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
On which parameters do TCR T-cells need to be tested? (3)
- Sensitivity
- Specificity
- Efficacy
How can sensitivity of TCR T-cells be tested?
Co-culture of TCR T-cells with target tumour cell line expressing target antigen
How can specificity of TCR T-cells be tested?
Co-culturing TCR T-cells with various tissues & cell lines to make sure that there is no cross-reactivity
Why is it necessary to increase longevity of TCR T-cells?
Patients can relapse due to short persistence of TCR T-cells in blood
True or false: TCR T-cells do not proliferate after infusion, explaining their relatively short effect
False; TCR T-cells do show proliferation in vivo, but are unable to keep proliferating at a level high enough to induce long-term regression
What are modifications that can be made to TCR T-cells to increase their longevity? (4)
- Co-stimulatory TCRs/CARs
- Chemokine/cytokine receptors
- Inducible mediators
- Gene deletion/silencing
How can co-stimulatory TCRs/CARs increase adoptive T-cell longevity?
The tumour micro-environment in which these T-cells operate lacks effective costimulation. By engineering costimulatory domains to the intracellular domain of the TCR, TCR activation automatically ensures the desired level of costimulation.
What are the in vivo results of engineered TCRs with engineered intracellular costimulatory domains?
Longer T-cell surivival, effective tumour lysis & long-term regression
