Immunology 4: Tumour immunology and immunotherapy of cancer

Question 1

Summarise the evidence for the importance of tumour surveillance by the immune system? Breast cancer

Answer 1

Breast tumour expresses antigen –> immune response generating an antibody –> these antibodies travel to the brain and destroy purkinje cells. you get neurological defects which become present.

This shows there is potential humoral ant-tumour response

1. At least certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues.
2. The immune system can, in principle, detect such abnormally expressed antigens and, as a result, launch an attack against the tumour.
3. In certain cases, this may result in auto-immune destruction of normal somatic tissues.

Question 2

What is the circumstantial evidence for immune control of tumours in humans?

Answer 2

1. Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease. Immune control?
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. Donor had developed ‘immunity’ to the melanoma, but the transplant recipients had 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)

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

Immunotherapy tries to enhance immune responses to cancer.

Question 3

Describe the T cells and B cells

Answer 3

alpha beta T cell receptor
‘MHC restricted’ - recognise peptides presented by MHC molecules.

B cell receptor (antibody)
- have a vast range of molecules which they can recognise.

Question 4

Describe the cancer immunity cycle

Answer 4

See slide - 14

1) Release of cancer cell antigens (cancer cell death)
2) Cancer antigen presentation (dendritic cells/APCs)
3) Priming and actication (APCs and T cells)
4) Trafficking of T cells to tumours (CTLs)
5) Infiltration of T cells into tumours (CTLs, endotherlial cells)
6) Recognition of cancer cells by T cells
7) Killing of caner cells

There is immune selection pressure.

You want to remove the negative signals in this cycle to enhance the positive immunity cycle.

Question 5

What does tumour growth eventually cause?

Answer 5

Inflammatory signals - recruitment of innate immunity and subsequent recruitment of adaptive, antigen-specific immunity. (DC, NK, Macrophages - can capture antigens and generate immune responses.)

Question 6

What are the requirements of activation of an adaptive anti-tumour immune response?

Answer 6

1. Local inflammation in the tumour (“danger signal”)
2. Expression and recognition of tumour antigens

If requirements for ‘spontaneous’ activation of the adaptive anti-tumour response are not met, can we ‘teach’ the adaptive immune system to selectively detect and destroy tumour cells? Cancer immunotherapy - Potential alternative/supplement to conventional therapies (surgery, chemotherapy, radiotherapy)

Question 7

What are the problems in immune surveillance of cancer?

Answer 7

1. It takes the tumour a while to cause local inflammation

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

Question 8

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

Answer 8

T cells can ‘see’ inside cells, and can recognise tumour-specific antigens.

MHC class I//II - 'Display’ contents of cell for surveillance 
by T cells: infection, carcinogenesis

Question 9

What are some tumour specific antigens?

Answer 9

Viral proteins

• EBV
• HPV

Mutated cellular proteins
- Transforming Growth Factor - Beta receptor III

Question 10

Describe cancers of viral origin?

Answer 10

Opportunistic malignancies: Immunosuppression

• EBV-positive lymphoma: Post-transplant immunosuppression
• HHV8-positive Kaposi sarcoma: HIV

Also in immunocompetent individuals:

• HTLV1-associated leukaemia/lymphoma
• HepB virus- and HepC virus-associated hepatocellular carcinoma
• Human papilloma virus-positive genital tumours. This tumour cells express viral antigens. This is associated with cervical cancer.

Question 11

What are the target antigens for preventive HPV vaccination?

Answer 11

The surface proteins

Question 12

What happens when you give the HPV16 vaccine?

Answer 12

HPV16 infection:
>99% - strong immunity –> clearance of HPV infection and immunological memory

Immune failure –> Cervical neoplasia.

Question 13

What are tumour associated antigens?

Answer 13

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

Because they are normal self proteins, for an immune response to occur tolerance may need to be overcome.

Question 14

What are TAAs?

Answer 14

Cancer-testes antigens (developmental antigens): Silent in normal adult tissues except male germ cells (some expressed in placenta).

e.g. MAGE family: Melanoma associated antigens. Identified in melanoma also expressed in other tumours.

These proteins produced in the tumour are not found in normal cells.

Question 15

Give some examples of tumour-associated antigens?

Answer 15

Human epidermal growth factor receptor 2 (HER2): overexpressed in some breast carcinomas

Mucin 1 (MUC-1): membrane-associated glycoprotein, overexpressed in very many cancers

Carcinoembryonic antigen (CEA): normally only expressed in foetus/embryo, but overexpressed in a wide range of carcinomas

PROSTATE:

1) prostate-specific antigen (PSA)
2) prostate-specific membrane antigen (PSMA)
3) prostatic acid phosphatase (PAP)

Question 16

Tolerance induction by negative selection in the thymus: central tolerance

Answer 16

?

Question 17

?

Answer 17

?

Question 18

What are the major problems with targeting Tumour-associated auto-antigens for T cell mediated immunotherapy of cancer

Answer 18

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

Question 19

What are the approaches being used and developed for tumour immunotherapy?

Answer 19

Antibody-based therapy
Therapeutic vaccination
Immune checkpoint blockade
Adoptive transfer of immune cells
Combinations of 1) to 4) above

Question 20

Describe monoclonal antibody-based therapy?

Answer 20

“Naked”
- e.g. Trastuzumab (Herceptin®), anti HER2

“Conjugated”
- radioactive particle e.g. Ibritumomab tioxetan (Zevalin®), anti CD20 linked to yttrium-90

• drug e.g. Trastuzumab emtansine (Kadcyla®), anti HER2 linked to cytotoxic drug

“Bi-specific” antibodies
- Genetically engineered to combine 2 specificities, e.g. anti CD3 and anti CD19 (Blinatumomab, approved for use in patients with some B cell tumours)

Question 21

Describe therapeutic cancer vaccination

Answer 21

There is one FDA approved vaccine to treat cancer (also licensed for sale in the UK, but not NICE approved):

Provenge® (sipuleucel-T) for advanced prostate cancer

Patient’s own WBC are treated with a fusion protein between prostatic acid phosphatase (PAP) and the cytokine GM-CSF

Stimulates DC maturation and enhances PAP-specific T cell responses

Question 22

Describe personalised tumour specified cancer vaccines

Answer 22

Slide 46

Question 23

Describe immune checkpoint blockade?

Answer 23

Rather than directly stimulate responses, this approach seeks to reduce/remove negative regulatory controls of existing T cell responses

Targets CTLA-4 and PD-1 pathways:

• CTLA-4 is expressed on activated and regulatory T cells, binds to CD80/86 (costimulatory molecules on APC)
• PD-1 is expressed on activated T cells, binds to PD-L1/L2 (complex expression patterns, may be upregulated on tumours)

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

The problem with this is that it may allow autoimmune responses.

Question 24

What is adoptive transfer of cells?

Answer 24

Cells taken from a patient with a tumour.
The T cells are extracted and can be expanded. Genetically engineer the T cells can also be done.
Then they are put back into the patient.

Chimaeric Antigen Receogtors.