A8 - Tumour immunology

What causes the development of cancer?

A single cell which has become transformed and begins uncontrollably dividing while failing to respond to signals from surrounding cells.

What is metastasis?

Movement of cancer cells away from the original tumour. This can lead to secondary tumours developing around the body.

What is Minimal Residual Disease (MRD) in cancer?

MRD refers to the amount of cancer left after therapeutic interventions.

What is the immunosurveillance theory?

Theory which states that many tumours arise spontaneously around the body but are recognised and destroyed by our immune systems.

What are two human-based evidences of the immunosurveillance theory?

Transplant patients who are on immunosuppressive drugs have an increased risk of certain tumours.

HIV patients who have a weakened immune system have a higher risk of tumours.

What is one experimental piece of evidence which supports the immunosurveillance theory?

A tumour can be induced in a mouse and these tumour cells can be extracted and irradiated so they no longer divide.

The irradiated cells can be put into a healthy mouse. The original tumour cells can then also be put into the mouse and a tumour will not develop.

This is because the mouse has been “vaccinated” for the tumour but not to new unrelated tumour cells.

Tumours express ‘tumour antigens’. What types of antigens can these be?

• Strictly tumour-specific

• Antigens usually expressed by stem cells

• Normal antigens but extremely over-expressed

• Abnormally modified antigens

• Antigens encoded by viral oncogenes

• Tissue-specific antigens

How can tumour antigens be used in diagnosis?

Can measure serum levels of the antigen to monitor tumour load.

Can detect metastasis by staining the antigen in tissue samples.

What 5 ways can tumours actively evade the immune system?

• Loss of MHC expression by many tumours

• Tumour antigens are not different from self-antigens

• Tumours may lose/alter antigens

• Tumours may produce immunosuppressive factors

• Tumour may lack PAMPs/co-stimulatory molecules to induce a T-cell response

How can dying tumour cells lead to activation of local APCs?

DAMPs may be released when the tumour cell dies. These can be detected by Pattern Recognition Receptors on local APCs.

What is one example of a vaccine to prevent cancer development?

HPV vaccine which was based on the human papilloma virus (HPV) antigens

Helped immunise against cervical cancer.

What lead to the development/discovery of Coley’s toxin?

Coley observed a cancer patient ‘recover’ following dermal Strep infections.

Other cancer patients were then immunised with Strep. Pyogenes which had some success

A modified mixture of two bacterial spp. was developed = Coley’s toxin.

What was Coley's toxin, and what did it provide evidence of?

Coley's toxin was a mixture of bacterial species used to stimulate a non-specific immune response in hopes of treating cancer patients.

This provided evidence that non-specific immune activation can be effective.

What is the most widely used form of cancer immunotherapy?

Monoclonal antibodies.

Either used alone or coupled with drugs/toxins/radioisotopes.

How do monoclonal antibodies on their own help treat cancer?

IgG monoclonal antibody specific to a tumour antigen is administered to patient.

CD16 on NK cells bind IgG coated tumour cells which activates NK cells to kill the tumour cell

What is Alemtuzumab and what does it do?

Monoclonal antibody specific to CD52 which is expressed on B cells with B-cell chronic lymphocytic lymphoma

What is Rituximab and what does it do?

Monoclonal antibody specific to CD20 on B-cells

Once it binds to CD20, the B-cell will die.

What is Herceptin and what does it do?

Receptor antagonist.

Binds to tumour cells over-expressing HER-2 and blocks Epidermal Growth Factor binding to HER-2.

This induces a signal with reduces tumour growth and induces ADCC

What is Anti-CTLA-4 mab and what does it do?

Binds to CTLA-4 and prevents it from binding to B7 on ACPs.

Binding of CTLA-4 to B7 inhibits T-cell activation by displacing CD28. When it is blocked, CD28 can binds to B7 which induces T-cell activation

This allows a sustained T-cell response against the tumour.

What are some limitations of antibody-based therapy?

May not penetrate tumour mass

May bind normal cells which express the antibody too

May be ‘mopped up’ before it reaches the tumour if a circulating antigen is present.

What is CAR-T cell therapy?

Cancer patient T-cells are isolated and engineered in vitro to express a receptor which recognises antigens on tumour cells.

These CAR-T cells are then reinfused into the patient and will attack the cancer cells.

What are some benefits of CAR-T cell therapy?

Antigen recognition region can be engineered to recognise a range of tumour antigens.

CAR-T cells do not use TCRs to see MHC molecules but can recognise antigens. This hopefully means they can be used in many different patients as they don’t rely on individual MHC alleles.

What is Provenge?

Cancer patients APCs are collected and are exposed to a protein called PAP-GM-CSF in vitro. This allows them to recognise and attack prostate cancer cells expressing PAP.

Cells are then reinfused back into the patient where they migrate to lymph nodes and present processed PAP antigen to T-cells, activating an immune response against prostate cancer cells.