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

08/10/2018 4

Collect T-cells from Patient Expansion of tumour specific T cells T-cells returned to Patient Issues: low frequency of tumour specific T cells No suitable tumour specific antigen with which to select T cells

Adoptive T cell Therapy

08/10/2018 5

Collect T-cells from Patient Expansion of tumour specific T cells T-cells returned to Patient

Gene Modification

Engineered T cells

08/10/2018 6

T-cell receptor gene therapy Antibody targeted T-cells

Recombinant TCR

Chimeric Antigen receptor

scFV (single chain variable fragment) CD3 Signalling domain

Avoidance of HLA restriction

08/10/2018 7

     

MHC-epitope-TCR complex Single chain antibody fragment Cell surface antigen Signalling domain

z

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

08/10/2018 10

Kawalekar et al. Immunity 2016

The result

08/10/2018 11

Hartman et al. EMBO Mol Med. 2017 Sep; 9(9): 1183– 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

08/10/2018 14

• Challenging
• Technical
• Low throughput
• Expensive

Miltenyi Biotec

Product Variability

08/10/2018 15

Hartman et al. EMBO Mol Med. 2017 Sep; 9(9): 1183– 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

08/10/2018 17

90% CR – 30 patients

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

2nd 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

08/10/2018 25

Collect T-cells from patient Genetic modification with viral vector Virus encoding Chimeric Antigen Receptor Expansion of cells Re-infusion to conditioned patient

Manufacturing Clinical Management

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?

08/10/2018 32

• E. Vivier et al., Nature Imm. Rev. 2012

Activating receptor Inhibitory receptor

Natural Killer Receptors

Natural Killer Receptors – NKG2D

08/10/2018 33

Charles Sentman

NKR2 - Multiple Targets

08/10/2018 34

• 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

NKG2D Binding Ligands MICA MICB ULBPs 1-6

NKG2D can bind to any of eight naturally occurring ligands that are known to be

• verexpressed on over 80% of solid and hematological tumors

NKG2D tumor ligand expression

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

NKR2 in vitro characterization

08/10/2018 36

Predicted CAR MW 38.5 kDa

K 5 6 2 N K R 2 5 1 0 1 5

2 :1 E ffe c to r:T a rg e t ra tio IF N - (n g /m L )

P AN C -1 N K R 2 2 4 6 8 1 0

2 :1 E ffe c to r:T a rg e t ra tio IF N - (n g /m L )

N o A n tib o d y Is o ty p e C D 3 1 4 5 0 1 0 0 1 5 0

IF N - (n g /m L )

K 5 6 2 P A N C -1

In vivo activity

08/10/2018 37

MULTIPLE MYELOMA 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

OVARIAN CANCER

First observation of objective clinical response in AML

08/10/2018 38

Complete Response in AML patient receiving CYAD-01

08/10/2018 39

40 High level of NKG2D ligands expression on bone marrow blast cells at baseline

Complete Response in AML patient receiving CYAD-01

41

Patient’s CYAD-01 CAR-T recognize specifically NKG2D ligand positive cell lines

Complete Response in AML patient receiving CYAD-01

CYAD-01: THINK trial (solid arm) promising early results at first dose level

Promising early results at first dose level (3x108)

• 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

Contact: info@celyad.com

Charles Sentman

Research and Development: Peggy Sotiropoulou Sophie Agaugue Eytan Breman Benjamin Demoulin Sébastain Mauën Jennifer Bolsée Lorraine Springuel Alexandre Michaux Susanna Raitano Martina Fontaine Dorothée Daro Céline Jacques-Hespel Céline Marchand Fanny Huberty Nancy Ramelot Jérôme Marijsse Julien Houssa Thuy Nuygen Benjamin Violle

Dana Farber Cancer Institute Sarah Nikifarrow

Clinical Development: Frederic Lehman Caroline Lonez