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CHOLANGIOCARCINOMA AUSTRALASIA

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RESEARCH | MUTATIONS | TREATMENT | IMMUNOLOGY

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The PD-1 /PD-L1 PATHWAY

  • WHAT: Check point inhibitors
  • WHY: Treatment option
  • HOW: Immunology

Simple

Our immune system is like a security checkpoint that scans our bodies’ cells to protect us from things that are harmful. Once detected, abnormal cells are attacked and removed by T-cells. A molecule found on the surface of cancer cells, PD-L1 functions as a disguise that allows cancer cells to go undetected. Dr Dan Chen explains how cancer immunotherapy may affect the PD-L1 pathway, enabling the body’s immune system to better detect, fight and kill cancer cells.

Simple

The role of the immune system is to protect the body from foreign invaders. In responding to cancer, T cells play a central role in the immune system. Programmed death ligand 1 (PD-L1) is one of the inhibitory ligands that, under normal conditions, help maintain immune homeostasis. In many cancers, however, PD-L1 can help tumour cells evade immune system surveillance.

Technical -Easy

US Pathologist, Dr. Michael Lynch, from the Medical and Scientific Affairs (MSA) department for Roche Tissue Diagnostics discusses on: 1. The PD-L1 biomarker and its role in immunotherapy – time in video 00:50 2. Development of an FDA-approved IHC diagnostic assay – time in video 02:26 3. How to manage tissue heterogeneity – time in video 08:04 4. PD-L1 assay in clinical trial – time in video 09:14

Technical -Easy

US Pathologist, Dr. Michael Lynch, from the Medical and Scientific Affairs (MSA) department for Roche Tissue Diagnostics discusses: 1. How and why PD-L1 is present on tumor cells as well as being present on immune cells 2. The different tumor types that show PD-L1 expression 3. The dramatic response of some patients to anti-PD- L1 or anti-PD- 1 therapy, or immunotherapy 4. The diagnostic tests that are available for PD-L1 and how they should be used 5. The SP142 diagnostic assay and how it stains both tumor cells and immune cells 6. The patterns of staining and why they might be important

PD-1 / PD-L1 Explained 

The image above shows a tumour cell expressing a PD-L1 ligand and attempting to bind with the T Cells, PD-1 (Check Point Protein) A successful binding will result in the PD-1 switching off the T Cell attack. The image also shows the presence of the “Checkpoint inhibitor drug” Keytruda intercepting and blocking this binding /connection.

What are Immune Response T Cells

T Cells are relentless and very efficient killing machines.
But they need to see the threat.

When the immune system activates its T Cell army against a new threat, the activated T Cells express a check point protein called PD-1 onto their surface

What are PD-1’s

PD-1 is an Immune inhibitory checkpoint molecule that is expressed by an ”Activated” T Cell. The PD-1 function is to bind and communicate with PDL-1 receptors that sit on the surface of healthy cells. When PD-1 successfully binds with a PD-L1 ligand protein, it then transmits an inhibitory signal back to the T Cell to cease the attack.

What is PD-L1

PD-L1 Ligand is an elongated cluster protein that a cell expresses. PD-L1 ligands attach themselves to the membrane surface of a healthy cell. It’s function is to act as an immune regulatory molecule (A Check Point Molecule) that protects healthy cells form being attacked by T Cells.

The immune System has Check Points

Our immune system is essentially in a permanent attack mode and has inbuilt check points (PD-1) to switch off attacks when encountering healthy Cells. Tumours have learnt to exploit this by expressing the PD-L1 ligand on their cell surface.

What are Check point inhibitors

What are they?

Checkpoint inhibitors are a type of immunotherapy. (Drug)
A drug that is infused (delivered) into the patients arm.

Check Point Inhibitor Immunotherapy allows our own Immune System to do its job and destroy the previously unseen cancer threat.

The drug blocks (Inhibits) the proteins on the surface of the immune systems T Cells from doing their job. These proteins are called “Check Point Proteins” and their job is to switch off attacks on healthy cells. The drugs now prevent the attacks from being switched off.

There are 2 Check Point Proteins on a T Cell (1) CTLA-4 (2) PD-1
Other important factors in the success of this therapy are detailed in other chapters “MMR /dMMR” “MSI-High” “PD-1/PD-L1″ TMB”
There is also another new and exciting /emerging immunotherapy called “CAR T Cell”

Checkpoint inhibitors – How do they work

Our immune system protects us from viruses, diseases, and bacteria and cancer. The immune system has an army of warriors called a T cells that eliminate all foreign threats. T cells have “Check Point” Proteins on their surface. these proteins send signals to the T Cell to switch off mistake attacks on healthy cells.

The 2 protein “Check Points”  have different jobs (1) CTLA-4) turn on the attack,  (2) PD-1 switches off the attack

How does PD-1 switch off an attack?
Healthy cells can make a protein Ligand PD-L1 is one of many such ligands.

These protein ligands act as signal receptors. When an activated T Cell comes to attack the surface of a suspicious cell, this is when the PD-1 “Check Point” Protein activates and detects the presence of the Cells PD-L1 and initates a friendly binding. This successful binding switches off the T Cell attack -the T Cell no longer recognises the cancerous cell as a threat.It

It is thought that High Mutation Tumours express higher levels of PD-L1 ligand proteins and thus exploit this to their advantage.

Currently successful Check Point Inhibitor drugs
Keytruda and Odivo’s  Nivolumab block the PD-1 from binding to PD-L1. Opdivo also has Ipilimumab a drug developed to block CTLA-4 Nivo and Ipi are often used /combined into one treatment.

The Immune systems basic process
  1. Identify – APC (Antigen Presenting Cells) are the immune system messengers. Their job is to seek out cancers, grab a piece of the suspicious cell, and deliver it back to the T Cells. This excites the T Cells.
  2. Activate – CTLA-4 (Check Point Protein) sits on the T Cells surface. Its job is to activate – Switch ON a T Cell attack based on the APC’s findings.
  3. Infiltrate – PD-1: (Programmed Death 1) Another Check Point Protein sits on the T Cells surface. Its job is to deactivate – Switch OFF a T Cell attack based on binding with a friendly PD-L1 on the surface of the suspicious cell, thus preventing healthy cells from being destroyed.

Our Immune System is very clever it has B Cells
It has an army of cells to remember encounters with threats – cells that remember our flu viruses also remember cancers.

Once a cancer is discovered, the B-Cell’s swing into action by searching within its ranks for one cell the can engage and learn this new threat. When one of the B Cell’s learn the DNA finger print of this new threat, it begins to replicate itself into the thousand who now know this cancer.

The B Cell replication creates 2 types of new B-Cells 

  1. ‘Memory B cells’ that remember the cancer
  2. ‘Effector B cells.’ These Effector B-Cells – antibody factories that produce millions more B-Cell antibodies should the cancer ever return.

This is the huge upside to Check Point Inhibitors that not only keeps the T Cell’s attack switch in the ON position, but it also allows the B Cells to remember, thus one the immunotherapy is ceased after 2 years the B Cells will take over from there.

APC Explanation Video Resource 

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