CAR T-cell therapy Flashcards
What is the function of Helper T cells (CD4)?
Upon binding to a specific antigen, helper T cells secrete cytokines to stimulate the differentiation of B cells into plasma cells (antibody-producing cells)
What is the function of Cytotoxic cells (CD8)?
Upon activation, cytotoxic T cells bind and kill infected cells and cancer cells (or any substance marked as foreign by the immune system)
How are cytotoxic T cells activated?
By simultaneous interactions of surface molecules (TCR-MCR and CD28-CD80) between cytotoxic T cell and APC cells
These two cell stimulating interactions result in T cell proliferation and activation
What is the first T cell activation signal?
Between TCR of the cytotoxic T cell and MHC I of the APC
What is the second T cell activation signal?
Between CD28 of cytotoxic T cell and CD80 of APC
What are the co-stimulators for T cell activation?
CD80/86
What is the TCR-CD3 complex?
It is a signalling complex comprised of TCR and three CD3 subunits
When TCR-CD3 is activated by MHC I from APC, it will bind ZAP70 ro initiate the activation of T cells via TCR pathway
see slide 5
How do T cells actually destroy targeted cells?
Cytotoxic T cells release perforin, granzyme, and granulysin
All substances are involved in the destruction and breakdown of cells
What are the functions of perforin?
Forming pores on target cell membranes
What are the functions of granzyme?
Inducing apoptosis of target cells
What are the functions of granulysin?
Forming pores in microbial cell walls
What are some techniques used by cancer cells to evade immune response?
- Overexpression of CD47 (binds to SIRPa)
- Downregulation of MHC I molecules
- Lack of costimulatory signals (downregulation of CD80)
- Secretion of immunosuppressive molecules (recruited immune cells are inactivated)
- Modulation of antigens (old T-cells can no loger bind to cancer cells)
What is CAR T-cell therapy?
Chimeric antigen receptor (targeting a specific antigen in cancer cells such as CD19)
CAR T cells are engineered T cells with CAR on the surface
In general, how are CAR T cell therapies designed?
- Collect T cells from a patient’s blood
- Add the chimeric gene (encoding CAR) into the T cells in a laboratory (gene should be unique to cancer)
- Grow and collect CAR T cells in the laboratory
- Infuse CAR T cells into the patient
What is the latest generation of CAR T cell therapies to be approved for regular use?
2nd generation CAR T cell therapies
What are the components of the chimeric antigen receptor (CAR)?
- scFv (single-chain variable fragment)
- Hinge
- Transmembrane domain
- CD3 (activates TCR signalling pathway)
What is a single-chain variable fragment (scFv)?
It is a fusion protein of the variable regions of the heavy chain and light chain.
The two are combined into a single unit
What is most significant difference between different generations of CAR T cells?
Newer generations have more costimulators
1st gen: 0 co-stimulators (low efficacy)
2nd gen: one co-stimulator along with CD3
3rd gen: two co-stimulators along with CD3
What are some challenges associated with CAR T cell therapy?
- Time consuming
- High cost (about $500,000 per treatment course)
- Hostile tumour microenvironment
- T cell exhaustion (loss of effector function due to prolonged antigen stimulation)
- Regulatory hurdles
What are some characteristics of tumour cells that express CD19?
Biomarker for lymphoma and leukemia (universally expressed in B-cell avute lymphoblastic leukemia)
Serves as a target for CAR T-cell therapy
What are some characteristics of B-cell maturation antigen (BCMA)?
Biomarker for multiple myeloma
Overexpression and activation are associated with multiple myeloma
Member of TNF-receptor superfamily
What are some characteristics of the drug Kymriah (tisagenlecleucel)?
- 4-1BB as the co-stimulator
- Targeting CD 19 antigen
Indicated for B-cell precursor acute lymphoblastic leukemia and diffuse large B-cell lymphoma
What are some characteristics of the drug Yescarta (axicabtagene ciloleucel)?
- CD28 as the co-stimulator
- Targeting CD19 antigen
Indicated for Diffuse large B-cell lymphoma and Follicular lymphoma
What are some characteristics of the drug Tecartus (brexucabtagene autoleucel)?
- CD28 as the co-stimulator
- Targeting CD19 antigen
Indicated for Mantle cell lymphoma
What are some characteristics of the drug Breyanzi (lisocabtagene maraleucel)?
- 4-1BB as the co-stimulator
- Targeting CD19 antigen
Indicated for large B-cell lymphoma
What are some characteristics of Abecma (idecabtagene vicleucel)?
- 4-1BB as the costimulator
- Targeting B-cell maturation antigen (BCMA)
Indicated for multiple myeloma
What are some characteristics of Carvytkti (ciltacabtagene autoleucel)?
- 4-1BB as the co-stimulator
- Targeting B-cell maturation antigen (BCMA)
Indication for relapsed/refractory multiple myeloma
What is the advantage of using 4-1BB as a costimulator vs CD28?
4-1BB as a co-stimulator for CAR T cell therapies shows better survival in B-cell acute lymphoblastic leukemia
