Flashcards in Tumour immunology and immunotherapy of cancer Deck (23)
How can breast cancer be linked to the following symptoms: severe vertigo, unintelligible speech, truncal and appendicular ataxia?
Paraneoplastic cerebellar degeneration
Explain how breast cancer can lead to the degeneration of the cerebellum.
The antigen that the immune response is directed against is normally expressed in neural tissue
It is only expressed in breast tissue when there is a tumour
The abnormal expression of this antigen in the breast was noticed and an immune response was mounted, which then also reacted with the normal antigens in the neural tissue => destruction of purkinje cells in the cerebellum
Summarise the evidence for immune control of tumours in humans
1. Presence of asymptomatic microscopic cancer colonies in accident victims following autopsy - immune control?
2. 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’.
3. Deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy
4. Men have twice as great chance of dying from malignant cancer as do women (women typically mount stronger immune responses)
Describe the cancer-immunity cycle.
Antigens are released from cancer cells and captured by APCs (e.g. dendritic cells), which then migrate to local draining lymph nodes => priming and activation of T cells
Once the T cells are activated they go back to the tumour and infiltrate it– the processed antigens are then recognised by the T cells, which then kill the cancer cells.
=> Release of cancer cell antigens upon cancer cell death
How does the immune system act as a selection pressure for the tumour cells?
Mutant variant tumour cells within the cancer are able to avoid recognition by T cells and hence are allowed to proliferate and become the dominant cell type
Describe the effect of the PD-1 – PDL-1 signalling on the T cell response.
When a T cell has been exposed to an antigen several times, it starts to express PD-1 receptors
Tumour cells upregulate expression of the PDL-1 ligand, which can bind to the PD-1 receptor and downregulate the T cell response
Blockade of the PD1-PDL1 interaction could help stimulate the T cell response
What are the requirements for 'spontaneous' activation of an adaptive anti-cancer immune response?
- Local inflammation in the tumour
- Expression and recognition of tumour antigens
What are the main problems with the immune surveillance of cancer?
- It takes a tumour a while to cause inflammation
- Antigenic differences between normal and tumour cells can be very subtle
What are two example types of tumour-specific antigens?
Viral proteins (i.e. tumour cells expressing viral antigens)
Mutated cellular proteins
Give two examples of opportunistic malignancies (arise due to immunosuppression)
1. EBV-positive lymphoma (post-transplant immunosuppression)
2. HHV8-positive Kaposi sarcoma (occurs in HIV)
State three examples of viral infections that can cause cancer in immunocompetent individuals.
1. HTLV1-associated leukaemia/lymphoma
2. HepB virus- and HepC virus-associated hepatocellular carcinoma
3. HPV positive genital tumours
Which oncoproteins of HPV are responsible for the induction andmaintenance of cervical cancer?
Name and describe an important HPV vaccine
= HPV surface proteins (encoded by L1 and L2 genes) incorporated into Virus-Like Particles
What are the two different times at which vaccines can be given?
Preventative vaccination (before the disease)
Therapeutic vaccination (try to control the disease once it has occurred)
What are tumour-associated antigens?
Normal (self) cellular proteins which are aberrantly expressed, in terms of timing, location or quantity.
- For an immune response to occur, tolerance may need to be overcome.
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)
Melanoma associated antigens (ectopically expressed)
Describe the problem with tolerance in cancer immunotherapy.
T cells that react strongly with self are deleted (central tolerance) so most people have tolerance against tumour-associated antigens
What are the two major obstacles for the targeting of tumour-associated antigens in immunotherapy of cancer?
Autoimmune responses against normal tissues (e.g. Immunotherapy against melanoma in mice is accompanied by vitiligo)
Immunological tolerance (Normal tolerance to auto-antigens and Tumour-induced tolerance)
What are three possible approaches to tumour immunotherapy?
1. Cancer vaccination – immunisation to stimulate natural anti-cancer responses
2. Genetic modification of T cells to express a receptor capable of recognising the tumour – these are then inserted back into the patient so that the T cells can kill the tumour cells
3. Blockade of molecules that inhibit T cell responses
Summarise approaches being used and developed for tumour immunotherapy
Immune checkpoint blockade
Adoptive transfer of immune cells
Summarise approaches being used and developed for tumour immunotherapy - antibody based therapy
- The killing of tumour cells using monoclonal antibodies (mAbs)
“Naked” e.g. Trastuzumab (Herceptin®) anti HER2,anti CD20, anti CD52, anti EGFR
“Conjugated” with radioactive particle e.g. Ibritumomab tioxetan, anti CD20 linked to yttrium-90; or with a drug e.g. Trastuzumab emtansine, 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 B cell tumours)
Summarise approaches being used and developed for tumour immunotherapy - therapeutic vacccination
Provenge® (sipuleucel-T) for advanced prostate cancer (only FDA approved vaccine to treat 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