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CAR T-cells, MUC1 CAR T-Cells - Coggle Diagram
CAR T-cells
IMPROVING THE EFFICACY and INFILTRATION
TME MODULATION w/ CT
CAF
fucntion inhibited by thymoquinone (TQ)
TQ inhibit growth factor: EGF, VEGF, FGF, sources of CAF
inhibtion of Wnt3 and PI3K pathway --> no survival of cancer cell after interaction w/ T-cells activated by CAR
VASCULARIZATION MODULATION
HEV production (high endothelial venules) = good prognosis (formation induced by the LTbetaR pathway
improve T-cells infiltrtation
amplified effect w/ PD1/PDL1 blockade
specific marker: MECA-79
express high levels of the ligand of L-Selectin/CD62L, the classic homing receptor for T and B-lymphocytes
prediction tool, infiltration marker
spontaneous formation : expression of OVA-antigen or SV40 large T-antigen
induce by CD3+ and CD8+ cells infiltration
induced by LTbetaR ligand LIGHT (or LTbetaR agonist) fused to vascular zip code peptide in different mouse tumour
induce by TNFalpha in a LTbetaR independent way
EXPERIMENTAL DESIGN
CAR T-cells structure
M-Ab TAB004 MUC28z - 4-1BB construct
CD73 and A2AR expression
MUC28z - antiPDLA as a control to compare with CD73 or A2AR
IMPROVING THE SURVIVAL OF CAR T-CELLS
STRUCTURE MODIFICATION
4-1BB co-stimulatory domain boost CAR T-cells persistence, delay the exhasution (compared to CD28)
CD73 inhibition & A2AR antagonism ==> CD73 is an Adenosine Generating Enzyme and A2AR is an Adenosine receptor, Adenosine is known to inhibit T-cells
M-AB TAB004 MUC28z
CONTEXT
MUC1 expressed in 95% of breast cancer cells
MUC1 CAR T-Cells
immune checkpoint inhibitor (ICI)
PD1/PDL1 blockade, enhance MUC1 CAR T-cells lytic role in vitro (better to target PDL1)
M-Ab TAB004 MUC28z highly specific to mutated tumoral MUC1 and does not recognizes healthy tissues
increase IFNgamma, granzyme B and Th1 chemokines production
