Tumour Immunology L8

Question 1

True or false? Many tumours arise spontaneously, but are recognised and destroyed by an immune response.

Answer 1

True.

Question 2

True or false? Most tumours in immunosuppressed patients are caused by bacteria.

Answer 2

False. Most tumours in immunosuppressed patients are caused by viruses.

Question 3

What are tumour-specific antigens?

Answer 3

• Antigens that are expressed preferentially by tumour cells (compared with normal counterparts)
• Recognised by B cells (Abs) or T cells

Question 4

What may tumour-specific antigens be?

Answer 4

• Strictly tumour-specific
• Antigens of germ cells aberrantly expressed by tumours
• Tissue-specific differentiation antigens
• Over-expressed compared to normal cells
• Abnormally modified post-translation
• Encoded by viral oncogenes

Question 5

Describe why tumours may avoid immune surveillance?

Answer 5

Loss of MHC expression

Produce immunosuppressive factors e.g. TGF-b, IL-10

Lack of danger signals

• To induce a response costimulator molecules have to be expressed
• Endogenous danger signals may be released by dying cells

Question 6

How would one use tumour-specific antigens in diagnosis of cancer?

Answer 6

• Measure serum levels to monitor tumour load/provide evidence of metastasis e.g. antibodies to prostate-specific antigen (PSA) or carcinoembryonic antigen (CEA)
• Detection of metastases in stained tissue samples (e.g. bone marrow, cerebro-spinal fluid)

Question 7

Define Immunotherapy.

Answer 7

Attempts to harness immune response against tumours.

Question 8

What did Coley’s toxin provide?

Answer 8

Evidence that non-specific immune stimulation can be effective in treating cancers.

Question 9

To date the most widely-used form of tumour immunotherapy has involved _____.

Answer 9

Antibodies.

Question 10

What are the limitations of antibody therapy in the treatment of cancer?

Answer 10

• May not penetrate tumour mass
• May bind normal cells expressing Ag or FcR
• May induce immune response

Question 11

Give examples of immunotherapy in current use.

Answer 11

• Herceptin in breast cancer: a monoclonal antibody to Her-2
• Alemtuzumab (Campath) targets CD52 which is expressed on B cells in patients with B cell chronic lymphocytic lymphoma
• Rituximab (Rituxan): Targets CD20 in Non-Hodgkins lymphoma

Question 12

How do antibodies kill cells?

Answer 12

• Antibody-dependent cell-mediated cytotoxicity (ADCC)

- Complement dependent cytotoxicity (CDC)

Question 13

Describe the use of antibodies to CTLA4 in immunotherapy.

Answer 13

• CTLA4 binds B7 and plays a role in downregulating T cell activation
• Postulated that CTLA4 blockade might enhance anti-tumour responses
• Trials of CTLA-4 either alone or in combination with a cancer vaccine

Question 14

Give 2 examples of cytokines used to treat cancer.

Answer 14

• IFN-a in hairy cell leukaemia

- IL-2 in melanoma

Question 15

Describe the 3 approaches to therapeutic immunisation to induce tumour-specific responses in immunotherapy.
Give examples.

Answer 15

Immunisation with tumour antigens or tumour cells
- e.g can use adjuvants such as BCG

Transfection of tumour cells – e.g. with B7 (costimulator)
- GM-CSF (attracts dendritic cells)

Immunisation with DCs engineered to express tumour antigens

Question 16

Read:

Prostvac.

Answer 16

• A therapeutic vaccine for prostate cancer
• Comprises vaccinia or fowl pox virus with gene for prostate-specific antigen
• Also includes genes for B7 and two adhesion molecules, LFA-3 and ICAM-1
• Phase II randomized, controlled study in metastatic castration-resistant prostate cancer reported an 8.5 month improvement in median overall survival for patients who were treated with Prostvac
• Now in phase III trials

Question 17

Read:

Provenge (sipuleucel).

Answer 17

• Produced by Dendreon
• Autologous cellular therapy for prostatic cancer
• FDA approved (April 2010) for use in castration-resistant prostate cancer
• Patients’ blood mononuclear cells isolated and pulsed with a fusion protein containing an antigen (prostatic acid phosphatase) linked to GM-CSF (to stimulate the maturation of antigen-presenting cells)
• Reinfused into the patient: 3 infusions, once every 2 weeks
• Mode of action unclear
• Median survival 25.8 months in treated patients compared to 21.7 months in controls
• High cost: $93,000 per patient ($23,000 per month survival advantage)