immunology 4: Tumour immunology and immunotherapy of cancer

Question 1

summarise the evidence for the importance of tumour surveillance by the immune system

Answer 1

e. g in breast cancer
- -> Spontaneous immune response against tumour-expressed antigen
- -> can cause autoimmune disease cause by tumour in the breast

1. Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease.
2. Patients treated for melanoma, after many years apparently free of disease, have been used as donors of organs for transplantation. —> Transplant recipients have developed tumours.
   - -> suggests Donor had developed ‘immunity’ to the melanoma, BUT new transplant recipients = no such ‘immunity’.
3. Deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy
4. Men have twice as great chance of dying from malignant cancer as do women (women typically mount stronger immune responses)

immunosurveillance’: malignant cells are generally controlled by the action of the immune system.

Question 2

explain how immune responses to tumours have some similarities with those to virus infected cells

Answer 2

T cells can sample internal contents of the cell , and can recognise tumour-specific antigens

a) cancers of viral origin = often opportunistic
- likely to affect immunosuppressed / immunocompetent
- e.g HIV –> HHV8 caused Kaposi Sarcoma
- e.g HepB, HepC –> virus associated hepatocellular carcinoma

–> Tumour cells express
viral antigens

Question 3

explain the concept of tumour-associated antigens giving named examples

Answer 3

Tumour-associated antigens (TAA) derive from normal cellular proteins which are aberrantly expressed (timing, location or quantity).

Because they are normal self proteins, you wouldn’t expect immune system to recognized them - you would expect immune system to be tolerant to it –> so you need to over come the tolerance

• ectopically expressed = cancer-testes antigens
• HER 2
• MUC-1
• CEA

Question 4

and explain how tumour-associated antigens differ from tumour-specific antigens

Answer 4

Tumour-specific antigens:

• e.g viral proteins (EBV , HPV)
• e.g TGF-B receptor III / BCR-ABL

Question 5

what are some approaches being used and developed for tumour immunotherapy,

Answer 5

1) Antibody-based therapy [expensive]
- -> naked e.g trastuzumab (herceptin) /
- -> conjugated - use radioactive particles linked to a drug (anti- CD20 linked to yttrium 90)
- -> bispecific antibodies (genetically engineered antibodies)

2) Therapeutic vaccination
- -> e.g provenge (treats prostate cancer)
- fusion protein btw PAP and GM CSF –> stimulates DC maturation –> enhances PAP specific T cell responses

• -> Personalized tumour specific cancer vaccines
• take tumour cell + normal cell from same patient
• take RNA + DNA from each
• use candidate neoantigen + adjuvant –> to make personalized vaccine –> to stimulate adaptive immune response against mutant proteins

3) Immune checkpoint blockade -EXAM CONTENT
- -> remove the negative influencer / regulatory controls of existing T cell responses
- -> targets CTLA-4 + PD-1 pathways
- CTLA-4 = expressed on activated + regulatory T cells –> binds to CD80/86
- PD-1 = expressed on activated T cells –> binds to PD L1/L2

e.g. Ipilimumab (anti CTLA-4), Nivolumab (anti PD-1), antagonistic antibodies

4) Adoptive transfer of immune cells
- extract tumour infiltrative lymphocytes –> expand t cells in vitro
byt stimulating with tumour specific antigen / cytokines
- OR genetic engineering to modify
–> put back in patient ‘

e. g Chimaeric Antigen Receptors (CARs)
- binds to antigen
- delivers fully activating signal to T cells
- activates T cells
- -> destroy tumour cells

5) Combinations of 1) to 4) above

Question 6

What are some problems in immune surveillance of cancer ?

Answer 6

a) It takes the tumour a while to cause local inflammation

b) Antigenic differences between normal and tumour cells can be very subtle (e.g. small number of point mutations)

Question 7

Immunotherapy = minimal side effects

Answer 7

-

Question 8

HPV vaccine - uses surface proteins of the virus associated with the cancer –incorporated into virus like particles

Answer 8

• in minority = there is failure of immune response against HPV –> can cause cervical cancer
• as preventative vaccine
• therapeutic vaccine
• as

Question 9

Cervical cancer is induced and maintained by the oncoproteins ___ and ___ of HPV

Answer 9

E6

E7

Question 10

HPV vaccine - uses surface proteins of the virus associated with the cancer –incorporated into virus like particles

Answer 10

• in minority = there is failure of immune response against HPV –> can cause cervical cancer
• as preventative vaccine
• therapeutic vaccine

Question 11

Two major problems of targeting tumor associated auto-antigens for T cell-mediated immunotherapy of cancer :

Answer 11

Two major problems:

1. Auto-immune responses against normal tissues
2. Immunological tolerance
   - Normal tolerance to auto-antigens
   - Tumour-induced tolerance

Question 12

If you use tumour associated antigens for immunotherapy –> it also acts on normal cells containing the antigen –> cause auto immune reactivity

Answer 12

-