Tumour immunology and immunotherapy of cancer Flashcards
Give a diagnostic test for paraneopalstic cerebellar degeneration
Detection of anti-CDR2 antibody in the serum
Describe the use of anti-CDR2
Brown colour shows Ig binding
Describe how a cancer can lead to auto-immune diseases
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
What is the evidence for immune control of tumours in humans
Many adults have microscopic colonies of cancer cells
Patients treated for melanoma are used as donors for organs but their recipient develop tumours
What is the relationship between immunosuppression and malignancy
Deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy
What is the relationship between malignancy mortality and gender
Men have twice as great chance of dying from malignant cancer as do women (women typically mount stronger immune responses)
Which receptors are found on T and B cells
alpha-beta T cell receptor
(MHC restricted)
B cell receptors (antibodies)
Describe the cancer-immunity cycle
- Release of cancer cell antigens (cancer cell death)
- Cancer antigen presentation on dendritic cells/APCs
- Priming and activation, APCs and T cells
- Trafficking of T cells to tumours
- Infiltration of T cells into tumours (CTLs, endothelial cells)
- Recognition of cancer cells by T cells (CTLs, cancer cells)
- Killing of cancer cells
What events may imitate cancer
Irradiation
Chemical mutagens
Spontaneous errors during NDA replication
Tumour virus-induced changes in genome
Describe the initiation of tumour growth
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
Which cells are unbolted in innate immunity to tumours
Dendritic cell
Macrophage
Natural killer cell
What are the requirements for activation of an adaptive anti-tumour immune response
Local inflammation in the tumour (“danger signal”)
Expression and recognition of tumour antigens
What are the problems that can arise in immune surveillance of cancer
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)
Describe the recognition of tumour cells by T cells
T cells can ‘see’ inside cells, and canrecognise tumour-specific antigens
Give examples of tumour-specific viral antigens
Epstein Barr Virus (EBV) Human Papillomavirus (HPV)
Give and example of tumour-specific mutated cellular antigens
TGF-beta receptor III
What cancer is caused by post-transport immunosuppression
EBV-positive lymphoma
What cancer is caused by post-transport HIV
HHV8-positive Kaposi sarcoma
Give examples of cancers found in immunocompetent individuals
HTLV1-associated leukaemia/lymphoma
HepB virus- and HepC virus-associated hepatocellular carcinoma
Human papilloma virus-positive genital tumours
Which cancer is HPV associated with
Cervical cancer
Which antigens are expressed on tumour cells in HPV
E6 and E7 oncoproteins
Maintain and induce cervical cancer
Describe the HPV vaccination
Target antigens (no DNA)
Surface proteins, incorporated into Virus-Like Particles (VLPs)
Intracellular Onco proteins (E6,E7) are targets
GARDASIL
What happens in the patients who do not produce an immune response to the HPV16 infection
Immune failure
Cervical neoplasia
No immunity
Non-functional immunity
What are tumour-associate antigens
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.
Give an example of an ectopically expressed auto-antigen
Cancer-testes antigens (developmental antigens): Silent in normal adult tissues except male germ cells (some expressed in placenta).
Give an example of cancer-testes antigen
MAGE familexpressed in other tumoursy: Melanoma associated antigens. Identified in melanoma also
Give examples of tumour-associated antigens
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)
What is tolerance induced by
negative selection in the thymus: central tolerance
Describe the tolerance of melanocytes/melanomas
differentiation antigens
e.g. tyrosinase (melanin production): poor self-tolerance
Local auto-immune depigmentation in melanoma patients
What are the two major problems of targeting tumour-associated auto-antigens for T-cell mediated immunotherapy of cancer
Auto-immune responses against normal tissues
Immunological tolerance
- Normal tolerance to auto-antigens
- Tumour-induced tolerance
What are the approaches used for tumour immunotherapy
Antibody-based therapy Therapeutic vaccination Immune checkpoint blockade Adoptive transfer of immune cells Combination of those above
Give examples of “naked” monoclonal antibody-based therapy
Trastuzumab (Herceptin®) anti HER2, anti CD20, anti CD52, anti EGFR
Give examples of “conjugated” monoclonal antibody-based therapy
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
Describe “bi-specific” antibodies and give an example
Genetically engineered to combine 2 specificities, e.g. anti CD3 and anti CD19 (Blinatumomab, approved for use in patients with B cell tumours)
Which vaccine is FDA approved to treat cancer
Provenge® (sipuleucel-T) for advanced prostate cancer
What does Provenge do
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
Describe the immune checkpoint blockade
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
What does CTLA-4 and PD-1 bind to
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)
Give examples of immune checkpoint blockade drugs
Ipilimumab (anti CTLA-4), Nivolumab (anti PD-1), antagonistic antibodies
What are CARs cells
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
