Immunotherapy Flashcards
Name 5 novel therapeutic strategies of immunotherapy
- Biologics
- Adjuvants
- Allergy Immunisation
- Helminithic therapy
- Cancer therapy
- T-cell engineering
Name 4 conventional immunosuppressive drugs
- Corticosteroids
- Cytotoxic drugs
- Cyclosporin A
- Rapmycin
How do corticosteroids work?
Inhibit inflammation
- Inhibit transcription of inflammatory genes
- Promote transcription of anti-inflammatory genes
How do Cytotoxic drugs work?
Interfere with DNA synthesis
- Non specific - e.g., azathioprine, cyclophosphamide, mycophenolate
How does Cyclosporin A work?
suppresses IL-2 - inhibits T-cell proliferation
- via NFAT
How does rapymycin work?
Inhibits mTOR pathway - inhibits cell proliferation, translation and auto-Nagy
Definition of Immunotherapy
Treating disease via immune modulation - activation, suppression or skewing
4 methods of immunotherapy
- Soluble mediators - cytokines, cytokine antagonists, adjuvants
- Antibody therapy - receptor/ligand blocking
- Cell based - DC vaccination/ genetic engineering of T-cells
- Skewing/suppression
4 examples of cytokines in immunotherapy
- GM-CSF/G-CF (growth factors) - treats neutropenia in cancer patients - increases WBCs
- PEGylated interferon alpha - treats hepatitis B/C (viral infection)
- Bone marrow donors - injection - increases WBCs
- Interferon gammar - treats CGD patients - activates macrophages/neutrophils
3 examples of cytokine antagonists
- Anakinra - soluble IL-1 receptor antagonist - targets auto inflammatory diseases
- Rilonacept - IL-1-Fc fusion protein
- Etanercept - recombinant TNF-alpha receptor-fusion protein
3 examples of adjuvants
- CpG (ligand) - imiquimod - cancer/warts
- Beta glucans - yeast cell walls
- Hypomethylated DNA - activate toll-like receptors - useful for viral/type-1 response
what is CTLA-4 and what do CTLA-4 inhibitors do?
- CTLA-4/CD152 protein receptor - is an immune checkpoint and downregulates immune responses
- Checkpoint inhibitors - like anticancer drugs block CTLA-4 - which inhibits T-cell costimulation
3 examples of the therapeutics of monoclonal antibodies
- Anti-TNF-alpha - major pro inflammatory cytokine (infliximab)
- B-cell leukaemia anti-CD20 - (Rituximab)
- Breast cancer - anti-HER2/neu receptor - (Herceptin/trastuzamab)
Modes of action of monoclonal antibodies
- Ligand/receptor blocking
- Induction of apoptosis
- Complement mediated killing
Problems with monoclonal antibodies
- Expensive
- Hard to copy
- Repeat doses are often immunogenic - neutralising anti-antibody antibodies
- Can humanise antibody - but keeps loops as mice/rat - which are less immunogenic
What is the role of adjuvants?
- Enhance immune response
- Upregulate costimulatory molecules - increase migration and presentation to DCs - increases longevity of antigen
- pore proteins are not immunogenic - so you need to add adjuvants
- magnitude and type of response can be manipulated via coupling and type of adjuvant used
What is squalene used for ?
- Is a lipid - added to adjuvants as soluble adjuvants can be cleared by circulation easily
How are allergies caused? (1 point)
- Excessive Th2 immunity
- Th2/IgE mediated response activate mast cell degranulation - and cause inflammation and tissue damage
How can immunotherapies prevent allergies?
6 points
- By suppressing/skewing the Th2 response to a Th1 response
- By immunising APC or DC
- Enhancing Th1 = Switches off Th2
- Stops generation of IgE
- Can use mutated allergens - with agonists - leads to IgG response e.g., CpG/TLR4
- Higher dosage of allergen - T reg cells can switch off Th2 response
Why is dangerous too inject allergens? (1 point)
What can you do to stop this? (1 point)
- Can cause anaphylactic shock
- Can inject anti-IgE therapy
Examples of diseases caused by excessive Th1/Th17 immunity? (4 points)
- Inflammatory bowel disease
- Type 1 diabetes
- Multiple sclerosis
- Rheumatoid arthritis
What are helminths and what are they used for?
2 points
- are parasitic worms
- Can be used to skew immune system from Th1 to Th2 - so Th2 will regulate Th1
- uses dendritic cells
How do you use tolergenic dendritic cell therapy to suppress the immune response and what can it prevent? (3 points)
- Remove DCs and grow in growth factor - to form tolergenic DCs.
- Inject into human - helps switch off T cells directly, generate T reg cells (to switch off T cells) or cause T cells to undergo apoptosis
- prevent allergy or inflammatory type 1/2 disease
What is transplantation and name 2 methods?
- Prevention of transplant rejection
- Can use long term immunosuppressives or short term
What are used as long term immunosuppressives and why are they not good?
- Corticosteroids
- Can mean patient is immunocompromised for a long time
How do short term immunosuppressives work?
And name 3 examples? ( 3 points)
- Induce T cell unresponsiveness - ‘reset’ tolerogenic mechanisms
- Campath-1 monoclonal antibody
- Basiliximab - prevents T cell activation (anti-IL-2 receptor)
- Non-FcR binding anti CD3 monoclonals - anti-alpha-Beta- TcR monoclonals
How do tumours grow? (2 points)
- Create anti-inflammatory environment - switch off immune cells
- use inhibitory receptors that switch them off
Name 4 ways to enhance immune response against cancerous tumours? (4 points)
- Checkpoint inhibitors - inhibit the inhibitory receptors
- Monoclonal antibodies - anti-CD20 (B-cells), anti-erb2 receptor (block growth receptors), anti-VEGF - stop oxygen and nutrient availability for tumours
- Soluble mediators - GM-CSF - enhance blood cells - after bone marrow transplant
- Imiquimod - TLR 7/8 agonist - enhance anti-tumoural/antiviral response
Why are tumours hard to vaccinate against?
2 points
- They are very immunosuppressive - switch off immune system
- Lots of normal cells have the same receptors as tumours - don’t want to kill them too
Name 4 ways we can overcome tumour suppression? (4 points)
- Activate T cells - blockade inhibitory receptor on T-cells - allows their activation
- Block IL-10/TGF-beta - adoptive transfer of IL-2 treated cells
- Up regulate MHC1-IFNgammar treatment
- Engineer ‘super T cells’ - highly active (Dont require MCH1)
Name and describe a novel anti-tumour strategy
1 point
- Dendritic cell vaccination therapy
- Remove DCs - add adjuvants - reinject
Explain ‘super’ T cell/Car-T therapy (2 points)
- Engineer antigen binding part of antibody onto T cell receptor
- Add activatory domains to T cell receptor - which adds many activation signals - as tumours can deactivate T cells
Why is antibody-CD3 good? (2 points)
- Is a hybrid - circumvents need for MHC1 for T cell activation
- So the tumours antigen no longer need to be protein derived
How can NK cells be used for treating tumours?
2 points
- Increases the homing and maturation of NK cells - by changing sugars on surface/homing receptors
- Create CAR receptors - for NK cells
Explain host-directed therapy - for infectious disease
3 points - virus, bacteria, fungi
- Doesn’t target pathogen - targets host
Viruses - Uses interferon therapies - Targets host dependent life cycle - unlikely this will mutate - no resistance
Bacteria - e.g., tuberculosis - promotes phagosome maturation - induces antimicrobial peptides - targets inflammatory response and prevents resistance
- Fungi - statins - reduces cholesterol/ergoesterol
What is TGN1412? (1 point)
- It activated all T cells - caused huge inflammation
- Example of immunotherapy going wrong
