Immune 4 - Tumour immunology and immunotherapy of cancer Flashcards
What causes paraneoplastic cerebellar degeneration (PCD)
Anti-CDR2 antibody
CDR2 = cerebellum degeneration-related antigen 2
Elimination of purkinje cells by tumour induced auto-immune response
What is meant by tumour “immunosurveillance”
Malignant cells - generally controlled by the action of the immune system
Immunotherapy tries to enhance immune responses to cancer
Highlight quick differences between T cells and B cells
T cells = “MHC restricted”. Alpha and beta T cell receptor
B cells = vast range of molecules recognised by antibody
Explain the cancer-immunity cycle
- Death of cancer cell - loads of antigen released
- Cancer antigen presented on APC
- T cell recognition at lymph node - T cell activation
- T cell moves to tumours
- T cell infiltration into tumours (TIL)
- Recognition of cancer cells by T cells
- Killing of cancer cells (consequently more antigens are released)
Certain inhibitory signals are involved in the cancer immunity cycle - these are targeted in cancer immunotherapy. Eg?
“immune checkpoint blockade”
- CTL-A4 / PD-L1 / PD-1
- PD-L1
Were trying to remove the negative signals inhibiting the immune response
What are the 2 requirements for activation of an adaptive anti-tumour immune response?
- Local inflammation in the tumour (“danger signal”)
- Expression and recognition of tumour antigens
Tumour inflammation takes a while to trigger adaptive immune response
What are the problems with immune surveillance
- 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
What is the basis of cancer immunotherapy
“teaching” the adaptive immune system to selectively detect and destroy tumour cells - potential alternative/supplement to conventional therapies
usually minimal side effects
How might immune responses to tumours be similar to virus infected cells?
T cells can see inside cells - and can recognise tumour specific antigens (presented on MHC class 1/2).
Name some tumour specific antigens to target
Viral proteins:
- Epstein Barr virus (EBV)
- Human Papillomavirus (HPV)
Mutated cellular proteins:
1. TGF-beta receptor
(The above all may cause cancer)
Which opportunistic malignancies can cause cancer (viral origin) in immunosuppressed individuals
- EBV positive lymphoma - post transplant immunosuppression
2. HHV8-positive Kaposi sarcoma: HIV
In immunocompetent individuals, what cancers arise from viral origin
- HTLV1-associated leukaemia/lymphoma
- HepB and HepC virus-associated hepatocellular carcinoma
- HPV - positive genital tumours
Which are the oncoproteins of HPV that induce and maintain cervical cancer
E6 and E7
What are the target antigens for preventive HPV vaccination
“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)
To whom is the HPV vaccine given therapeutically?
NB can also be given preventively
To those who are infected by HPV16 and have not been successful in clearing it (immune failure)
What are tumour-associated antigens (TAAs)
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
Tumour associated antigens are ectopically expressed auto-antigens. They are so called developmental antigens, meaning?
They are silent in normal adult tissues except male germ cells (some expressed in placenta).
Give an example of a tumour associated antigen
- e.g. MAGE family - melanoma associated antigens.
- Human epidermal growth factor receptor 2 (HER2) - overexpressed in some breast cancers
- Mucin 1 (MUC-1) - membrane associated glycoprotein - over expressed in many cancers
- 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)
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
Melanocyte/melanoma - tyrosinase (melanin production) - has poor self tolerance
What are 2 major problems with 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
Describe monoclonal antibody based therapy for cancer
Can be:
- “naked” - e.g. Perception (anti-HER2)
- “Conjugated” - radioactive particle, e.g. anti-CD20 linked to yttrium-90, or anti-HER2 linked to cytotoxic drug (trastuzumab emtansine)
- “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)
Give an example of therapeutic cancer vaccination
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
Describe “personalised” tumour specific cancer vaccines
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
Describe the basis for immune checkpoint blockade approach to cancer treatment
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
Describe what adoptive transfer of cells (ACT) is
- Take WBCs from patient with tumour
- Expand T cells in vitro (can be antigen specific expansion or non specific expansion)
- We can also genetically engineer the T cells, e.g. by introducing new antigens into them
- Once T cell culture has expanded, we can put them back into the human
Give an example of a genetic-engineering type approach to cancer therapy
It has been used for B cell tumours using CD19
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
