CAR expression to redirect T-cells to tumor cells 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) Increased activity of CAR T-cells following CS1 inactivation Increased yield of CD8 + cells Higher in vitro anti-tumor activity Less differentiated T cell phenotype

35 35 UCARTCS1 cells 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 Patient s cells from: M -protein (µ g /m L ) M-Protein (ug/ml M -protein (µ g /m L ) Jin He, Jing Yang, and Sattva Neelapu UCART CS1 exhibits durable in vivo efficacy in high-risk MM in PDX-MM models

36 36 CART cells Conclusions & Perspectives Engineering immune cells to seek and destroy cancer cells is a revolution in cancer treatment CART cells have a major therapeutic potential against certain types of cancer, with encouraging results for treatment of hematological cancers Improvement in the management of secondary effects is easing the clinical implementation of CART cell treatments Current research aims to improve expansion and persistence of CART cells upon patient treatment Next generation of CART cells currently in early phases of development will allow to improve safety and limit toxicity of treatments, as well as making these therapies widely and rapidly available

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38 38 CAR T-cells Structure and Mechanism of Action

39 39 Efficient depletion of RQR8+ cells CDC and ADCC Mechanisms ADCC Assay QBend10 (CD34) epitope Rituxan (CD20) mimitope CD8 stalk and TM CDC Assay

40 40 CAR T-cells CARTs in clinical development Liquid Tumors (targeting CD19 or CD20) Fesnak, June and Levine; Nature Reviews Cancer. 2016

41 41 CAR T-cells CARTs in clinical development Liquid Tumors (additional targets) Fesnak, June and Levine; Nature Reviews Cancer. 2016

42 CAR T-cells CARTs in clinical development Solid Tumors Fesnak, June and Levine; Nature Reviews Cancer