Immune 4 - Tumour immunology and immunotherapy of cancer

Question 1

What causes paraneoplastic cerebellar degeneration (PCD)

Answer 1

Anti-CDR2 antibody

CDR2 = cerebellum degeneration-related antigen 2

Elimination of purkinje cells by tumour induced auto-immune response

Question 2

What is meant by tumour “immunosurveillance”

Answer 2

Malignant cells - generally controlled by the action of the immune system

Immunotherapy tries to enhance immune responses to cancer

Question 3

Highlight quick differences between T cells and B cells

Answer 3

T cells = “MHC restricted”. Alpha and beta T cell receptor

B cells = vast range of molecules recognised by antibody

Question 4

Explain the cancer-immunity cycle

Answer 4

1. Death of cancer cell - loads of antigen released
2. Cancer antigen presented on APC
3. T cell recognition at lymph node - T cell activation
4. T cell moves to tumours
5. T cell infiltration into tumours (TIL)
6. Recognition of cancer cells by T cells
7. Killing of cancer cells (consequently more antigens are released)

Question 5

Certain inhibitory signals are involved in the cancer immunity cycle - these are targeted in cancer immunotherapy. Eg?

“immune checkpoint blockade”

Answer 5

1. CTL-A4 / PD-L1 / PD-1
2. PD-L1

Were trying to remove the negative signals inhibiting the immune response

Question 6

What are the 2 requirements for 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

Tumour inflammation takes a while to trigger adaptive immune response

Question 7

What are the problems with immune surveillance

Answer 7

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

2. Antigenic differences between normal and tumour cells may be very subtle - e.g. a small number of point mutations

Question 8

What is the basis of cancer immunotherapy

Answer 8

“teaching” the adaptive immune system to selectively detect and destroy tumour cells - potential alternative/supplement to conventional therapies

usually minimal side effects

Question 9

How might immune responses to tumours be similar to virus infected cells?

Answer 9

T cells can see inside cells - and can recognise tumour specific antigens (presented on MHC class 1/2).

Question 10

Name some tumour specific antigens to target

Answer 10

Viral proteins:

1. Epstein Barr virus (EBV)
2. Human Papillomavirus (HPV)

Mutated cellular proteins:
1. TGF-beta receptor

(The above all may cause cancer)

Question 11

Which opportunistic malignancies can cause cancer (viral origin) in immunosuppressed individuals

Answer 11

1. EBV positive lymphoma - post transplant immunosuppression

2. HHV8-positive Kaposi sarcoma: HIV

Question 12

In immunocompetent individuals, what cancers arise from viral origin

Answer 12

1. HTLV1-associated leukaemia/lymphoma
2. HepB and HepC virus-associated hepatocellular carcinoma
3. HPV - positive genital tumours

Question 13

Which are the oncoproteins of HPV that induce and maintain cervical cancer

Answer 13

E6 and E7

Question 14

What are the target antigens for preventive HPV vaccination

Answer 14

“Late genes”
L1 and L2

These are surface proteins, incorporated into Virus-Like particles (VLPs)

(we don’t use E6 & E7 oncoproteins - as potentially dangerous)

Question 15

To whom is the HPV vaccine given therapeutically?

NB can also be given preventively

Answer 15

To those who are infected by HPV16 and have not been successful in clearing it (immune failure)

Question 16

What are tumour-associated antigens (TAAs)

Answer 16

They are normal cellular proteins which are aberrantly expressed (timing / location / quantity)

They are normal self proteins, so tolerance may need to be overcome to generate an immune response

Question 17

Tumour associated antigens are ectopically expressed auto-antigens. They are so called developmental antigens, meaning?

Answer 17

They are silent in normal adult tissues except male germ cells (some expressed in placenta).

Question 18

Give an example of a tumour associated antigen

Answer 18

1. e.g. MAGE family - melanoma associated antigens.
2. Human epidermal growth factor receptor 2 (HER2) - overexpressed in some breast cancers
3. Mucin 1 (MUC-1) - membrane associated glycoprotein - over expressed in many cancers
4. Carcinoembryonic antigeen (CEA) - normally only expressed in foetus/embryo - but overexpressed in variety of cancers

Prostate:

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

Question 19

Some tumours escape central tolerance - these are often the targets of cancer therapy. The may express auto-immune reactivity against normal cells. Give an example

Answer 19

Melanocyte/melanoma - tyrosinase (melanin production) - has poor self tolerance

Question 20

What are 2 major problems with targeting tumour associated auto-antigens for T cell mediated immunotherapy of cancer?

Answer 20

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

Question 21

Describe monoclonal antibody based therapy for cancer

Answer 21

Can be:

1. “naked” - e.g. Perception (anti-HER2)
2. “Conjugated” - radioactive particle, e.g. anti-CD20 linked to yttrium-90, or anti-HER2 linked to cytotoxic drug (trastuzumab emtansine)
3. “Bispecific antibodies” - genetically engineered - combines 2 specificities, e.g. anti-CD3 and anti-CD19 (e.g. Blinatumomab, used in some patients with B cell tumours)

Question 22

Give an example of therapeutic cancer vaccination

Answer 22

Provenge (Sipuleucel-T) - not NICE approved but FDA approved

Patients own WBC treated with fusion protein between prostatic acid phosphatase (PAP) and GM-CSF cytokine. Stimulates DC maturation and enhances PAP-specific T cell responses

Question 23

Describe “personalised” tumour specific cancer vaccines

Answer 23

Normal cell DNA and tumour cell RNA taken, and sequenced. HLA typing done. Neoantigens formed, which are combined with an adjuvant and given as a personalised vaccine

Question 24

Describe the basis for immune checkpoint blockade approach to cancer treatment

Answer 24

This approach reduces/removes negative regulatory controls of existing T cell responses

Targets CTLA-4 and PD-1 pathways.

CTLA-4 = expressed on activated and regulatory T cells, binds to CD80/86

PD-1 = expressed on activated T cells, binds to PD-L1/L2

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

problem is, it may incite an autoimmune response

Question 25

Describe what adoptive transfer of cells (ACT) is

Answer 25

1. Take WBCs from patient with tumour
2. Expand T cells in vitro (can be antigen specific expansion or non specific expansion)
3. We can also genetically engineer the T cells, e.g. by introducing new antigens into them
4. Once T cell culture has expanded, we can put them back into the human

Question 26

Give an example of a genetic-engineering type approach to cancer therapy

It has been used for B cell tumours using CD19

Answer 26

CARs (Chimaeric Antigen Receptors)

Can introduce a CAR into a T cell where the binding bit of receptor has been derived from an antibody - variable region of antibody can be scFv (Single chain fragment variable)

scFV stuck on the outside of the cell - an extension of the T cell receptor chain

If CAR binds to (tumour) antigen –> it will deliver an activating signal to the T cell –> then destroys T cell