Tumour immunology and immunotherapy of cancer

Question 1

Give a diagnostic test for paraneopalstic cerebellar degeneration

Answer 1

Detection of anti-CDR2 antibody in the serum

Question 2

Describe the use of anti-CDR2

Answer 2

Brown colour shows Ig binding

Question 3

Describe how a cancer can lead to auto-immune diseases

Answer 3

Certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues. The immune system can detect such abnormally expressed antigens and launch an attack against the tumour.

In certain cases, this may result in auto-immune destruction of normal somatic tissues

Question 4

What is the evidence for immune control of tumours in humans

Answer 4

Many adults have microscopic colonies of cancer cells

Patients treated for melanoma are used as donors for organs but their recipient develop tumours

Question 5

What is the relationship between immunosuppression and malignancy

Answer 5

Deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy

Question 6

What is the relationship between malignancy mortality and gender

Answer 6

Men have twice as great chance of dying from malignant cancer as do women (women typically mount stronger immune responses)

Question 7

Which receptors are found on T and B cells

Answer 7

alpha-beta T cell receptor
(MHC restricted)

B cell receptors (antibodies)

Question 8

Describe the cancer-immunity cycle

Answer 8

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

Question 9

What events may imitate cancer

Answer 9

Irradiation
Chemical mutagens
Spontaneous errors during NDA replication
Tumour virus-induced changes in genome

Question 10

Describe the initiation of tumour growth

Answer 10

Aberrant regulation of apoptosis and cell cycle results in tumour growth
Tumour growth (eventually) results in inflammatory signals
Recruitment of innate immunity and subsequent recruitment of adaptive, antigen-specific immunity

Question 11

Which cells are unbolted in innate immunity to tumours

Answer 11

Dendritic cell
Macrophage
Natural killer cell

Question 12

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

Answer 12

Local inflammation in the tumour (“danger signal”)

Expression and recognition of tumour antigens

Question 13

What are the problems that can arise in immune surveillance of cancer

Answer 13

It takes the tumour a while to cause local inflammation

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

Question 14

Describe the recognition of tumour cells by T cells

Answer 14

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

Question 15

Give examples of tumour-specific viral antigens

Answer 15

Epstein Barr Virus (EBV)
Human Papillomavirus (HPV)

Question 16

Give and example of tumour-specific mutated cellular antigens

Answer 16

TGF-beta receptor III

Question 17

What cancer is caused by post-transport immunosuppression

Answer 17

EBV-positive lymphoma

Question 18

What cancer is caused by post-transport HIV

Answer 18

HHV8-positive Kaposi sarcoma

Question 19

Give examples of cancers found in immunocompetent individuals

Answer 19

HTLV1-associated leukaemia/lymphoma
HepB virus- and HepC virus-associated hepatocellular carcinoma
Human papilloma virus-positive genital tumours

Question 20

Which cancer is HPV associated with

Answer 20

Cervical cancer

Question 21

Which antigens are expressed on tumour cells in HPV

Answer 21

E6 and E7 oncoproteins

Maintain and induce cervical cancer

Question 22

Describe the HPV vaccination

Answer 22

Target antigens (no DNA)
Surface proteins, incorporated into Virus-Like Particles (VLPs)
Intracellular Onco proteins (E6,E7) are targets
GARDASIL

Question 23

What happens in the patients who do not produce an immune response to the HPV16 infection

Answer 23

Immune failure
Cervical neoplasia
No immunity
Non-functional immunity

Question 24

What are tumour-associate antigens

Answer 24

Tumour-associated antigens (TAA) are normal cellular proteins which are aberrantly expressed (timing, location or quantity).
Because they are normal self proteins, or an immune response to occur tolerance may need to be overcome.

Question 25

Give an example of an ectopically expressed auto-antigen

Answer 25

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

Question 26

Give an example of cancer-testes antigen

Answer 26

MAGE familexpressed in other tumoursy: Melanoma associated antigens. Identified in melanoma also

Question 27

Give examples of tumour-associated antigens

Answer 27

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-specific antigen (PSA) Prostate-specific membrane antigen (PSMA) Prostatic acid phosphatase (PAP)

Question 28

What is tolerance induced by

Answer 28

negative selection in the thymus: central tolerance

Question 29

Describe the tolerance of melanocytes/melanomas

Answer 29

differentiation antigens e.g. tyrosinase (melanin production): poor self-tolerance Local auto-immune depigmentation in melanoma patients

Question 30

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

Answer 30

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

Question 31

What are the approaches used for tumour immunotherapy

Answer 31

``` Antibody-based therapy Therapeutic vaccination Immune checkpoint blockade Adoptive transfer of immune cells Combination of those above ```

Question 32

Give examples of "naked" monoclonal antibody-based therapy

Answer 32

Trastuzumab (Herceptin®) anti HER2, anti CD20, anti CD52, anti EGFR

Question 33

Give examples of "conjugated" monoclonal antibody-based therapy

Answer 33

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

Question 34

Describe "bi-specific" antibodies and give an example

Answer 34

Genetically engineered to combine 2 specificities, e.g. anti CD3 and anti CD19 (Blinatumomab, approved for use in patients with B cell tumours)

Question 35

Which vaccine is FDA approved to treat cancer

Answer 35

Provenge® (sipuleucel-T) for advanced prostate cancer

Question 36

What does Provenge do

Answer 36

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 37

Describe the immune checkpoint blockade

Answer 37

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

Question 38

What does CTLA-4 and PD-1 bind to

Answer 38

CTLA-4 binds to CD80/86 (costimulatory molecules on APC) | PD-1 binds to PD-L1/L2 (complex expression patterns, may be upregulated on tumours)

Question 39

Give examples of immune checkpoint blockade drugs

Answer 39

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

Question 40

What are CARs cells

Answer 40

Chimaeric Antigen Receptors Allows modification of T cell specificity Activation of CARs as it binds to tissue, it recognises the antibody fragment and causes activation of T cells