RCTS

MHRA Manufacturing Authorisation for - Investigational Medicinal Products (MA-IMP) - Specials

•  Cells for cellular therapies •  Viral vectors for gene therapy •  Stem cells for regenerative medicine

Production Manager - Lucas Chan Quality Control Manager - Joti Bhalla Qualified Person - David Farrer

Farzin Farzaneh

The Rayne Cell Therapy Suite MHRA Manufacturing Authorisation for Investigational Medicinal Products (MA-IMP)

KCL/KCH - new Cell & Gene Therapy Unit (Q3, 2011)

•  Hepatocyte Transplantation

•  Islet Cell Transplantation

•  Haematological Stem Cell Transplantation

•  Cell and Gene Therapy of Cancer

•  Stem cells for regerative medicine applications

The Rayne Cell Therapy Suite (RCTS)

GeneTherapy Products (Phase-I/II Trials)

50-100 litre batches of retrovirus / lentivirus

•  Immune gene therapy of relapsed Acute Myeloid Leukaemia -  Self-inactivating lentivirus vector (5x1010 IU) - completed

•  Control of graft versus host disease - Retrovirus vector (approx. 1010+ IU) - completed

•  Cancer vaccination with a dendritic cell targeted vector -  Lentivirus (1011 IU) – in process development

AML as a target for cell, gene and peptide based immune therapies

Professional antigen presenting cells

Schwartz 1992

Acute Myeloid Leukaemia (AML) •  AML blasts express both HLA class-I, and class-II •  Express AML associated antigens (WT1, PRAME, GP250, etc) •  Share common lineage with APCs – efficient antigen presentation •  Express many surface markers present on DC, including CD86

(CDB7.2) – but not CD80 (B7.1) !

Rejection of established mouse leukaemia, by vaccination with leukemia cells expressing CD80 (B7.1) and IL-2

Leukemia initiation

(105 32Dp210 cells iv)

32D/M3P (Vector)

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32D/CD80

32D/IL-2

32D/IL-2/CD80

Cell vaccine ●

100 80

60 40

20

0

% S

urvi

val

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■ ■

■ ■

■ ■

■ ■ ■

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Time (days) 100 20 40 60 80 0

Vaccination (106 irradiated cells)

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In mouse leukaemia and solid tumour models, vaccination with the same tumour cell, modified to express CD80 (B7.1) and IL-2, induces immune mediated tumour rejection.

Autologous CTL activity

Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3): 379-88.

E:T ratio = 50:1

CM

Autologous CTL activity in 3 representative

patients

Remission PBLs, stimulated by autologous IL-2/CD80 (B7.1) AML, display cytolytic activity against unmodified AML blasts

Autologous CTL activity

Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3): 379-88.

E:T ratio = 50:1

CM

Autologous CTL activity in 3 representative

patients

Remission PBLs, stimulated by autologous IL-2/CD80 (B7.1) AML, display cytolytic activity against unmodified AML blasts

- Remission T cells are not defective in cytolytic activity

- AML cells are not resistant to cytotoxicity

Specificity of the in vitro stimulated T cells

Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3): 379-88.

Specificity of the in vitro stimulated T cells Secondary targets

AutologousStimulators Unstimulated (media only)

unmodified AML cells

IL-2/CD80 AML

Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3): 379-88.

No target Normal AML CD14+ blasts

Specificity of the in vitro stimulated T cells Secondary targets

Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3): 379-88.

No target Normal AML CD14+ blasts Autologous

Stimulators Unstimulated (media only)

unmodified AML cells

IL-2/CD80 AML

Specificity of the in vitro stimulated T cells Secondary targets

Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3): 379-88.

No target Normal AML CD14+ blasts Autologous

Stimulators Unstimulated (media only)

unmodified AML cells

IL-2/CD80 AML

Specificity of the in vitro stimulated T cells

No target Normal AML CD14+ blasts

Secondary targets

Greater specificity of the CD80/IL-2 stimulated T cells against AML blasts, rather than the remission CD14+ normal bone marrow cells.

Hardwick N et al (2010). Cancer Immunol. Immunther. 59(3): 379-88.

AutologousStimulators Unstimulated (media only)

unmodified AML cells

IL-2/CD80 AML

NK cell stimulation by IL-2/CD80 expressing AML cells

CD3

CD

56

PBMC PBMC + AML

PBMC + IL-2/CD80/AML PBMC + CD80/AML PBMC + IL-2/AML

Ingram W et al (2009). Br J Haematol. 145: 749-60.

Enhanced cytotoxicity of NK cells against K562 and autologous AML cells following co-culture with CD80/IL-2 expressing AML cells

•  Patient NK cells can be expanded & stimulated to express cytolytic activity

•  AML cells not resistant to the cytolytic activity of the stimulated NK cells

Base line +Unmodified + CD80/IL-2 AML modified AML

Base line +Unmodified + CD80/IL-2 AML modified AML

51Cr release assay – isolated NK cells

% S

peci

fic ly

sis

% S

peci

fic ly

sis Target

K562 cells AML Cells

51Cr release assay – isolated NK cells

Target K562 cells AML Cells

Ingram W et al (2009). Br J Haematol. 145: 749-60.

B7.1/IL-2 immune gene therapy for poor prognosis relapsed AML

Chemotherapy

Allo-HSCT RIC

Day 28 Day 56 Day 100

Day 0

Day 100+

Donor Leuckocyte Infusion (DLI) if no evidence of GvHD

reduced leukaemia burden

Reconstituted immune system

(donor chimerism)

Cohort 1

Cohort 2 DLI + AML Cell Vaccine

DLI Alone

105 106 107 108 AML Cell Vaccine

(“autologous”) every 3 weeks

Intensive Chemotherapy but no CR or PR

Advanced  Therapy  Medicinal  Products  

EC  Regula:on  No  1394/2007  

Why  legislate?  Because  there  was  a  gap…  

Chemicals e.g. aspirin

Biologicals e.g. insulin

Gene Therapy

Cell therapy

Tissue engineering

Medical devices

= extent of expertise and legislation

ATMP’s

ATMP: Key definitions •  Non-viable and viable cells are included

•  Products which do not contain viable cells and which do not act principally by metabolic action are excluded

•  Where a product contains viable cells, the pharmacological, immunological or metabolic action of those cells shall be considered as the principal mode of action

•  The association of cells with a device is no longer considered essential for the cells to be termed “engineered”

•  In case of doubt, products will be defined as being in the most tightly regulated category: gene therapy > tissue engineering > somatic cell therapy

Key  principles  of  the  legisla<on  

•  No marketing without prior authorisation

•  Demonstration of Quality, Safety and Efficacy

•  Post authorisation vigilance

•  Centralised procedure mandatory (European Medicines Agency)

“Hospital  Exemp<on”  scheme  

A  specific  exclusion  from  EC  Regula:on  No  1394/2007  

Hospital exemption scheme

•  Based on Section 6 of EC Regulation 1394/2007 (Advanced Therapy Medicinal Products)

•  Allows for unlicensed ATMPs to be used, under very specific conditions: –  prepared on a non-routine basis

–  with specific quality standards

–  used within a hospital in the same Member State

–  a custom-made product for an individual patient

“Specials” scheme •  Sometimes called “compassionate use” or “named

patient use” •  Based on Article 5.1 of Directive 2001/83/EC (the

main directive relating to medicinal products for human use)

•  Allows unlicensed medicines to be supplied to meet special needs:

–  In response to a bona fide unsolicited order –  Formulated in accordance with the specifications of an

authorised health care professional –  For use by an individual patient under the health care

professional’s direct personal responsibility

Similarities between the two schemes

•  Both cover the supply and use of unlicensed medicines (i.e. those without a Marketing Authorisation)

•  A Manufacturer’s Licence, specific to each scheme, is required in order to produce the unlicensed medicines

•  Neither scheme requires a QP to certify batches

Differences between the two schemes

ATMP  hospital  exemp<on   Specials  Product  has  to  be  made  and  used  in  the  same  Member  State  

Specials  may  be  imported/exported  

Product  must  be  used  in  a  hospital   No  restric<on  on  where  a  product  may  be  used  

Manufacture  must  be  non-­‐rou<ne   Manufacture  can  be  rou<ne  Quality,  pharmacovigilance  and  traceability  requirements  equivalent  to  those  products  with  a  Manufacturing  Authorisa<on  

Different  requirements  

Commissioned  by  a  medical  prac<<oner  

Prescribed  by  a  doctor,  den<st  or  supplementary  prescriber  

UK legislation

•  As well as incorporating EC Regulation 1394/2007, the MHRA has also included the following provisions in the UK legislation for the hospital exemption scheme: –  Pharmacovigilance - notification of adverse reactions

–  Possible requirement for a risk management plan

–  Traceability records from donor to use/destruction, kept for 30 years

–  Specific requirements for patient information on the label and in a leaflet

–  An annual return to the MHRA

Qualified Person

Qualifications and requirements

European Directive 2001/83/EC

•  A qualified person shall complete a university course of study in one of the following:

–  pharmacy

– medicine

–  veterinary medicine

–  chemistry

–  pharmaceutical chemistry and technology

–  biology

Directive 2001/83/EC continued…

•  The course shall include theoretical and practical study of the following: –  Applied physics –  General and inorganic chemistry –  Organic chemistry –  Analytical chemistry –  Pharmaceutical chemistry –  General and applied biochemistry –  Physiology –  Microbiology –  Pharmacology –  Pharmaceutical technology –  Toxicology –  Pharmacognosy (composition & effects of natural active substances)

Directive 2001/83/EC continued…

•  The qualified person shall have acquired practical experience over at least two years at a manufacturing site, including analysis of medicinal products and active substances and of the testing and checking necessary to ensure the quality of medicinal products.

•  A person carrying out QP activities before May 1985 shall be eligible to continue to engage in those activities (“grandfather clause”)

To become a QP in the UK…

•  The MHRA require the Society of Biology, the Royal Pharmaceutical Society and the Royal Society of Chemistry to assess the eligibility of their members for Qualified Person status.

•  These organisations provide guidance notes, study guides and the code of practice, as well as the application forms.

RCTS

Production Manager - Lucas Chan

Quality Control Manager - Joti Bhalla

Qualified Person - David Farrer

Angela Osborne

Asthma and Allergy

Alistair Noble James Wells

Infection & Immunity

Adrian Hayday Mark Peakman

Mayo Clinic Stephen Russell

University College London

Mary Collins Bobby Gaspar Waseem Qasim Adrian Thrasher

UCLA Noriyuki Kasahara

Sharon Williams Nigel Slater

University of Cambridge

Imperial College London Colin Casimir Myrtle Gordon Nagy Habib

Mark Aloysius Lindy Durant Oleg Eremin Adrian Robbins

University of Nottingham / QMC

University of Geneva Didier Trono

San Raffaele Institute, Milan Luigi Naldini

Cytokine profile of human autologous T cells following in vitro stimulation (Cytokine Bead Array – CBA)

•  The in vitro stimulated T cells have a predominantly Th1 phenotype

n=3

IFNγ

IL-4

TNF-α

IL-2

IL-6 IL-10

IFNγ

IL-4

TNF-α

IL-2

IL-6 IL-10

IFNγ

IL-4

TNF-α

IL-2

IL-6 IL-10

RCTS