Tumour immunology and immunotherapy of cancer

Question 1

What is CDR2 and its relevance to cancer?

Answer 1

Cerebellum degeneration-related antigen 2. Paraneoplastic cerebellar degeneration (PCD) patient serum reacts with CDR2 protein in tumour tissue.

Question 2

What can cause paraneoplastic cerebellar degeneration?

Answer 2

Elimination of Purkinje cells (motor neuron in cerebellum) by tumour-induced autoimmune response.

Question 3

Discuss the circumstantial evidence fo immune control of tumours in humans.

Answer 3

Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease- immune control?

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’.

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

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

Question 4

What is the concept of tumour ‘immunosurveillance’?

Answer 4

Malignant cells are generally controlled by the action of the immune system.
Immunotherapy tries to enhance immune responses to cancer.

Question 5

What are the stages in the cancer-immunity cycle?

Answer 5

Release of cancer cell antigens (cancer cell death).

Cancer antigen presentation (dendritic cells/APCs).

Priming and activation in lymph nodes (APCs and T cells).

Trafficking of T cells to tumours (CTLs).

Infiltration of T cells into tumours (CTLs, endothelial cells)- TIL.

Recognition of cancer cells by T cells (CTLs, cancer cells).

Killing of cancer cells (immune and cancer cells)- immune selection pressure.

Question 6

What molecules are targeted in immune checkpoint blockade?

Answer 6

CTLA4

PD-L1/PD-1

Question 7

What does initiation of cancer usually result from?

Answer 7

Multiple sporadic events over time.
Irradiation, chemical mutagens, spontaneous errors during DNA replication, tumour virus-induced changes in genome.
Induction of mutations in cellular DNA.

Question 8

What does aberrant regulation of apoptosis and the cell cycle result in?

Answer 8

Tumour growth.

Question 9

What does tumour growth result in eventually?

Answer 9

Inflammatory signals.
Recruitment of innate immunity- dendritic cells, macrophages, NK cells.
Subsequent recruitment of adaptive, antigen-specific immunity.

Question 10

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

Answer 10

Local inflammation in the tumour (‘danger signal’).

Expression and recognition of tumour antigens.

Question 11

What are the problems in immune surveillance of cancer?

Answer 11

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 12

How do immune responses to tumours have some similarities with those to virus infected cells?

Answer 12

T cells can ‘see’ inside cells, and can recognise tumour-specific antigens.
Presentation by MHC molecules- ‘display’ contents of cell for surveillance by T cells in infection and carcinogenesis.

Question 13

Give some tumour-specific antigens.

Answer 13

Viral proteins: Epstein Barr virus (EBV), human papilloma virus (HPV).
Mutated cellular proteins: TGF-beta receptor III, Bcr-Abl.

Question 14

List some cancers of viral origin.

Answer 14

Opportunistic malignancies- immunosuppression:

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

Also in immunocompetent individuals:

• HTLV1-associated leukaemia/lymphoma
• hepatitis B virus and hepatitis C virus associated hepatocellular carcinoma
• human papillomavirus positive genital tumours

Question 15

What induces and maintains cervical cancer?

Answer 15

E6 and E7 oncoproteins of HPV- intracellular antigens.

Question 16

What is the relation between consequences of cervical HPV infection and HPV-specific T cell immunity?

Answer 16

Preventive vaccination against HPV16 infection leads to strong immunity and clearance of the HPV infection, then immunological memory, in >99%.

The minority of people receiving the same vaccine will experience immune failure leading to cervical neoplasia- 50% with no immunity, 50% with non-functional immunity. These individuals can then be given therapeutic vaccination.

Question 17

What are tumour-associated antigens (TAAs)?

Answer 17

Derived from normal cellular proteins which are aberrantly expressed (timing, location or quantity). As they are normal self proteins, tolerance may need to be overcome for an immune response to occur.

Question 18

Give examples of tumour-associated antigens.

Answer 18

Ectopically expressed autoantigens, e.g. cancer-testis antigens (developmental antigens)- silent in normal adult tissues except male germ cells (some expressed in placenta).

MAGE family- melanoma associated antigens, identified in melanoma and also expressed in other tumours.

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:

• prostate-specific antigen (PSA)
• prostate-specific membrane antigen (PSMA)
• prostatic acid phosphatase (PAP)

Question 19

What are the 2 major problems of targeting tumour-associated autoantigens for T cell mediated immunotherapy of cancer?

Answer 19

Autoimmune responses against normal tissues.

Immunological tolerance:

• normal tolerance to autoantigens
• tumour-induced tolerance

Question 20

What approaches are being used and developed for tumour immunotherapy?

Answer 20

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

Question 21

What are the different types of monoclonal antibody-based tumour immunotherapies?

Answer 21

‘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 22

What is the only FDA-approved vaccine to treat cancer?

Answer 22

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 23

How does the immune checkpoint blockade work as a tumour immunotherapy?

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

Question 24

What are the steps involved in adoptive transfer of cells as tumour immunotherapy?

Answer 24

T cell source (from patient).
Antigen-specific expansion, non-specific TIL expansion or genetic engineering.
Culture.
Expansion.
Reinfusion into patient.