CAR T-Cell Therapy Flashcards
What is the role of helper T cells?
upon binding of a specific antigen, helper T cells secrete cytokines to stimulate the differentiation of B cells into plasma cells (antibody-producing cells)
What is the role of cytotoxic T cells?
upon activation, cytotoxic T cells bind and kill infected cells and cancer cells
How are cytotoxic T cells activated?
simultaneous interactions of surface molecules between cytotoxic T cell and APC –> T cell proliferation
first signal: interaction between TCR of cytotoxic T cell and MHC I of APC
second signal: interaction between CD28 of cytotoxic T cell and CD80/CD86 of APC
What are CD80 and CD86?
co-stimulators of T cell activation
What makes up the TCR-CD3 complex?
TCR is noncovalently associated with a signaling complex consisting of:
-CD3y heterodimer
-CD3S heterodimer
-CD3 homodimer
ITAM: immunoreceptor tyrosine-based activation motif
-bind ZAP70 to initiate the TCR signaling pathway–>activation of T cells
What is the effector function of cytotoxic T cells?
upon exposure to target cells, activated cytotoxic T cells release perforin, granzyme and granulysin
-perforin: forming pores on target cell membranes
-granzyme: inducing apoptosis of target cells
-granulysin: forming pores in microbial cell walls
How do cancer cells evade immunosurveillance?
overexpression of CD47 expression
-binds to SIRPa on macrophages and reduces the attack on cancer cells
downregulation of MHC I molecules
-unrecognition of antigens
lack of costimulatory signals
secretion of immunosuppressive molecules
modulation of antigens
What are the strategies in developing immunotherapy against cancer?
bring cytotoxic T cells to cancer cells via an interaction other than TCR-MHC I
-overexpression of cancer antigens on cancer cell surface
-develop binding options against cancer antigens
-express cancer antigen-specific receptor on the surface of cytotoxic T cells
maintain and enhance the stimulatory signals within cytotoxic T cells (keep CD3)
add a hinge and transmembrane domain to link the surface receptor and CD3
leading to the development of 1st gen CAR
What is CAR T-cell therapy?
CAR: chimeric antigen receptor (targeting a specific antigen in cancer cells)
CAR T cell: engineered T cell with CAR on the surface
How is CAR T cell therapy made?
collect T cells from patients blood
add the chimeric agene into the T cells in a lab
grow and collect CAR T cells in the lab
infuse CAR T cells into the patient
What is the core of CAR 1st gen?
scFv: single-chain variable fragment
-bind cancer antigen molecule
hinge
transmembrane domain
CD3
-bind ZAP70 and activate TCR signaling pathway
What is scFv?
fusion protein of the variable regions of heavy chain (Vh) and light chain (Vl) of antibodies
CDR: complementary determining regions (binding specific antigens)
What are the components added to CAR since the second generation?
co-stimulators:
-CD28: binding CD80/CD86
-4-1BB: binding 4-1BBL
2nd gen: one co-stimulator along with CD3
3rd gen: two co-stimulators along with CD3
NFAT transcription factors: stimulating IL-12 production
-4th gen
JAK-STAT activation domain derived from IL-28: stimulating cell proliferation and inhibiting terminal differentiation
-5th gen
What are the challenges of CAR T-cell therapy?
time consuming
high cost
hostile tumor microenvironment: interfering with T cell activity differentiation and exhaustion
T cell exhaustion: progressive loss of effector function due to prolonged antigen stimulation
What are the FDA approved CAR T-cell therapies?
all are 2nd gen
Kymriah
Yescarta
Tecartus
Breyanzi
Abecma
Carvykti
