Immunotherapy Flashcards
How is Immunity related to Cancer?
= tumours are altered as ‘self’
= cancer cells are subtly different to normal cells
(BUT frequently recognised and eliminated by immune system)
TILs (Tumor-Infiltrating Lymphocytes)
= immune cells found in and around tumours
= people with tumours containing TILs = have better prognosis
= cancer incidence high in immunosuppressed patients
(e.g. HIV , organ recipients)
How does Immune Evasion by Cancer cells occur?
= cancers may have genetic changes that make them less visible to immune system
(e.g. upregulate immune checkpoint proteins)
= change the normal cells around the tumour so they interfere with how the immune system responds to the cancer cells
= immunotherapy helps immune system to better act against cancer
What cells are involved in cancer immunity?
Antibodies
Cytotoxic T cells
Natural Killer Cells
Antigen presenting cell
Helper T cells
What are the main types of immunotherapy?
Cancer specific:
1. Immune checkpoint inhibitors
= block immune checkpoints
= e.g. PD1.PDL1 inhibitors
= e.g. CTLA-4 inhibitors
- T-cell transfer therapy
= e.g. TIL therapy
= e.g. CAR-T cell therapy - Monoclonal antibodies
- Cancer Treatment Vaccines
Non-cancer specific:
5. Immune system modulators: cytokines
= interferons
= interleukins
What are checkpoint inhibitors?
Immune checkpoints are a normal part of immune system
= role is to prevent an immune response from being so strong it destroys healthy cells in the body
= immune checkpoint proteins engage with receptors on T-cells to downregulate their activity
= cancer cells can overexpress immune checkpoint proteins to dampen T-cell activity
= e.g. Anti-PDL and Anti-PDL1
= PDL and PDL1 bind = T cell not activated = inhibition of T cell activity
= anti-PD1 antibodies (immune checkpoint inhibitors)
= bind to PD1 = T cell activated = upregulation of immune response
e.g. CTLA-4 inhibition
= it’s ligands: protein B7-1 and B7-2 expressed on APCs
= when they interact, inhibits T cell activity
= helps prevent excessive immune activation
(cancer cells can hijack this to evade immune response, tumour cells express high levels of CTLA-4 = suppress activity of T cells = prevent tumour attack)
What is T-cell transfer therapy?
= uses a patient’s own T-cells, artificially expanded in lab, to kill cancer cells
2 main types:
- tumour-infiltrating lymphocytes (or TIL) therapy
- Car T-cell therapy
= both involve collecting patient’s own T cells, growing them in large numbers in the lab and transferring back to patient
(also known as: adoptive cell therapy, adoptive immunotherapy and immune cell therapy)
What is TIL therapy?
= TILs (tumour-infiltrating lymphocytes) found in tumours
= these cells may already be acting against the cancer, but may not be in sufficient numbers to have effect
= lymphocytes tested to identify population that best recognises cancer cells
= these treated with factors to induce rapid expansion
= injected back into patient and attack cancer cells
What is CAR T-cell therapy?
= similar to TIL therapy but cells genetically engineered in lab to make them more potent at killing cancer cells
= T cells removed are engineered to express chimeric antigen receptor (CAR) protein
= CARs are designed to allow the T cells to attach to specific proteins on the surface of the cancer cells
(improving their ability to attack the cancer cells)
What is the Chimeric Antigen Receptor?
= genetically engineered receptor designed to enhance ability of T cells to recognise and attack cancer cells
= made by combining antigen-binding domain of a monoclonal antibody with T-cell receptor signalling components
= creates a hybrid receptor that can recognise specific antigens on the surface of cancer cells and activate T cells to attack and kill them
= binding of CAR receptor allows formation of an immunological synapse and killing of cancer cell
What are the side-effects of CAR T-cell therapy?
Cytokine Release Syndrome
= occurs when transferred T cells release a large amount of cytokines into the blood
Sudden increase in cytokines can cause:
= fever, nausea, headache, rash, rapid heartbeat, low blood pressure, trouble breathing
Most people = mild form
Some = severe / life-threatening
CAR-T cells designed to recognise proteins that are only found on cancer cells
= BUT sometimes recognise normal cells
= can cause side effects e.g. organ damage
What are monoclonal antibodies?
= can be used in various ways to treat cancer:
- Target systemic radiotherapies
- Block signalling from receptor tyrosine kinase (e.g. herceptin)
- Aid immune system to recognise and destroy cancer cells
e.g. Bilinatumomab - binds both CD19 (on leukaemia cell surface) and CD3 (on T cell surface)
What are cancer treatment vaccines?
= a type of immunotherapy to treat (rather to prevent) cancer
= can help immune system to recognise and react to these antigens and destroy cancer cells that contain them
Cancer treatment vaccines may be made in 3 ways:
- From patient’s own tumour cells
= custom-made so they cause an immune response against unique features of a patient’s cancer
= rejects tumour cells and prevents tumour formation - From tumour-associated antigens
= found on cancer cells of many people with a specific type of cancer
= antigen is processed and loaded onto MHC class II on APC surface
= generates antigen specific T-cells - From patient’s dendritic cells
= stimulate immune system to respond to an antigen on tumour cells
What are Immune modulating agents?
Cytokines (non-target chemotherapies)
= recruit and activate immune cells
= in some cases, are directly ‘toxic’ to tumours
= specific for certain cancer types and cytokines
Interferons (INFs)
= e.g. INF-alpha
= activates dendritic cells and natural killer cells
Interleukins (ILs)
= e.g. IL-2 = boosts white blood cell numbers, including cytotoxic T cells and natural killer cells
= BUT some e.g. IL-7 , IL-15 significantly enhance survival survival of tumour cells
What are some pro and cons of different cancer treatments?
