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
