CAR T cell Therapy for cancer David Gilham Vice President R&D - PowerPoint PPT Presentation

CAR T cell Therapy for cancer David Gilham Vice President R&D Hon Reader, Institute for Cancer Sciences, University of Manchester

Forward looking statements 08/10/2018 2

Overview Adoptive T cell therapy • Chimeric Antigen Receptor (CAR) • CD19 and beyond • Natural Killer receptors for CAR T cell approaches • 08/10/2018 3

Adoptive T cell Therapy Issues: low frequency of tumour specific T cells No suitable tumour specific antigen with which to select T cells Expansion of tumour specific T cells T-cells returned Collect T-cells to Patient from Patient 08/10/2018 4

Adoptive T cell Therapy Gene Modification Expansion of tumour specific T cells Collect T-cells T-cells returned from Patient to Patient 08/10/2018 5

Engineered T cells T-cell receptor Antibody scFV (single chain variable gene therapy targeted T-cells fragment) Chimeric Recombinant Antigen CD3 TCR Signalling receptor domain 08/10/2018 6

Avoidance of HLA restriction Cell surface antigen MHC-epitope-TCR complex Single chain antibody fragment       Signalling domain z 08/10/2018 7

CAR Structure 08/10/2018 8

Differential effects of the co-stimulatory signaling domain 08/10/2018 9 Kawalekar et al. Immunity 2016

Differential effects of the co-stimulatory signaling domain Kawalekar et al. Immunity 2016 08/10/2018 10

The result Hartman et al. EMBO Mol Med. 2017 Sep; 9(9): 1183 – 08/10/2018 11 1197.

CAR T cell therapy 08/10/2018 12 https://labiotech.eu/medical/immuno-oncology-history-car-t-nyt/

Novartis – CD19 CAR Process 08/10/2018 13 https://directorsblog.nih.gov/2017/08/30/fda-approves-first-car-t- cell-therapy-for-pediatric-acute-lymphoblastic-leukemia/

CAR-T cell Manufacturing Challenging • Technical • Low throughput • Expensive • Miltenyi Biotec 08/10/2018 14

Product Variability Hartman et al. EMBO Mol Med. 2017 Sep; 9(9): 1183 – 08/10/2018 15 1197.

Kinetics of chemotherapy versus CAR T 08/10/2018 16 Jain et al. Therapeutics and clinical management 2018

CD19 CAR T cell therapy - Complete Responses in bALL 90% CR – 30 patients 08/10/2018 17

CD19 CAR T cell therapy 08/10/2018 18 http://celltrials.info/2017/09/28/analysis-published-results-car-t-cell-therapy-trials/

Novartis CD19 CAR - Kymriah 08/10/2018 19

Novartis CD19 CAR - Kymriah 08/10/2018 20

2 nd licensed CD19 CAR T cell product – relapsed / refractory NHL 08/10/2018 21

EU licensing of CD19 CAR T 08/10/2018 22

08/10/2018 23 http://celltrials.info/2017/09/28/analysis-published-results-car-t-cell-therapy-trials/

China is now leading the CAR T wave 08/10/2018 24 http://celltrials.info/2017/09/28/analysis-published-results-car-t-cell-therapy-trials/

CAR-T cell therapy Clinical Management Re-infusion to conditioned Collect T-cells patient from patient Expansion of cells Manufacturing Virus encoding Chimeric Genetic modification with Antigen Receptor viral vector 08/10/2018 25

Clinical Management: Current CAR-T cell therapy is dependent upon patient pre-conditioning • Removal of competing patient white cells for ‘ space ’ • ‘ Damage ’ to lymphoid compartment – stimulates IL-7 / IL-15 secretion driving homeostatic expansion of adoptively transferred T cells. • Impact upon resident immune suppressive factors • Probable impact upon tumour (transient reduction in tumour cells?) T cell infusion soon after pre-conditioning • Window of opportunity to exploit the pre-conditioning effect • Remains unclear if there is a dose dependent response – likely to be a threshold 08/10/2018 26

Toxicity – is an issue 08/10/2018 27

Potential Toxicities 08/10/2018 28 Bonifant et al. Molecular Therapy – Oncolytics (2016)

Control systems 08/10/2018 29 Labbiotech.Eu

08/10/2018 30 http://celltrials.info/2017/09/28/analysis-published-results-car-t-cell-therapy-trials/

08/10/2018 31 http://celltrials.info/2017/09/28/analysis-published-results-car-t-cell-therapy-trials/

A different route to target solid (and hematological) tumors? Activating receptor Natural Killer Receptors Inhibitory receptor E. Vivier et al., Nature Imm. Rev. 2012 08/10/2018 32

Natural Killer Receptors – NKG2D Charles Sentman 08/10/2018 33

NKR2 - Multiple Targets NKG2D can bind to any of eight naturally occurring ligands that are known to be overexpressed on over 80% of solid and hematological tumors NKG2D Binding Ligands MICA MICB ULBPs 1-6 Several NKG2D ligands can be expressed by stressed cells during infection, • tumorigenesis or DNA damage Tumor types that express NKG2D ligands include: bladder, breast, colorectal, leukemia, • myeloma, ovarian and pancreatic 08/10/2018 34

NKG2D tumor ligand expression Tumor type Expressed NKG2D ligand References [18 – 24] Acute lymphoblastic leukemia 28-67% MICA/B 9-20% ULBP1-3 [17 – 19, 22, 23, 25 – Acute myeloid leukemia 0-75% MICA/B 16-50% ULBP1 35] 4-64% ULBP2 16-100% ULBP3 Bladder Carcinoma 70% MICA [36, 37] Brain cancer 90% MICA, MICB and ULBP1-3 [6, 38, 39] [8, 40 – 43] Breast cancer 35-100% MICA/B, ULBP 1-5 Cervical cancer 20% MICA, ULBP2 [44, 45] Chronic Lymphocytic 0-85% MICA/B [19, 22, 23, 46, 47] Leukemia 10-20% ULBP1-3 Chronic Myeloid Leukemia 28-100% MICA/B [19, 23, 48, 49] 12-20% ULBP1-3 Colorectal cancer 80-100% MICA/B, [8, 50, 51] ULBP 1-5 [52 – 54] Gastric Carcinoma 40-100% MICA/B, ULBP2 [5, 55 – 57] Hepatocellular Carcinoma 60-100% MICA, Head and neck squamous cell 100% MICA/B (7/7 cell lines) [58, 59] carcinoma [21, 23, 24, 60 – 67] Lymphoma 28-44% MICA/B 12-20% ULBP1-3 [14, 68 – 70] Melanoma 50% MICA/B [16, 71 – 76] Multiple Myeloma 10-60% MICA 0-34% ULBP1-3 Neuroblastoma 86% MICA/B, ULBP1-3 [77] [8, 78 – 80] Non-small-cell lung carcinoma 20-30% MICA/B, ULBP1-3 [8, 15, 81 – 83] Ovarian carcinoma 50-97% MICA/B, ULBP1-5 [84 – 86] Pancreatic cancer 68-89.3% MICA/B 08/10/2018 35 Prostate cancer 75-95% MICA/B, sMICA/B [8, 87] Renal Cell Carcinoma > 95% MICA/B [8, 49, 88, 89]

NKR2 in vitro characterization 1 0 1 5 8 IF N -  (n g /m L ) IF N -  (n g /m L ) 1 0 6 4 5 2 0 0 P AN C -1 N K R 2 K 5 6 2 N K R 2 2 :1 E ffe c to r:T a rg e t ra tio 2 :1 E ffe c to r:T a rg e t ra tio K 5 6 2 1 5 0 P A N C -1 IF N -  (n g /m L ) 1 0 0 5 0 0 N o A n tib o d y Is o ty p e C D 3 1 4 08/10/2018 36 Predicted CAR MW 38.5 kDa

In vivo activity MULTIPLE MYELOMA OVARIAN CANCER LEUKEMIA 1. Barber, A. et al., J. Immunol (2009) 183(4):2365-72 2. Barber, A. et al., J. Immunol (2009) 183(11):6939-47 3. Barber, A. et al., J. Immunol (2008) 180(1):72-8 4. Barber A. et al.,Exp. Hematol. (2008) 36(10):1318-28 08/10/2018 37

First observation of objective clinical response in AML 08/10/2018 38

Complete Response in AML patient receiving CYAD-01 08/10/2018 39

Complete Response in AML patient receiving CYAD-01 High level of NKG2D ligands expression on bone marrow blast cells at baseline 40

Complete Response in AML patient receiving CYAD-01 Patient’s CYAD-01 CAR-T recognize specifically NKG2D ligand positive cell lines 41

CYAD-01: THINK trial (solid arm) promising early results at first dose level Promising early results at first dose level (3x10 8 ) Two metastatic colorectal cancer patients reported as Stable Disease at 3- • months follow-up* Refractory pancreatic patient was in progression at the same time point • No toxicity signals reported up to now • Higher doses, longer follow-up + SHRINK and LINK * According to recent studies conducted on similar patient populations, median progression free survival in these patients under standard of care is between 1.9 and 3.2 months. Sources: Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy (CORRECT), Grothey A., Lancet Oncol. 2015 Aug;16(8):937-48 ; Asian Subjects With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy (CONCUR), Li J., Lancet Oncol. 2015 Jun;16(6):619-29 42

Summary CAR T cell therapy is now established as a clinically relevant therapeutic approach 08/10/2018 43

What is next? Currently based on an autologous approach Is this feasible in the long term? Allogeneic cell therapy? 08/10/2018 44

Allogeneic CAR T cell therapy 08/10/2018 45

Research and Development: Clinical Development: Peggy Sotiropoulou Frederic Lehman Sophie Agaugue Caroline Lonez Eytan Breman Benjamin Demoulin Charles Sentman Sébastain Mauën Jennifer Bolsée Lorraine Springuel Dana Farber Cancer Institute Alexandre Michaux Susanna Raitano Sarah Nikifarrow Martina Fontaine Dorothée Daro Céline Jacques-Hespel Céline Marchand Fanny Huberty Nancy Ramelot Jérôme Marijsse Julien Houssa Thuy Nuygen Benjamin Violle Contact: info@celyad.com