Immuno 101

IMMUNOTHERAPY

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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 

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.

When MMR stops working

Mismatch Repair Genes (MMR) work like genetic “spell checkers”

Each one of our ‘4’ MMR genes express a protein, it is these expressed proteins that become our DNA ‘Spell Checkers’. They correct errors that occur when our DNA code typos occur – just like a computer spell checker does. These errors often occur when cells divide.

When one or more of the 4 Key MMR genes (MLH1, MSH2, MSH6, and PMS2 ) are silenced or absent (ie do not express their protein) then the repair process malfunctions and is then referred to as deficient ie. dMMR

This failure impacts our ‘Microsatellites’ which are integral to the DNA replication process. – see MSI section

Notes:
  1. dMMR environments are only found in a small percentage of Cholangiocarcinoma diagnosis.
  2. MLH1 protein absence is linked to Lynch syndrome
Microsatellite Instability (MSI)

dMMR causes Microsatellite Instability

An IHC Test is imperative.
Immunohistochemistry Test – fast and Efficient  (3 -5 days) see Testing  Page 
What you testing for is MSi-high result, as immunotherapy responds well to this.

Our 4 MMR genes each express a protein, these protein expressions are our DNA ‘Spell Checkers.’ If one or more fail to express then repairs to errors and mistakes that occur in our DNA’s replication will go unchecked, creating instability in our ‘Microsatellites’

What do Microsatellites do?
They are the containers that hold our repetitive sequences of nucleotides (DNA code).

What are Nucleotides?

  1. Nucleotides are sequences of our DNA code. (Sequence repeats)
  2. Nucleotides are our “DNA Building Blocks”
  3. Nucleotides typically have 2 to 7 different types of pre programmed sequences of repeat code –
  4. Each sequence can contain between 2 -25 characters (string or stretch of code) – see diagram below.
  5. Nucleotide sequences continually replicate.
  6. Everyone has different pre programmed sequences.There can be hundreds of different code sequences.

The Nucleotide replication process can often go wrong
The MMR expressed proteins corrects these spontaneous errors as they occur. When our MMR spell Checker is compromised or weakened then inconsistencies in the Microsatellites Nucleotides repeats over and over, this is when cancers can form.

Lab testing  (IHC) can easily discover this when comparing a healthy cells numbers or sequence, with cancer cells. If a difference is identified, then this is referred to as “microsatellite instability”.

MSI levels/identification
  1. MSI-high: (MSI-H) occurs if two or more microsatellite markers show instability
  2. MSI-low: (MSI-L) occurs if there is only one marker unstable
  3. MSI-Stable : (MSS) results when all the five microsatellite markers are stable

Reporting often describes as

  1. MSI-h > 30%
  2. MSI-L <30%
  3. MSS – 0% instability

Image
Microsatellite Markers
Samples of Nucleotide code sequences contained within a microsatellite, these are supposed to replicate exactly the same in tandem.

Scott Paulson MD

Extract from CURE who spoke with Scott Paulson, M.D. medical oncologist with Texas Oncology, an affiliate of The US Oncology Network, to break down exactly what MSI-H status is, and the effects it may have on certain malignancies. Full Article link 

MSI-high tumours form a well defined group with distinct clinicopathologic features (more easily identifiable) which characterises an overall better long-term prognosis.

MSI-H is a feature of cancer’s genetic coding, which results in it behaving and “looking” a certain way on a microscopic level. Due to defects in the way that DNA in the cancer cells repairs itself, it creates changes and mutations to normal body cells that can eventually let them turn into cancer. However, these cells become so abnormal, because of this feature, that the immune system, which is used to protecting the body against bacteria and viruses and other foreign invaders, can actually look at the cancer and recognize that something is very wrong. This can call the body’s normal defenses against invaders to try to attack the cancer.

TMB is also a factor

Something to be aware of.
When the body has a dMMR/MSI-High environment it typically sees a higher TMB (tumour mutation burden) in the body and these tumours also have a strong correlation to higher expression of the protein ligand PD-L1 which anchors to the surface of the tumour cells.

Tumor Mutation Burden (TMB) refers to the total amount of cancer tissue in the body. The survival of a patient relates to the tumor mutation burden, disease location and most importantly, the pace of the disease. In general, patients with a high burden of tumors have a high pace of disease and therefore a very short survival without therapy.

More About TMB

Source
Onclive 2018

Patients most likely to respond to immune checkpoint inhibitors (ICIs), tumor mutational burden (TMB) has emerged as a highly promising and clinically validated biomarker. Results from studies have demonstrated that subsets of patients with high TMB exist across almost all cancer types and that assessing TMB through whole-exome sequencing (WES) or next-generation sequencing (NGS) can predict response to a range of different types of immunotherapy.

TMB has been a hot topic at oncology conferences this year. Investigators and test developers must overcome a variety of challenges before it is ready for prime time as a biomarker, but it appears poised to bring immunotherapy into the era of personalized medicine.

A Heavy Load

It is a central tenet of cancer biology that tumors arise and evolve as a result of the acquisition of damage to the genome, generating characteristic genomic alterations that lead to the dysregulation of key cellular processes termed cancer hallmarks. In addition to identifying individual frequently altered genes that function as drivers of particular cancer types, results from genome sequencing studies have revealed the global spectrum of somatic mutations across a given tumor, known as the TMB or mutational load. TMB is defined as the number of mutations per megabase (Mb) of DNA.

Seeds of Their Own Destruction

It has long been suspected that cancers with a greater number of gene mutations may provoke a stronger antitumor immune response. The thinking behind this hypothesis relates to the production of neoantigens—fragments of proteins expressed on the surface of cancer cells that are encoded by mutated genes. Neoantigens are unique to cancer cells because they are derived from a mutant gene, which may encode a mutant protein that differs from that expressed by normal cells. Therefore, neoantigens have the potential to be recognized as foreign by the cells of the immune system that patrol the body. A greater number of neoantigens might mean increased stimulation of those immune cells and a stronger immune response. In this way, cancer cells may generate the seeds of their own destruction.

My Kingdom for a Biomarker

MSI and dMMR and are just 2 of the many phenotypes that can cause hypermutant tumors and contribute to high levels of TMB. If tumors with higher TMB provoke a stronger immune response, then it stands to reason that TMB could provide a means for more comprehensive assessment of patients who might respond to ICIs and potentially other immunotherapies. In the past several years, investigators have started to evaluate TMB in this capacity, and it has emerged as a powerful predictor of response to ICIs in a range of tumor types Investigators are seeking to correlate TMB with clinical and biological outcomes in a number of ongoing clinical trials.

High TMB

Source

Caris life Sciences

Tumor Mutational Burden (TMB) is an emerging, quantitative indicator for predicting response to novel immune checkpoint inhibitors across a wide spectrum of tumor types. TMB measures the total number of non-synonymous, somatic mutations identified per megabase of the genome coding area (a megabase is 1,000,000 DNA basepairs).

Tumors with high TMB likely harbor neoantigens and may respond more favorably to immune checkpoint inhibitors. Caris Molecular Intelligence defines TMB as 17 or more mutations per megabase. TMB is included for all MI Profile orders, at no additional cost, added tissue or delay in turnaround time.

How Tumor Mutational Burden Works
  • Non-synonymous mutations are changes in DNA that result in amino acid changes in the protein.
  • The new protein changes result in new shapes (neo-antigens) that are considered to be foreign to the immune system.
  • Immune checkpoint inhibitors are able to stimulate and allow the immune system to detect these neoantigens and destroy the tumor.
  • Germline (inherited) mutations are not included in TMB because the immune system has a higher likelihood of recognizing these alterations as normal.

A different approach, bypassing the Check Point Inhibitor.

What is the role of T-cells in the immune system?

T Cells are the immune systems soldiers who search out and destroy the foreign invaders, such as flu and cancer.

Chimeric antigen receptor CAR T Cell
  • CAR T Cell Therapy is a way of engineering the bodies T Cells to recognise cancer, by reprogramming the bodies own T Cells to recognise and destroy the cancer.
  • T Cells are removed from the patient and then the patients Tumour antigens are added to teach the T Cells.
  • The newly modified T Cells are then grown into the millions and then reintroduced into the patients body.
  • CAR T-cell therapy, is a new form of immunotherapy that uses specially altered T cells to directly and precisely target cancer cells.

The immune system is made up of a variety of cells and organs that normally protect the body from infection and cancer. An important component of the immune system are T cells, which have the capacity to hunt down and destroy abnormal cells, including some cancer cells.

Sometimes, cancer cells find ways to evade the immune system; so, the immune system needs to be retrained and enhanced to recognize and attack cancer cells. CAR T-cell therapy is one innovative approach to program and strengthen the immune system to attack some forms of cancer.

After a small portion of a patient’s own T cells has been collected from the blood, these cells are re-engineered in a special laboratory so they now carry special structures called chimeric antigen receptors (CARs) on their surface.

When these CAR T cells are reinjected into the patient, they multiply rapidly and these engineered receptors may help the T cells to identify and attack cancer cells throughout the body.

CAR T-cell therapy has been shown to be effective in B-cell acute lymphoblastic leukaemia (ALL) and adult diffuse large B-cell lymphoma (DLBCL).

There are no approved CAR-T treatments worldwide for solid cancers. However, research is underway at Peter Mac in CAR-T cell treatment of solid cancers.  Please see Clinical Trials.gov for further information.

Page Source https://www.petermac.org/car-t

Terminologies in Immuno 101

APC: Antigen Presenting Cells: The immunes messengers.
B Cells: learn the tumour or virus DNA to recognise if they return.
Biopsy: A tissue sample extracted from your tumor and used by a laboratory to discover Biomarkers.
CTLA-4: A Check Point protein that sits on the surface of the T Cells. They prevent mistake attacks on healthy cells.
Check Point Inhibitor– See PD-1 below
Car T Cells: An new innovating immunotherapy technique
IHC: Immunohistochestry Test for discovering PD-L1 and MSi status
Ligand: An elongated strand of protein receptor that anchors to a cells surface. (ie PD-L1 is a Ligand receptor)
Molecular Profiling: Provides a DNA road map of the tumours finger print (Genomic) and your hereditary finger print (Genetic)
Microsatellites: Microsatellites are stretches of DNA that contain a repetitive sequence of nucleotides
Nucleotides: Nucleotides are the repetitive strings of DNA code that make us – us. example of a code  string;  “AAAAA or CGCGCGCG”  (codes are short tandem sequences that replicate)

MSI: is a measure of Microsatellite Instability
MSI-LOW: is a low recorded measure of Microsatellite Instability.
MSI-HIGH: is a high recorded measure of Microsatellite Instability.
MSS: is  Microsatellite Stable, which means no instability is present

MMR: Mismatch Repair is the DNA repair pathway that plays a key role in maintaining our genomic stability. MMR is our “Spell Checker” correcting  any errors  in our DNA replication process as they occur. MMR is made up of 4 proteins (MLH1, MSH2, MSH6, & PMS2 )
dMMR:  Deficient Mismatch Repair means that one or more of the 4 MMR proteins absent and as a result the MMR is not functioning correctly and is described as deficient
TMB: means Tumour Mutation Burden

PD-L1: means Programmed Death Ligand 1 – a cluster protein that generally coats and protects healthy cells from the immune systems T Cells
PD1: is an Immune Check Point Inhibitor – its function is to switch off a T Cell attack. It does by binding and communicating with the PD-L1 anchored to a cells surface.
PD1/ PD-L Pathway: A communication pathway / channel that dampens or deactivates (switches off) an immune response – (T Cell attack) on healthy cells.

Important

Simple explanations and Video

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