4. Tumour immunology and immunotherapy of cancer Flashcards
How can antibodies in a patient with breast cancer cause a neurological disease?
- Breast tumour recognised by immune system
- Antibodies produced against tumour cells (CD2R protein, which is over-expressed)
- Antibodies cross the BBB and cause a neurological disease
- Like an autoimmune condition
- Can destroy Purkinje cells in the brain
How can it be possible for a patient to be treated for a tumour successfully, have their organ donated can cause the recipient to develop a tumour?
- The donor could have developed immunity to the tumour
- The recipient may have no had such immunity
- Immunosuppression in transplantation also increases the risk of malignancy
How do T cells initially detect cancer?
- Tumour releases antigens
- Antigens captured by APCs and migrate to local lymph nodes
- Antigen presented to T cell
- T cell activation
What happens once T cells are activated by the tumour antigens?
- Go to circulation then leave it to infiltrate the tumour (TILs - tumour infiltrating lymphocytes, include monocytes)
- Lots of immune selection pressure on the tumour - T cells select cancer cells that have lost the ability to present MHC + peptide to the T cells
- However, mutations lead to the outgrowth of the tumour cells - no longer capable of being recognised
What is targeted and blocked to enhance the T cell response?
- Molecules that deliver inhibitory signals to T cells in the immune checkpoint blockade
- E.G. CTLA4 and PD-1
When does a tumour start to send out inflammatory signals, and what cells are initially recruited at this stage?
- Only when the tumour reaches a relatively large size
* Recruitment of cells involved in innate immunity (macrophages, NK cells, dendritic cells)
Is the peptide MHC enough to activate a naïve T cell? Why?
No
• There must be co-stimulation - inflammatory “danger signal”
• Antigenic peptide needed
Can T cells recognise tumour antigens intracellularly?
Yes, similarly to viral antigens
What can act as tumour specific antigens, that is not in the tumour?
Some viral proteins
What is the TGF-beta receptor III (referring to importance in immune recognition)?
- Mutated cellular protein that is different from the normal cellular protein
- Tumour specific antigen
- Immune system can recognise and differ it from normal body cells
What cancer is EBV associated with?
B cell lymphoma
Which oncoproteins of HPV induce and maintain cervical cancer and how?
E6 and E7 (intracellular antigens that can be presented on MHC)
E6 - binds to p53 (a TSG)
E7 - inactivates RB
Do HPV vaccine target E6 and E7 directly?
- No
- Gardasil (recombinant vaccine) has coat protein proteins from 9 different types of HPV
- Surface proteins (late genes L1 and L2) are incorporated into viral-like particles
Does HPV (specific cancer type) always lead to cancer?
No, in most people, the natural immune response is good enough to control the infection
Is it useful to give the HPV vaccine after the tumour begins to grow?
Yes, as a therapeutic measure to stimulate the immune response
What are cancer/testis antigens?
- Tumour-associate antigen (ectopically expressed auto-antigen)
- Important in development and cancer immunotherapy
- Expressed in early life - silent in normal adult tissues except male germ cells (and placenta)
- Can be re-expressed in cancer and serve as locus of immune activation
- e.g. melanoma associated antigens
What is Mucin 1?
Membrane-associated glycoprotein, over-expressed in many cancers (tumour associated (auto)antigen)
What is carcinoembryonic antigen?
- Tumour associated antigen (auto-antigen)
- Normally expressed in foetus
- Over-expressed in a wide range of carcinomas
What is the negative effect of making an effective immune response against a tumour-associated antigens?
- These antigens are also normally expressed in the body
- Potential for autoimmunity
- e.g. immune response in melanoma may be accompanied by vitiligo
What are the 3 types of monoclonal antibody-based therapy?
- Naked - antibody on its own
- Conjugated - antibody attached to chemotherapy drug or radioactive particle
- Bi-specific antibodies - can attach to 2 different things at the same time e.g. anti CD3 and anti CD19
What is the one FDA approved vaccine to treat cancer and how does it work?
- Provenge for advanced prostate cancer
- Patient’s WBCs are treated with a fusion protein between PAP (prostate specific antigen) and GM-CSF (cytokine)
- Stimulates dendritic cell maturation and enhances PAP-specific T cell responses
How do you create a personalised tumour specific cancer vaccine?
1) Start with tissue from the patient (from tumour and from equivalent normal cell)
2) Sequence RNA/DNA - whole exome sequencing + HLA typing
3) Mutations specific to the tumour can be identified - RNA sequencing confirms expression
4) Can predict which peptides can be presented via HLA molecules - end up with some candidate neo-antigens
5) Vaccinate patient with these antigens + inflammatory signal (adjuvant)
Very expensive, but possible
What does an immune checkpoint blockade involve?
Remove negative regulatory controls of existing T cell responses - to cause stimulatory response (rather than directly stimulate response)
• Targets CTLA-4 and PD-1 pathways
Where is CTLA-4 expressed and what does it bind to?
- Expressed on activated and regulatory T cells
* Binds to CD80/86
