Cellular therapies Flashcards
What is adoptive T-cell therapy?
Isolation of T-cells, expansion & transfer back to patients
Which T-cell types are being explored for adoptive T-cell therapy?
- Tumour-infiltrating lymphocytes (TILs)
- Gene-engineered T-cells
What is the strategy of adoptive T-cell therapy using TILs?
Ex vivo expansion of naturally occuring TILs isolated from the tumour
Where are T-cells for genetic engineering isolated?
Patient peripheral blood
What is usually changed in engineered T-cell therapy?
Genetically engineered receptor to make the T-cells (more) tumour-specific
Which two options are there for T-cell receptor engineering?
- CAR T-cell receptor
- TCR-cells
What is a CAR T-cell receptor?
Chimeric antigen receptor
Do CAR or TCR T-cells have higher antigen affinity? Why?
CAR T-cells have higher antigen affinity due to its antigen-recognizing domain being an antibody
What are the characteristics of TCR T-cells? (3)
- Recognition of peptides in MHC
- Access to intra- en extracellular peptides
- Low-to-intermediate affinity binding
What are characteristics of CAR T-cells?
- Recognition of peptides independent of MHC
- Access to extracellular peptides only
- High affinity binding
What is the advantage of the MHC-independence of CAR T-cells?
Allows these cells to circumvent downregulation of MHC, which often happens in tumours
What are the goals of the field of adoptive T-cell therapy? (2)
- Expand the number of target antigens to be able to treat (nearly) all types of tumours
- Increase longevity of T-cells to induce long-term regression
What are requirements for TCR/CAR therapy targets? (5)
- Not expressed in healthy tissues
- Abundantly expressed in tumour
- Preferably expressed in multiple tumour types
- Preferable expressed shared between patients
- Immunogenic
What are the groups of suitable TCR/CAR therapy antigens? (3)
- Target antigens related to oncogenesis
- Antigens related to immune evasion in tumours
- New antigens related to HLA mis-match
What are target antigens related to oncogenesis? (5)
- Differentiation antigens
- Over-expressed antigens
- Cancer germline antigens
- Onco-viral antigens
- Cancer neoantigens
What is the downside of using differentiation antigens as targets for TCR/CAR therapy?
They are ovexpressed in tumours, but not completely absent in healthy cells
What is the downside of using over-expressed tumour-associated antigens as targets for TCR/CAR therapy?
They are highly selective, but not completely selective for tumour cells
What are the advantages of using cancer germline antigens as targets for TCR/CAR therapy? (2)
- They are often not expressed in mature tissues -> high tumour-specificity
- Shared by tumour types & among patients
What is the advantage and what is the disadvantage of using oncoviral antigens as targets for TCR/CAR therapy?
Advantage: highly tumour-specific
Disadvantage: only found in tumours derived from viral infections
What are cancer neoantigens?
Non-physiological antigens, resulting from gene mutations/abberations in tumour cells
What are the advantages of cancer neoantigens as targets for TCR/CAR therapy? (2)
- Exclusively expressed by tumour cells
- Can be shared between multiple tumour sites, as they often occur in the same genes
What is the disadvantage of cancer neoantigens as targets for TCR/CAR therapy?
They are not necessarily shared between many patients
What is the process of antigen discovery for TCR/CAR therapy? (7)
- In silico prediction of antigens from databases
- Checking absence of expression in healthy tissues using mRNA & protein expression assays
- Checking expression of antigen in target tumour tissue
- Antigen epitope selection using in silico prediction
- Confirmation of selected epitopes using immunopeptidomics
- Exclusion of potential cross-reactivity using expitope screen
- Selecting of most promising epitopes according to HLA avidity
What is a disadvantage of TCR T-cell therapy?
The original TCR is not eliminated
