L10, Immunotherapy of Cancer Flashcards
Approximately how many active clinical trials for immunotherapy in Feb 2024?
~4000
Evidence for immune involvement in cancer regulation:
- Immune cells (Tumour Infiltrating Lymphocytes) are a type of WBC found in and around tumours
- People with TILs often do better
- Higher incidence of cancer in immunosuppressed patients (HIV, organ transplant etc)
How may a cancer cell evade the immune system?
- Genetic changes e.g. upregulating immune checkpoint proteins
- Altering normal cells to interfere with immune interactions
Immune agents that bind in a cancer specific manner:
- Cytotoxic T-cells
- Antigen presenting cells (APCs) e.g. dendrite cells
- Antibodies
Immune agents that directly attach to cancer cell:
- Natural Killer Cells
- Antibodies
Immune agents that recognise tumour via antigen presenting cells
- Helper T-cells
- Cytotoxic T-cells (activated by APCs)
Types of immunotherapy (4x Cancer Therapies, 1x Non-Cancer specific)
Cancer specific
- Immune checkpoint inhibitors (e.g. PD1/PDL1 inibitors)
- T-cell transfer therapy (TIL and CAR T-cell therapy)
- Monoclonal antibodies
- Cancer treatment vaccines
Non-cancer specific
- Immune system modulators; cytokines (e.g. interferons and interleukins)
How do immune checkpoint inhibitors work? Key example
- Immune checkpoints are useful in preventing overpowered immune responses that might threaten healthy cells
- The proteins expressed engage with receptors on T-cells to downregulate their activity
- Cancer cells can overexpress immune checkpoint proteins to dampen T-cell activity, thus inhibition makes them more vulnerable
- a-PDL1 binds receptor on tumour cell, a-PD1 on T-cell
CTLA-4 inhibition
- The CTLA-4 checkpoint protein stops dendritic cells from priming T-cells to recognize tumours
- Inhibitor cells block this checkpoint
Why is CML particularly susceptible to immunotherapy?
- Cutaneous melanomas have high mutational loads (UV exposure)
- Similar effect in cancers produced by smoking
T-cell transfer therapy: mode of action, 2 main types
- Collecting patients T-cells, growing large numbers in the lab and transferring them back in
- TIL therapy (lymphocytes tested to identify population that best recognises cancer cells -> rapid expansion factor treatment -> reinjection)
- CAR T-cell therapy (cells genetically engineered in lab to make them more potent at cancer killing; express chimeric antigen receptor (CAR) protein)
How has the CAR been optimised over time?
- Multiple generations
- 3rd generation: cytosolic domains from each of three relevant pathways -> stronger activation upon binding, as well as antigen recognition domain from mAb (light chain)
How does CAR binding affect cancer cell?
Immunological synapse formation
Immunological Synapse Formation
- Receptors direct cancer cell to target cell
- Receptor ligation and aggregation activates F-actin accumulation and granules to converge at one point
- M-tubules align towards junction; granules are delivered along them towards immunological synapse
- Contents of granule released across synapse -> attack cancer cell
Potential side effects of CAR T-therapy?
Cytokine release syndrome
- Occurs when transferred T-cells (or other immune cells responding to new T-cells), release a large amount of cytokines into the blood
- Mild and less-common severe form which can be life-threatening
Organ Damage
- Caused by CAR T-cells recognising proteins on normal cells
How can mAbs be utilised in treating cancer?
- Target systemic radiotherapies to cancers
- Block signalling from RTKs e.g. Herceptin
- Aid immune system to recognise and destroy cancer cells e.g. Blinatumomab, binds both CD19 on leukaemia cells and CD3 on T-cells
How do cancer treatment vaccines work?
- Not actually preventative
- Help immune system to recognise and react to antigens and destroy cancer cells that contain them
- Can be made from patients own tumour cells, from tumour-associated antigens common to a type of cancer, or from a patients dendritic cells (stimulate immune system to respond to antigen on tumour cells)
Tumour antigen based vaccination
- Antigen is processed by phagosome after engulfment and loaded onto MHC Class II on APC surface
- Generates antigen-specific T-cells (Tc and/or Th)
How do cytokines work as a cancer treatment?
- They recruit and activate immune cells
- Some are directly toxic to tumours
- Not cancer specific
Interferons and Interleukins: Mechanism and examples
Interferons
- e.g. INF-alpha; activates dendritic cells and natural killer cells
Interleukins
- e.g. IL-2; boosts WBC numbers, including cytotoxic T-cells and natural killer cells
- e.g. IL-7, IL-5 are however known to enhance survival of tumour cells (some cancers grow better in inflamed conditions)
Discuss.. Compare and contrast the types of cancer treatment (inc. aim, pros and cons)
See slide 23
