4 - Tumour Immunology and Immunotherapy of Cancer Flashcards
What is Paraneoplastic Cerebellar Degeneration (PCD)?
Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic syndrome associated with a broad variety of tumors. PCD is believed to be due to an autoimmune reaction targeted against components of the central nervous system, mostly to Purkinje cells.
For PCD due to breast cancer, what antigen can antibodies be formed that cause issues?
Cerebellum Degeneration-Related Antigen 2 (CDR2)
What occurs in PCD?
Immune response against antigen in tumour
Antibodies against antigen are formed
Antibodies travel via circulation to brain
Certain cells in brain express same antigens as the tumour
Antibody binds in brain
Autoimmune disease in brain caused by tumour elsewhere
What is PCD evidence of?
PCD shows that immune responses can be made against tumours
- At least certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues.
- The immune system can, in principle, detect such abnormally expressed antigens and, as a result, launch an attack against the tumour.
- In certain cases, this may result in auto-immune destruction of normal somatic tissues.
Outline circumstantial evidence (other than PCD) for immune control of tumours in humans
- 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 chance of dying from malignant cancer as do women (women typically mount stronger immune responses)
What is ‘tumour immunosurveillance’?
Malignant cells are generally controlled by the action of the immune system.
What does immunotherapy try to do?
Immunotherapy tries to enhance immune responses to cancer.
What is the overall difference between molecules that can be recognised by T cells and B cells as part of adaptive immunity?
What is the Cancer-Immunity Cycle?
When the tumour grows, some of the cells will die and release potential antigens.
These go via lymph carried by AP cells to lymph nodes,
Present antigens to recirculating lymphocytes.
Activate lymphocytes (primer and adaptive response)
Activated cells (e.g. t-cells) will go back to tumour via blood vessels
Enter tumour = tumour-infiltrating lymphocytes
Recognise antigen in the form of peptide presented by MHC
Try to kill the tumour cells
Release more antigens
—> CYCLE CONTINUES
- forms strong selection pressure
- if cell can avoid this killing, they can survive (e.g. by losing MHC)
What are the positive and negative signals that can be applied to The Cancer-Immunity Cycle?
Positive = Green
Negative = Red
- CTLA-4
- PD-1
- Immune-Checkpoint Blockade
- These are targeted in cancer therapy using antibodies
- Remove negative signals in order to enhance immunity against cancer
Outline the stages of initial cancer development
- Usually results from multiple sporadic events (mutations) over time
- irradiation
- chemical mutagens
- spontaneous errors during DNA replication
- tumour virus-induced changes in genoma
- Aberrant regulation of apoptosis and cell cycle results in tumour growth
- Tumour growth eventually results in inflammatory signals
- Recruitment of innate immunity
- Subsequent recruitment of adaptive, antigen-specific immunity
What requirements are there 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 for the process immune surveillance of cancer?
- It takes a while for the tumour to cause local inflammation
- Antigenic differences between normal and tumour cells can be very subtle (e.g. small number of point mutations)
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?
Yes, this is what is attempted with cancer immunotherapy
- Potential alternative/supplement to conventional therapies (surgery, chemotherapy, radiotherapy)
- minimal side effects by comparison
Which antigens should be targeted with cancer immunotherapy?
T cells can ‘see’ inside cells, and can recognise tumour-specific antigens
Tumour antigens are normally within cells (occasionally in membranes, in which case they can be recognised by antibodies)
What is the function of MHC Class I/II molecules?
Display contents of cell for surveillance by T cells
- infection
- carcinogenesis
What are tumour-specific antigens?
TUMOUR-SPECIFIC ANTIGENS
Antigens only found in tumour cells
There are some viruses which cause cancers and express viral proteins in the tumour cells
Also talking about mutated cellular proteins which have amino acid changes that alter their cellular function
- could be any protein that is important in regulating the cell cycle
These are ideal to target in immunotherapy
What cancers are of viral origin?
CANCERS OF VIRAL ORIGIN
LOTS OF THESE OCCUR IN IMMUNOSUPPRESED PEOPLE
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
What cancer is HPV associated with?
Particular strains of HPV are associated with cervical cancer
The tumour cells express viral proteins
- E6 and E7 oncoproteins
What is used in the vaccine against HPV?
Don’t use the viral E6 and E7 oncoproteins, as this would be potentially dangerous
Surface proteins are used instead
What is the name of the current HPV vaccine used?
Gardasil 9
- works against 9 different HPV strains
In what ways is the HPV vaccine used?
In most people, even without the vaccine, the immune system can normally deal with the HPV infection.
USED IN TWO WAYS:
Preventitive Vaccine
or
To people with cancer to eliminate the tumour cells
What are tumour-associated antigens (TAA)?
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.
Why would you not expect the immune system to react to TAAs?
You would not expect the immune system to react to TAAs because they are normal self proteins.
You would expect the immune system to be tolerant to them.
How would you further characterise TAAs?
TUMOUR-ASSOCIATED ANTIGENS: ectopically expressed auto-antigens
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. Initially identified in melanoma, but are also expressed in other tumours.
Give some examples of TAAs
EXAMPLES OF TAAs
Human epidermal growth factor receptor 2 (HER2): overexpressed in some breast carcinomas
Mucin1 (MUC-1): membrane-associated glycoprotein, overexpressed in very many cancers
Carcinoembryonicantigen (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)
How does the body normally remove T-cells that have a strong reaction to self?
Normally, tolerance induction by negative selection occurs in the thymus = central tolerance
This process is not 100% efficient
Some T-cells have the capability for auto-reactivity even after leaving the thymus
These T-cells that have some auto-reactivity are the ones that we want to stimulate in immunotherapy
Why can auto-reactivity be a problem in immunotherapy?
In immunotherapy, T-cells that have escaped central tolerance mechanisms with some auto-reactivity are the targets for stimulation
This can lead to some auto-immune reactivity against normal cells. This isn’t a problem for main antigens targeted because most normal adult cells don’t express them.
However, for tyrosinase (as found in melanomas) which is also important in melanocytes, there is often poor self-tolerance
Why is immunotherapy against melanoma often accompanied by auto-immune skin depigmentation (vitiligo)?
This is because tyrosinase is often the protein target of immunotherapy against melanomas, as it is an antigen that is overexpressed in this condition.
However, this antigen is also found in normal cells as it is important for melanin production.
Therefore, by targeting this protein, loss in normal cells can lead to skin depigmentation.
What are the two major problems of targeting tumour-associated antigens (TAAs) for T-cell mediated immunotherapy of cancer?
TWO MAJOR PROBLEMS
- Auto-immune responses against normal tissues
- Immunological tolerance
- Normal tolerance to auto-antigens
- Tumour-induced tolerance
Summarise approaches being used and developed for tumour immunotherapy
1) Antibody-based therapy
2) Therapeutic vaccination
3) Immune checkpoint blockade
4) Adoptive transfer of immune cells
5) Combinations of 1) to 4) above
Outline monoclonal antibody-based therapy
MONOCLONAL ANTIBODY-BASED THERAPY
Use single antibodies of defined specificity (monoclonal)
This type of therapy is very expensive
“Naked”
e.g. Trastuzumab (Herceptin), anti HER2
“Conjugated”
Radioactive particle e.g.Ibritumomabtioxetan (Zevalin®), anti CD20 linked to yttrium-90
Drug e.g. Trastuzumabemtansine (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). Can bind to two different things
Outline therapeutic cancer vaccination methods
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
The cytokine is thought to stimulate APCs
Stimulates DC maturation and enhances PAP-specific T cell responses
What are “personalised” tumour-specific cancer vaccines?
ATTEMPT TO PERSONALISE TUMOUR VACCINES
Take tumour and normal cells from the same person
Make DNA and RNA
Exome sequence: sequence all the RNA and coding parts of the DNA
Also HLA type the person as well
Identify the mutations found in the cancer cells that aren’t in the normal cells
Time-consuming and exspensive
Show that the mutations are expressed from the RNA
Predict which peptides bind to that patient’s HLA molecules and whether any of those peptides span where the mutations have been found
Use those peptides as vaccines (neo-antigens)
What is immune checkpoint blockade?
IMMUNE CHECKPOINT BLOCKADE
Rather than directly stimulate responses, this approach seeks to reduce/remove negative regulatory controls of existing T cell responses
Should apply to any cancer that is producing an immune response
If we use this, we might allow for more auto-immune responses so not a good idea to be used for a long period of time
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
What is Adoptive Transfer of Cells (ACT)?
ADOPTIVE TRANSFER OF CELLS (ACT)
Take cells (usually WBCs) from a patient with a tumour, either from the tumour or blood
Expand T-cells in vitro
- either with tumour-specific antigens or with cytokines
Could also do some genetic engineering of the T-cells by adding antigens against the tumour
Put the T-cells back into the patient
What are Chimaeric Antigen Receptors (CARs)?
An example of genetically engineered T-cells
Binding area of the receptor has been derived from an antibody
Generated single chain fragment variable (scFV) domains, where the variable domains are joined by a flexible linker sequence
Stuck on the end of a transmembrane of an internal T-cell receptor chain
If it binds to its antigen, delivers activating signal to the T-cell
