CELL AND GENE THERAPY
Introduction: legal framework ...............................................................................................................2
Handling of cells ..................................................................................................................................7
Donor eligibility .................................................................................................................................. 15
Histocompatibility ............................................................................................................................. 22
Somatic cell therapy medicinal products ............................................................................................ 29
Gene therapy medicinal products ....................................................................................................... 34
Labile blood products ........................................................................................................................ 54
Haematopoietic stem cell transplantation .......................................................................................... 62
Immunotherapy for cancer ................................................................................................................. 68
CAR-T cell therapy ............................................................................................................................. 80
mRNA-based therapeutics ................................................................................................................. 87
1
,INTRODUCTION: LEGAL FRAMEWORK
− Advanced therapy medicinal product
▪ Blood products SOHO = substances of
▪ Tissues and cells = menselijk lichaamsmateriaal = MLM human origin
▪ Organs
▪ Medicinal products
! must fall under 1 of the 4 legislations
(LABILE) BLOOD PRODUCTS
= Products derived from blood + used for transfusion
▪ Red cells = erythrocyte-concentrate
o Bulk of all transfusions – 400.000 units a year in Belgium
▪ Platelets = platelets-concentrate = PC
o Replaced by pharmaceutical plasma – 70.000 units a year in Belgium
▪ Plasma = viro-inactivated plasma
o Used in surgery and oncology – 70.000 units a year in Belgium
! does not include: cord blood – HSC collected by apheresis = tissues and cells
+ albumin – immunoglobulins – viro-inactivated plasma (pooling) = medicinal products
− Manufacturer + distributor: blood bank
Hospital blood bank = distributor in hospital
− No market authorization: alteration of production process or product characteristics
− European legislation + inspection by local authorities
(FAGG = federale agentschap voor gezondheidsproducten en geneesmiddelen)
▪ Donor criteria
▪ Quality controls on blood products
▪ Quality system
▪ Hemovigilance
! most used human product: threat of spread of communicable diseases
TISSUES AND CELLS
= Products derived from humans + non vascularized + minimally manipulated + not for transfusion
▪ Cord blood
▪ HSC collected by apheresis
▪ Bone (fragments: orthopedics)
▪ Cornea
▪ Skin – tendons – heart valves
▪ Gametes: sperm – oocytes – embryos (IVF)
▪ SOHO legislation: human breast milk – human faeces
! does not include: cells expanded by culture = more than minimal manipulation
E.g. grafts of the locomotory system – ocular tissue
2
, − Manufacturer + distributor: tissue establishment
E.g. bank voor hematopoëtische stamcellen – weefselbank voor reproductieve cellen
! Belgium: confidential data of patients should be handled in a hospital – not commercial
▪ Tissue establishment
o Must be located in a hospital – no commercial banks
o Responsible person: medical doctor
▪ Intermediate establishment
o Allowed outside a hospital – or commercial banks
= process – storage – distribution
o Under control of a tissue establishment
= collection – donor testing – donor confidentiality issues – ex/import
▪ Production establishment
o Allowed outside a hospital – or commercial banks
o Not under control of a tissue establishment = autonomous
= process – storage – distribution of autologous tissues and cells
o Responsible person: medical doctor
➔ pharmaceutical companies can generate advanced therapy medicinal products
Independent from a tissue establishment
! only depend on the hospital where the patients is treated
− No market authorization: alteration of production process or product characteristics
− European legislation + licensing and inspection by local authorities
▪ Donor criteria
▪ Quality controls on tissues
▪ Quality system
▪ Biovigilance
! volume = limited
ORGANS
− Cadaveric donors: organs harvested from patients that are brain death
▪ Heart-beating usually
E.g. trauma or intracranial bleeding
▪ Eurotransplant: law responsible for organ allocation
o Based on computer algorithm: urgency code – HLA – blood group – age – …
o Covers Germany – Belgium – Netherlands – ….
! high number of donations: opting-out legislation (2%)
− Living donation
= kidneys – left lobe of liver from adult to child
= intent to help a particular person
− Storage: hours (heart) ➔ days (kidneys)
! stored on ice ➔ stored with vessels perfused
! Waiting list for organ acceptors grows: paid donation is illegal
XENOTRANSPLANTS
− Remediate donor shortage + patients dying on the waiting list
E.g. transplantation of pig kidneys or hearts to patients
! innate immunity directed against different sugar chains on the cells
+ endogenous retroviruses which may transmit to humans
Minipigs
o Make more human polysaccharides
o Endogenous retroviruses deleted
3
, MEDICINAL PRODUCTS
− Any substance or combination of substances presented as having properties for treating or
preventing diseases in human beings
− Any substance or combination of substances which may be used in or administered to humans
▪ Restoring – correcting – modifying: physiological functions
▪ Usage of: pharmacological – immunological – metabolic actions
▪ Make a medical diagnosis
! substance: may be human – animal – microbial – vegetable – chemical
Anything for use in humans: should be saved + attractive to industry
+ studied according to GCP
+ produced according to GCP should be a medicinal product
‘not for profit’ producers can no longer develop new products
− Distributor: pharmacy
− Market authorization: product is fixed
▪ Dossier
o Manufacturer
o Composition of the product
o Production process
o Toxicology studies = safety
o Clinical studies = efficacy
▪ Labelling + information leaflets
▪ Pharmacovigilance
▪ Alteration of production process or product characteristics: analysed + reported
BIOLOGICAL MEDICINES
− SD-plasma = albumin + coagulating factors + immunoglobulins
ADVANCED THERAPY MEDICINAL PRODUCTS = ATMP
GENE THERAPY MEDICINAL PRODUCTS = GTMP
− Inclusion: anything that modifies the genome
▪ Plasmids DNA
o RNA produced by biological enzymes
▪ Viral vectors
▪ Genetically engineered microorganisms
▪ Human gene-editing technology
▪ Patient-derived cellular gene therapy products
e.g. CAR-T – correction of a genetic defect such as haemophilia A – thalassemia
− Exclusions
▪ Non-biological products
o RNA produced by chemical synthesis
▪ Vaccines against infectious diseases = recombinant vaccines
− Zolgensma
▪ Viral particles that contain genetic code for SMN1-gene
o Protein essential for motor neuron function
o Spinal Muscular Atrophy
4
Introduction: legal framework ...............................................................................................................2
Handling of cells ..................................................................................................................................7
Donor eligibility .................................................................................................................................. 15
Histocompatibility ............................................................................................................................. 22
Somatic cell therapy medicinal products ............................................................................................ 29
Gene therapy medicinal products ....................................................................................................... 34
Labile blood products ........................................................................................................................ 54
Haematopoietic stem cell transplantation .......................................................................................... 62
Immunotherapy for cancer ................................................................................................................. 68
CAR-T cell therapy ............................................................................................................................. 80
mRNA-based therapeutics ................................................................................................................. 87
1
,INTRODUCTION: LEGAL FRAMEWORK
− Advanced therapy medicinal product
▪ Blood products SOHO = substances of
▪ Tissues and cells = menselijk lichaamsmateriaal = MLM human origin
▪ Organs
▪ Medicinal products
! must fall under 1 of the 4 legislations
(LABILE) BLOOD PRODUCTS
= Products derived from blood + used for transfusion
▪ Red cells = erythrocyte-concentrate
o Bulk of all transfusions – 400.000 units a year in Belgium
▪ Platelets = platelets-concentrate = PC
o Replaced by pharmaceutical plasma – 70.000 units a year in Belgium
▪ Plasma = viro-inactivated plasma
o Used in surgery and oncology – 70.000 units a year in Belgium
! does not include: cord blood – HSC collected by apheresis = tissues and cells
+ albumin – immunoglobulins – viro-inactivated plasma (pooling) = medicinal products
− Manufacturer + distributor: blood bank
Hospital blood bank = distributor in hospital
− No market authorization: alteration of production process or product characteristics
− European legislation + inspection by local authorities
(FAGG = federale agentschap voor gezondheidsproducten en geneesmiddelen)
▪ Donor criteria
▪ Quality controls on blood products
▪ Quality system
▪ Hemovigilance
! most used human product: threat of spread of communicable diseases
TISSUES AND CELLS
= Products derived from humans + non vascularized + minimally manipulated + not for transfusion
▪ Cord blood
▪ HSC collected by apheresis
▪ Bone (fragments: orthopedics)
▪ Cornea
▪ Skin – tendons – heart valves
▪ Gametes: sperm – oocytes – embryos (IVF)
▪ SOHO legislation: human breast milk – human faeces
! does not include: cells expanded by culture = more than minimal manipulation
E.g. grafts of the locomotory system – ocular tissue
2
, − Manufacturer + distributor: tissue establishment
E.g. bank voor hematopoëtische stamcellen – weefselbank voor reproductieve cellen
! Belgium: confidential data of patients should be handled in a hospital – not commercial
▪ Tissue establishment
o Must be located in a hospital – no commercial banks
o Responsible person: medical doctor
▪ Intermediate establishment
o Allowed outside a hospital – or commercial banks
= process – storage – distribution
o Under control of a tissue establishment
= collection – donor testing – donor confidentiality issues – ex/import
▪ Production establishment
o Allowed outside a hospital – or commercial banks
o Not under control of a tissue establishment = autonomous
= process – storage – distribution of autologous tissues and cells
o Responsible person: medical doctor
➔ pharmaceutical companies can generate advanced therapy medicinal products
Independent from a tissue establishment
! only depend on the hospital where the patients is treated
− No market authorization: alteration of production process or product characteristics
− European legislation + licensing and inspection by local authorities
▪ Donor criteria
▪ Quality controls on tissues
▪ Quality system
▪ Biovigilance
! volume = limited
ORGANS
− Cadaveric donors: organs harvested from patients that are brain death
▪ Heart-beating usually
E.g. trauma or intracranial bleeding
▪ Eurotransplant: law responsible for organ allocation
o Based on computer algorithm: urgency code – HLA – blood group – age – …
o Covers Germany – Belgium – Netherlands – ….
! high number of donations: opting-out legislation (2%)
− Living donation
= kidneys – left lobe of liver from adult to child
= intent to help a particular person
− Storage: hours (heart) ➔ days (kidneys)
! stored on ice ➔ stored with vessels perfused
! Waiting list for organ acceptors grows: paid donation is illegal
XENOTRANSPLANTS
− Remediate donor shortage + patients dying on the waiting list
E.g. transplantation of pig kidneys or hearts to patients
! innate immunity directed against different sugar chains on the cells
+ endogenous retroviruses which may transmit to humans
Minipigs
o Make more human polysaccharides
o Endogenous retroviruses deleted
3
, MEDICINAL PRODUCTS
− Any substance or combination of substances presented as having properties for treating or
preventing diseases in human beings
− Any substance or combination of substances which may be used in or administered to humans
▪ Restoring – correcting – modifying: physiological functions
▪ Usage of: pharmacological – immunological – metabolic actions
▪ Make a medical diagnosis
! substance: may be human – animal – microbial – vegetable – chemical
Anything for use in humans: should be saved + attractive to industry
+ studied according to GCP
+ produced according to GCP should be a medicinal product
‘not for profit’ producers can no longer develop new products
− Distributor: pharmacy
− Market authorization: product is fixed
▪ Dossier
o Manufacturer
o Composition of the product
o Production process
o Toxicology studies = safety
o Clinical studies = efficacy
▪ Labelling + information leaflets
▪ Pharmacovigilance
▪ Alteration of production process or product characteristics: analysed + reported
BIOLOGICAL MEDICINES
− SD-plasma = albumin + coagulating factors + immunoglobulins
ADVANCED THERAPY MEDICINAL PRODUCTS = ATMP
GENE THERAPY MEDICINAL PRODUCTS = GTMP
− Inclusion: anything that modifies the genome
▪ Plasmids DNA
o RNA produced by biological enzymes
▪ Viral vectors
▪ Genetically engineered microorganisms
▪ Human gene-editing technology
▪ Patient-derived cellular gene therapy products
e.g. CAR-T – correction of a genetic defect such as haemophilia A – thalassemia
− Exclusions
▪ Non-biological products
o RNA produced by chemical synthesis
▪ Vaccines against infectious diseases = recombinant vaccines
− Zolgensma
▪ Viral particles that contain genetic code for SMN1-gene
o Protein essential for motor neuron function
o Spinal Muscular Atrophy
4
