CAR T Cells Flashcards
What CAR T cell therapies are approved in the UK for large B cell lymphoma?
Axicabtagene ciloleucel (Yescarta)
For treatment of adults with relapsed/refractory diffuse large B cell lymphoma
What CAR T cell therapy is approved in the UK for treatment of ALL?
Tisagenlecleucel (kymriah)
For children and young adults with relapsed/refractory B cell ALL
What is the mechanism of cytotoxic T cell killing?
Antigen specific (HLA-1)
Does not require co-stimulation
Apoptosis induced via perforin/granzyme or death receptor pathway (FasL)
CTL also produces cytokines such as IFN-gamma to act on target cell e.g upregulated HLA, sensitise to apoptosis
What is the process of CAR T cell receptor design?
Receptor must recongise something specific on the surface of a cancer cell
Extracellular recognition domain from antibodies is used - does not require HLA - binds directly to antigen
Intracellular signalling domains to mirror TCR - activate T cell
Can add additional intracellular domains - co-stimulation etc
How do CAR T cells kill the target cells?
Perforin and granzyme
FasL and Fas (target cell)
Secretion of IFN-gamma which sensities cancer cells to apoptosis
What is the basic process by which CAR T cells are developed?
Is an adoptive cell therapy
Manufactured from patients own leukocytes
Patient already has advanced cancer when cells are taken
Cells taken from peripheral blood, taken frozen to manufacturing site, takes a few weeks to produce
Return to hospital frozen for treatment
How are CAR T cells transduced?
Genetic sequence encoding of a CAR (recognition and signalling domain) is cloned and packaged into a lentiviral or retroviral vector
T cells activated and expanded by stimulating with anti-CD3 and anti-CD28 Ab.
Virsues transduce T cells which then proliferate.
T cells take up coding sequence to express the CAR
For the patient what is the process of CAR T cell therapy
- Testing for appropriateness
- Leukapheresis
- Bridging chemotherapy
- Lymphodepletion
- Infusion
- Management (treatment starts to work)
What is the process of Leukapheresis for CAR T cell therapy?
When patients own autologous T cells are removed from PB to undergo transformation to CAR T cells
Two IV lines - blood draw and blood return, fractiosn of blood seperated in machine by densiry, desired fraction routed to transfer bag and untapped material returned.
What is often used for bridging chemotherapy during CAR T cell treatment?
Prednisolone
Vincristine
Doxorubicin
What drugs can be used for lymphodepletion in CAR T cell therapy?
Fludarabine + cyclophosphamide
Contraindication for administration includes active infection.
What is required for the infusion of CAR T cells?
1 million cells /kg below 50Kg
Around 100 million cells/kg above 50Kg
Paracetamol and anti-histamine before infusion
Infusion at 10-20ml per minute
What are the possible side effect of CAR T cell therapy?
Low B cells and antibodies = immunocompromised
Cytokine release syndrome and neurotoxicity
Tumour lysis syndrome
What is cytokine storm as a side effect of CAR T cell therapy?
CAR T cell produced lots of cytokines = IL-6 (also from myeloid macrophages) = cause systemic inflammatory response.
Can be life-threatening - difficulty breathing, nausea, dirrhoea, fatigue, muscle pain, low BP, tachyHR, headache, liver injury - within 14 days of infusion
What is the treatment for cytokine storm as a side effect of CAR T cell therapy?
Tocilizumab - targets IL-6
What is neurotoxicity as a side effect of CAR T cell therapy?
Presentation - seizures, decreased consciousness, loss of reality, difficulty taking/walking/understanding.
Immune effector cell associated neurotoxicity, BBB disruption, microglial activation and neuroinflammation.
What is tumour lysis syndrome as a side effect of CAR T cell therapy?
Seen in bulk treatment of sensitive high burden haematopoetic malignancy
Dying cells release content into extracellular space
Hyperuricemia, hyperK+, hyperPO4-
Can cause acute renal failure, cardia arrhythmias and seizures.
What is the treatment for tumour lysis syndrome (side effect of CAR T cell therapy)?
Hydration
Anti-hyperuricaemic agent
What is the treatment for Low B cells and antibody?
(side effect of CAR T cell therapy)
IV immunoglobulin - IVIG
What is the cost of CAR T cell therapy?
How is this managed practically?
Very expensive - compared to standard chemo
In UK paid from Cancer Drugs Fund
What methods can be used to improve remission duration from CAR T Cell therapy?
Patient selection - low tumour burden, earlier treatment
Pre-infusion - lymphocyte depletion and immune checkpoint inhibitors
Post CAR - immune checkpoint inhibitors, maintenance therapy
What is the Universal CAR-T?
Endogenous TCR and Beta2m disrupted so don’t respond to allo MHC - prevents graft v host disease
SUPRA CAR - extracellular domain has a lock and key like function allows target antigen to be changed by changing ECD
Allows off the shelf CAR T cell therapy for any patient with any cancer
What is an armoud CAR T cell?
PD-1 gene knockout - unable to be exhausted
What is a TRUCK CAR T?
T cells redirected for universal cytokine mediated killing
Produces IL-12 dirve IFN-gamma -> dampens immunosuppressive environment and trigges bystanded immune activtion.
What is the purpose of a CAR T with NK receptor?
NK receptor binds stress ligand expressed by tumour
Provides alternative recongition pathway if target antigen is downregulated on cancer
Allows activation of T cell
What is the potential of CAR T cell therapy in treating solid tumours?
Poor efficacy
Low blood flow into tumour
Hypofunctional in tissue - low persistance and proliferation
Likely due to immunosuppressive microenvironment that induced T cell exhaustion and Treg
