CAR = chimeric antigen receptor
individualized treatment against cancer
patients T cells are reprogrammed
CAR is expressed to fight cancer cells
- to kill cancer cells: which specific antigens are only on cancer cells?
- CAR T are modified to detect cancer-specific antigens. they express chimeric antigen receptors that match antigen on tumor.
How are CAR T cells made?
- Isolate T cells from blood of patient
- Genetically modify T cell to incorporate CAR gene
- can use viral vectors e.g. lentivirus
- transduction: virus inserts CAR gene
- CAR (protein, receptor) is produced on surface of T cell → CAR T cell is born!
- CAR T cell population/growth happens in vitro
- CAR T cells infused back into patient
- CAR T cells patrol body and kill tumor cells w/ antigen that matches CAR
- Once the CAR recognizes the antigen, can trigger downstream pathways to kill the tumor, e.g. cytokine release, granzyme/perforin, FAS and FAS ligand
Key criteria for good CAR targets
- surface expression on tumor (CARs can’t target intracellular proteins)
- high expression level on cancer cells (ideal: uniquely expressed on cancer cells)
- limited/no expression on vital normal tissues
- essential for cancer cell survival (to prevent antigen escape)
Challenge: most tumor antigens are also expressed (albeit at lower levels) on some normal tissues, e.g.
- BCMA (target for multiple myeloma) is also on plasma cells
- GD2 (neuroblastoma target) is on peripheral nerves
- HER2 (breast cancer target) is on cardiac cells
videos to watch
- Justin Eyquem, Julia Carnevale: Bridging Synthetic Immunology and Genome Editing to Advance CAR-T Cell Therapies
- Carl June keynote: CAR T cells - the Convergence of Synthetic Biology and Cancer Immunotherapy
- Alex Marson: Reprogramming T cells with CRISPR