Co-ordinating Genetically Engineered Adoptive Cell-Based Immunotherapies - Immune Cells That Can Be Hijacked and Programmed to Target Cancer

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1 1 Co-ordinating Genetically Engineered Adoptive Cell-Based Immunotherapies - Immune Cells That Can Be Hijacked and Programmed to Target Cancer ADOPT SUMMIT nd March 2016 London Cedrik Britten

2 DISCLAIMER C. Britten Employee at GSK 2

3 SMALL MOLECULES, BIOLOGICALS & CELL THERAPIES Fundamental differences in size and other properties Molecular Weight: g/mol Molecular Weight: 145,000 g/mol Molecular Weight n.a. Weight Size 82 x g 8 Å Weight Size x g 10 nm Weight: Size g 11 mm Imatinib Rituximab T cell Bigger than other therapeutic modalities! Utilize a cellular carrier! ( living drugs ) Can be engineered! (immune-receptor & the cell) 3

4 NATURAL & ENGINEERED T CELLS T-cell therapeutics come in different flavours Natural T cells as medicines Science Sep 19;233(4770): A new approach to the adoptive immunotherapy of cancer with tumour-infiltrating lymphocytes. Rosenberg SA, Spiess P, Lafreniere R. CAR-T cells as medicines Transplant Proc Feb;21(1 Pt 1): Generation of effector T cells expressing chimeric T cell receptor with antibody typespecificity. Gross G1, Gorochov G, Waks T, Eshhar Z. TCR-T cells as medicines J Virol Sep;74(17): Transfer of specificity for human immunodeficiency virus type 1 into primary human T lymphocytes by introduction of T-cell receptor genes. Cooper LJ, Kalos M, Lewinsohn DA, Riddell SR, Greenberg PD.

5 THE POWER OF T CELLS T cells can control tumour growth in vivo First statement: Irrefutable evidence that an entirely immunologic approach can cause regression of a wide array of human cancers has come from the recent success of using monocloncal antibodies targeting checkpoints of immune activation including CTLA-4 and PD-1...* Second statment:...despite different mechanisms of action, these immunotherapies culminate with the activation and expansion of tumourreactive T cells! * *CA Klebanoff, SA Rosenberg & NP Restifo, Nature Medicine 2016

6 DISEASE TREATMENT CAR CAR TCR UNIQUE FEATURES / BIOLOGY Combination of cell with synthetic (NEW) receptors Cell Carrier LIVING CARRIER Cell Carrier + UNIQUE IMMUNE- RECEPTORS TUMOUR TARGETS Tumour cell Extracellular targets (10%) Intracellular targets (90%)

7 CAR-T in the News Transformational benefit in B cell malignancies! 7

8 VISION FOR CAR-T & TCR-T Transformational benefit made available for many patients CAR-T and TCR-T cell therapies will confer cure or long-term disease control in patients where other treatments cannot achieve similar effects be available for broad patient populations with multiple haematological and solid cancers and many non-oncologic diseases be supplied to patients in an cost-effective manner

9 CAR-T IN THE NEWS Transformational benefit beyond B cell malignancies? How to expand the observations from CD19 CAR-T to other targets and solid cancers? 9

10 CAR-T TARGETS More targets and increasing number of players Siemann DW (2002) Haematological malignancies Target Phase Players CD19 Preclin - PIII Novartis, Kite, Juno, Bellicum, Amarna, Cellectis, Takara CD20 PIIa Cellular Biomedicine Group CD138 PI/II Cellular Biomedicine Group CD22 Preclin - PI Juno, celgene, Cellectis, Novartis CD30 Preclin - PI Cellular Biomedicine Group, celgene BCMA Preclin - PI Novartis, Bluebird, Sorrento ROR-1 Preclin - PI Juno, Sorrento Therapeutics CD123 P0 Cellectis, Novartis CS1 preclin Cellectis, NantKwest, Sorrento CD38 preclin Cellectis-Pfizer CD23 preclin Formula Pharma CD33 preclin Formula Pharma CD44v6 Preclin MolMed Solid tumors Target Phase Players GD2 PI/II Bellicum, Baylor College of Medicine, NCI, CARsgen Therapeutics, Celgene EGFRvIII PI/II Novartis, Kite MUC-1 PI/II PersonGen Biomedicine Mesothelin PI Novartis, Chinese PLA General Hospital, NCI, CARsgen EGFR PI CARsgen Therapeutics, Cellular Biomedicine Group PSMA PI Sorrento Therapeutics, NantKwest, Formula Pharmaceuticals L1-CAM PI Juno, Sorrento MUC-16 + IL-12 PI Juno glypican-3 (GPC3) PI CARsgen Therapeutics CEA PI Sorrento Therapeutics, Sirtex medical cmet Phase 0 Novartis (RNA CAR-T) ROR1 Preclin-PI Juno, Sorrento Therapeutics 5T4 Preclin Cellectis, Oxford BioMedica Only a selection of publicly known targets listed HER2 Preclin Bellicum, Celgene, Sorrento PSCA Preclin Bellicum CSPG4 Preclin Sorrento CD44v6 Preclin MolMed 10

11 TCR-T TARGETS Few targets, slowly increasing number of players Siemann DW (2002) Haematological malignancies Target Phase Who? NY-ESO-I PI/II Adaptimmune WT-1 Preclin- PI/II Juno, UCL Solid tumors Target Phase Who? NY-ESO-1 PI/II Adaptimmune-GSK, Takara, Kite MAGE A4 PI Takara Mage A10 PI Adaptimmune HPV E6/E7 PI Kite MAGE A3/A6 PI Kite AFP Preclin. Adaptimmune PRAME Preclin. Bellicum Only a selection of publicly known targets listed 11

12 DISEASE TREATMENT CAR CHALLENGES & OPPORTUNITIES How to expand the use of CAR-T & TCR-T? OPTIMIZE SAFETY OPTIMIZE EFFICACY Cell carrier MODIFIERS OF CELL FUNCTION IMMUNE- RECEPTOR MODIFIERS OF CELL FUNCTION IMMUNE- RECEPTOR COMBI- NATIONS KNOWN TARGETS Tumour Cell NEW TARGETS NEW TARGETS 12

13 Time-limited cell persistence TREATMENT CAR TECHNOLOGY INNOVATIONS TO OPTIMIZE SAFETY Control of cell function to open Therapeutic windows OTHER MODIFIERS OF CELL FUNCTION NK cell carrier Tumour tissue Healthy tissue Klebanoff CA et al., Nature Medicine 2016 NEW TARGETS NK cell dies and loses function 13

14 TREATMENT CAR TECHNOLOGY INNOVATIONS TO OPTIMIZE SAFETY Control of Immune-receptor activity to open therapeutic windows IMMUNE-RECEPTOR Universal CAR Universal CAR Add redirection agent + Transiently redirected cell NEW TARGETS Klebanoff CA et al., Nature Medicine

15 TREATMENT CAR TECHNOLOGY INNOVATIONS TO OPTIMIZE EFFICACY Optimize effector function of cell carrier OTHER MODIFIERS OF CELL FUNCTION COMBI- NATIONS Activation Persistence Expansion Resistance to Inhibitory Factors Migration Effector Function NEW TARGETS 15

16 APPROACHES IN CLINICAL TESTING TILs, Ex Vivo-Derived CTL, CAR and TCR-Transgenic T cells PHASE I PHASE I/II PHASE II T cells + Experimental Vaccine (e.g. FowlPox, Dendritic Cell, Peptide) T cells + Anti-CTLA-4 mab TILs + BRAF inhibitor TILs with Forced CXCR2 + NGFR Expression TILs with Forced IL-2 Expression Defined T cell subsets: e.g. CD8 T CM + CD4 Virus Specific Hosts (e.g. EBV) VZV Specific Hosts + Zostervax T cells + Anti-PD-1 mab Dominant Negative TGF-b T cells + Vaccine + anti-vegf mab Forced IL-12 Expression TILs + Systemic rh IL-15 Some trials terminated due to toxicity 16

17 SELECTED EMERGING APPROACHES some published examples Cell Engineering Chimeric Activating Receptors: e.g. PD-1-CD28, IL-4-IL-7, TGF-b-TLR4 Co-Stimulator Expression: e.g. CD40L, 4-1BBL, OX40L Expression of IL-7/IL-15/IL-21 Expression of Heparanse Expression of CD8 Knockout/Knockdown of Negative Checkpoints and/or Regulators: e.g. PD-1, SOCS family Co-Therapy Additional Checkpoints e.g. anti-pd-l1, anti-ox40, Anti-4-1BBL Other Modulators of the Suppressive Tumor Microenvironment: e.g. by inhibition of COX-2, PDE 5, Adenosine Receptor (A2A/A2B), CD73, IDO, or induction of inflammation by PAMP such as TLR agonist Induction of Antigen and/or MHC by Epigenetic Modifying Drugs e.g. Decitabine 17

18 CAR TARGETS AND CLINICAL DATA Most data so far generated for a limited number of targets *clinicaltrials.gov.uk Haematological malignancies Target Trials Diseases CAR generations CD19 48 Lymphoma, leukemia 2nd, 3rd, 4th CD30 4 Lymphoma 4th CD123 2 Leukemia 2nd BCMA 1 Multiple myeloma 2nd ROR1R 1 Leukemia - CD33 1 Leukemia 2nd CD20 1 Lymphoma, leukemia 2nd CM-CS1 1 Lymphoma, leukemia - CD22 1 Lymphoma CD138 1 Multiple myeloma 2nd kappa 1 Lymphoma, leukemia, Myeloma 2nd Solid tumors Target Trials Diseases CAR generations Mesothelin 5 Mesothelioma, Ovarian, Pancreatic Cancer, Breast cancer 2nd, 4th HER-2 4 Breast cancer, Glioblastoma, Metastatic cancer 2nd GD-2 4 Osteosarcoma, Neuroblastoma, Melanoma, Metastatic Cancer 3rd, 4th MUC1 2 Glioma,Carcinoma, Lung cancer - CEA 2 Lung cancer, Liver cancer, Colorectal cancer, Gastric Cancer, Breast Cancer, Pancreatic Cancer - EphA2 1 Glioma - CD171 1 Neuroblastoma 2nd, 3rd GPC3 1 Hepatocellular carcinoma 2nd EGFR 1 Glioma - EGFRvIII 1 Glioma, Glioblastoma, Brain tumors - VEGFR2 1 Melanoma, Renal Cancer - cmet 1 Breast - CD133 1 Solid tumors 2nd IL13Ra2 1 Glioma 2nd PSMA 1 Prostate 2nd CD19 + Mesothelin 1 Pancreatic cancer 2nd FAP 1 Mesothelioma - ErbB 1 SCCHN 2nd

19 VISION FOR CAR-T & TCR-T Transformational benefit made available for many patients CAR-T and TCR-T cell therapies will confer cure or long-term disease control in patients where other treatments cannot achieve similar effects be available for broad patient populations with multiple haematological and solid cancers and many non-oncologic diseases be supplied to patients in an cost-effective manner

20 Manufacturing of CAR-T and TCR-T Automation Where and how?

21 VISION FOR CAR-T & TCR-T Transformational benefit made available for many patients CAR-T and TCR-T cell therapies will confer cure or long-term disease control in patients where other treatments cannot achieve similar effects be available for broad patient populations with multiple haematological and solid cancers and many non-oncologic diseases be supplied to patients in an cost-effective manner

22 A view into the future and into the past and the present

23 PATIENT JOURNEY IN 2025 The right treatment for the right patient In the future the healthcare environment will be different Comprehensive diagnostics to assess clinical, molecular, immunological, genomic, metabolic, and other assessments will be common We will know much more about the patients and his/her disease. Multiple therapeutic modalities (small molecules/biopharms, in vivo gene therapies and cell & gene therapies) will coexist and will be applied in a disease/patient-specific manner Highly fragmented use. Patient-derived data will be widely used for personalised treatment selections, supported by dynamically changing algorithms - Knowledge of the patient will be actively applied to select the best treatment for a given patient and/or the best patient for a given treatment.

24 Payers Patients 7 Reimbursement 1 Treatment algorithms 6 Consultation 2 Health Care Provider Pharmacy Treatment & follow-up Small molecules Biopharmaceuticals & in vivo Gene Therapies Cell & Gene Therapies Drug Supply Diagnosis -Clinical - molecular - immunological - other Treatment Selection Proposed Therapeutic Options Apheresis Unit 5 3 Prescription Cell Therapy Manufacturing Facility 4 Confirmation with companion Diagnostic(s) Pharmaceutical Industry (Therapeutics & Diagnostics)

25 Payers Patients 7 Reimbursement 1 Treatment algorithms Health Care Provider 6 Treatment & follow-up Drug Supply 5 Consultation Prescription 2 Diagnosis -Clinical - molecular - immunological - other Small The choice of the molecules treatment will be agnostic Biopharmaceuticals & for Pharmacy the therapeutic modality No privileges Apheresis Unit in vivo Gene Therapies Cell & Gene for Therapies cell therapies! Treatment Selection 3 Proposed Therapeutic Options Cell Therapy Manufacturing Facility 4 Confirmation with companion Diagnostic(s) Pharmaceutical Industry (Therapeutics & Diagnostics)

26 HOW TO REACH MANY PATIENTS? 3 areas need to be right! How to reach a high adoption for a given treatment and to make a medicine commercially viable? Clinical Benefit Offer best treatment option for a given patient Supply Chain & Cost of Goods Commercialisation & Reimbursement

27 Analogues: Sipuleucel-T A look into the past 4.1 mo. OS improvement Uncertainties about MoA Provenge Central Manufacturing Hubs Non-automated manufacturing $93,000 for a full course of treatment (3 doses). Reimbursement uncertainties at launch Decentivized physicians through high upfront treatment costs

28 Analogues: Sipuleucel-T 3 areas need to be right and there is competition! 4.4 mo. OS improvement 4.8 mo. OS improvement Zytiga 4.1 mo. OS improvement Uncertainties about MoA Xtandi Small molecule $99,000 Small molecule $59,600 Provenge Central Manufacturing Hubs Non-automated manufacturing $93,000 for a full course of treatment (3 doses). Reimbursement uncertainties at launch Decentivized physicians through high upfront treatment costs

29 CD19 CAR-T The present Transformational Benefit CD19 CAR Automated manufacturing Central Manufacturing Hubs??? $200,000 for a single treatment??? Reimbursement schemes still need to be defined???

30 CD19 CAR-T The present 32% complete remission median duration 6.7 months Blincyto Transformational Benefit Biopharm $178,000 per year CD19 CAR Automated manufacturing Central Manufacturing Hubs??? $200,000 for a single treatment??? Reimbursement schemes still need to be defined???

31 CD19 CAR-T The present 32% complete remission median duration 6.7 months Blincyto Transformational Benefit CD19 CAR (Sponsor 2) Biopharm $178,000 per year CD19 CAR CD19 CAR (Sponsor 3) Automated manufacturing Central Manufacturing Hubs??? $200,000 for a single treatment??? Reimbursement schemes still need to be defined???

32 In order for TCR-T & CAR-T to become a broad success all of the four mentioned factors will need to be optimized!

33 33 TCR-T and CAR-T are complex medicines and have multiple components Target Immune-receptor Technology Cell Carrier Patients TCR Pipeline Asset (company 1) NY-ESO-1 Affinity-matured TCR 1st gen Bulk Lymphocytes Sarcoma / Ovary Cancer / Melanoma CAR Pipeline Asset (company 2) New target CAR Optimized CAR Optimized carrier Solid cancer X New gene-modified Cell Therapy Asset (company 3) New Target Immune-Receptor x Technology y Cell Carrier Z Cancer Entitiy

34 34 Removing barriers... Towards a versatile CGT Tool Box and new product permutations Target Immune-receptor Technology Cell Carrier Patients TCR Pipeline Asset (company 1) NY-ESO-1 Affinity-matured TCR 1st gen Bulk Lymphocytes Sarcoma / Ovary Cancer / Melanoma CAR Pipeline Asset (company 2) New target CAR Optimized CAR Optimized carrier Solid cancer New gene-modified Cell Therapy Asset (company 3) New Target Immune-Receptor x Technology y Cell Carrier Z Cancer Entitiy Aim is to remove barriers between internal and external product lines AND connections between the different components of a given asset to reach synergy and to enable new and better product permutations.

35 35 COLLABORATION-BASED MODEL More than one technology innovation may be needed Target Immune-receptor Technology Cell Carrier Patients Target X 2nd gen CAR Solid Cancer z 2nd Gen TCR Safety Switch Virus-specific T cells 2nd gen CAR Enhanced Antigen Presentation Selected T cells Logic gate CAR dntgfbeta NK cells CAR with enhanced T cell signalling PD-1 KO gd T cells

36 LESSONS LEARNED Known limitations and unique opportunities o o o o o CAR-T and TCR-T have unique biological properties that fundamentally differ from small molecules and biopharms. Tailored use of safety technology innovations may overcome existing limitations for multiple known targets increased safety. The modular use of efficay technology innovations may allow to reach transformational benefit for CAR-T & TCR-T for multiple haematological and solid cancers increased efficacy. Automation will become a critical step towards decreasing the costs for CAR-T and TCR-T who will own & control the supply chain? As there is not a single technology innovation that will address all challenges collaborations across boundaries will be a key success factor. 36

37 THANK YOU! 37