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Aged just 5, Emily was diagnosed with acute lymphoblastic leukaemia (ALL) this form of blood cancer has around a 90% cure rate. However, 16 months of chemotherapy and Emily had relapsed an extremely resistant disease and was given several weeks/months to live.  Emily was placed in a pioneering programme using genetically reprogrammed T cells, to seek and destroy the disease. Amazingly, three yrs later and EMily remains in remission.

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Immune signatures: What are they and why are they important? 

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Immune signatures: What are they and why are they important? 

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I know this sounds like a really weird concept, but it is 100% legit. Immune signatures are found in tumors and relate to the number of immune cells found within that tumour. The technique Immunohistochemistry allows us to visualise these signatures and quantify as well as locate the immune cells within the tumor.
What can they tell us?

1. These signatures allow very accurate estimates to be mad eon how quickly a tutor will progress.

2. The number and location of significant immune cells, allow clinicians to properly determine the right therapy for the right patient.

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A dangerous game of 'Spot the difference' 

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A dangerous game of 'Spot the difference' 

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All of the immunotherapies work by activating the immune system. But how can out immune system recognise cancer cells when they look extremely similar to normal cells?

Well, cancerous cells all share one thing in common. They all involve a mutation within their DNA sequence, this mutation is translated into the proteins they make. These mutated protein fragments are then expressed on the cell surface on MHC molecules, which are recognised by T cells as 'foreign' and the whole cell is destroyed.

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How cancer cells 'push' all the wrong buttons!

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How cancer cells 'push' all the wrong buttons!

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Our immune system is a ridiculously powerful weapon against invading pathogens. However, all this power can be dangerous if not controlled. In order to ensure this moderation can be enforced, immune cells have stop switches expressed on their cell surface. Once ‘pushed’ the button triggers the immune cell to abort its ‘search and destroy’ mission. Cancer cells have learnt how to avoid our immune systems by ‘pushing’ these buttons.

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Week 2: Immunotherapy and cervical cancer

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Week 2: Immunotherapy and cervical cancer

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The HPV vaccine Gardasil minimises cervical cancer rates as out of the 4 strains vaccinated agaist two of them cause the most cases of cervical cancer. All together this vaccine offers 70% protection against cervical cancer.

However, this HPV vaccine has been upgraded to Gardasil9 that offers a whopping 90% protection against cervical cancer. As the name suggests this vaccine includes protection against 9 strains of HPV 7 are considered as cancer-inducing strains.

Cervical cancer remains the 4th most common cancers in woman across the world.

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 New blood cell cancer treatments (Adoptive T cell transfer) 

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 New blood cell cancer treatments (Adoptive T cell transfer) 

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Focuses on engineering immune cells to target a specific type of blood cancer.
One study using this engineering technique, found 94% of participants with acute lymphoblastic leukaemia have their symptoms vanish completely.
The process is outlined in the picture below, whereby, immune cells are removed form the patient, hardwired to target specific cancers and placed back into the patient.

Is this a revolution?
Yes! But not entirely ready...
T cells are a new type of drug, they are alive and can persist within the body for the rest of our live. In other words they are a life long living therapy that exists entirely in vivo.
They have promising remission rates, and have a life long memory of how to eliminate specific cancers!

BUT:
It is new and exciting, but it has to be applicable to other tumours also before it is hailed as a revolution.
Additionally, it remains unknown whether the patient that have gone into remission after this treatment will remain to be in remission. Only time will tell this.
Therapy such as this, remains as a last resort because our immune system is a very powerful biological weapon. Reprogramming it carries some very dangerous side effects such as SCRS (cytokine release syndrome), this overloads the defence cells.

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I found the application of Darwins theory of evolution by natural selection, super fascinating!
Cancer cells proliferate continuously, some where in this proliferation modification of the cells genes occur. Those most adapted at suppressing and evading our bodies immune system get to live and tell the tale (rather further replicate) thereby, passing on their code of survival to further generations Those poorly adapted will be engulfed/ destroyed by our immune cells.
Thus those that survive will eventually dominate the population.

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Infected cells: An infected cell looks very different to a normal cell. This could be because the cells in expressing stress signals, or an MHC displaying a viral fragment or and antibody has attached itself onto the cell.
Cancer cells: These cells on the other hand have very subtle changes. It is only upon very close inspection that they are recognised by immune cells and destroyed.

How do cancer cells stay so well hidden? Through a whole load of trickery.

1. Cancer cells release cytokines (direct messages) to immune cells that basically tell them to 'IGNORE ME'.

2. T cells hevily rely on cells displaying MHC molecules attached with bit of protein to recognise cancerous or infected cells. Cancer/tumour cells remove their MHCs on their cellular surface, meaning the immune cells cannot bind and therefore they evade close inspection

3. Sounds extremely strange I know but T cells have an emergency off switch on their cell surface. Our bodies insurance policy whether they need to deactivate a T cell gone haywire. Cancer cells have learned how to 'push' that button thereby halting the activation of a T cell lead immune response. Annoying... and sneaky!

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6 lines of evidence why our immune systems are awesome at recognising cancer:

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6 lines of evidence why our immune systems are awesome at recognising cancer:

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1. Immune decifiency conditions increase the risk of developing cancer
Case study of bubble boy who died of a bone cancer.
AIDS weakens the immune system and increases the risk of cancer

2. T cells in stem cell transplants are able to remove any remaining tumour cells in the body.
Stem cell transplants for blood cancers involve replacing faulty blood stem cells with healthy ones. Meaning the T cells produced from th healthy blood stem cells are able to eliminate any remaining cancer cells. Curing the patient (Graft vs Leukaemia effect)

3. Immune system activation by infection can lead to the regression of cancer:
Early clinicians injected patient with a bacterium in order to increase the immune response, this increase was thought to aidt he body in fighting cancer also
Nowadays, it is the BCG vaccine that is used for bladder cancer treatment. Still unsure of the mechanism through which this works.

4. Increased number of immune cells in tutors can improve patient survival.
We know that immune cells are able to leave the bloodstream and into surrounding tissue. The number of immune cells seen in a tumour is referred to as its 'immune signature' and it offers insght on how the tumour will progress.

5. Cancer cells can be recognised by immune cells in the laboratory

6. New immunotherapies are yielding clinical responses.

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The abscopal effect- the one for all approach

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The abscopal effect- the one for all approach

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Within week 2 of the course we were showed two knock on effects (the graft Vs tumour effect and the abscopal effect), however, I found the abscopal effect really interesting.
This is a phenomena that can occur during the treatment of metastatic cancer. This includes treating a cancer locally causing not only the shrinking of that tutor but also the tutors found in other bodily 'compartments'.
Common forms of localised treatments include:

Localised radiation therapy

Electroporation

Intr-tumoral injection of therapeutics

This phenomena is rare but can lead to the malignant growth throughout the body. It is not entirely known how this works but it is thought to be linked to the activation of the immune system.

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Proving our bodies ability to detect and respond to cancer: 

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Proving our bodies ability to detect and respond to cancer: 

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Transplantation and Immunosuppression:
Transplantation has significant risks to the patient of developing several cancers caused by infectious diseases.
Immunosuppressive drugs are given to patients after transplantation, to try and avoid rejection- however, it hinders the ability of the immune system to detect and destroy cancer cells as well as fighting off infections that could lead to cancer.

4 most common cancers:

Non-Hodgkin lymphoma: can be caused by Epstein-Barr virus

Liver Cancer: Chronic infection with Hep B and Hep C

Lung and Kidney cancer: Not caused by infections

Effect of HIV/AIDS
Increased risk of cancer caused by the human papillomavirus that causes cervical, anal and oropharyngeal.

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Rates of cancer are increasing despite the rise of cancer treatments. But why?
Firstly cancer hasn't just popped up in the 21st Century. Their lack of mention in old texts isn't due to an absence of cancer. But more people were busy dying of other infectious diseases.
Cancer risk rate increases with age ( I know it sucks but there you go!) Back in the Victorian era you would be lucky to live the grand age of 40. 40 years of age happens to be the peak time for getting cancer

In conclusion, rates of cancer have increased due to:

1. Increase in our life expectancy

2. Advances in health care

3. Control of infectious diseases

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Positive selection: T cells with the ability to bind to self MHC molecules expressed by epithelial cells within the thymus are retained. Those that fail to bind to these die.
Negative selection: T cells that are able to bind with a high affinity (very willing) to self MHC molecules attached to self molecules on the surface of dendritic cells and macrophages are exterminated.

As a result... T cells that have a T cell receptor that recognises self MHC attached to antigen molecules are the only survivors of this education process.

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Autoimmune disease case study: Bubble Boy

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Autoimmune disease case study: Bubble Boy

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His story:

David Vetter was born with an X linked chromosomes immunodeficiency disease known as SCID.
People with this condition are born with no immune system. In the year 1970, medicine was an extremelly promising field with the invention of the iron lung, artificial heart and the 1st successful heart transplant! Suddenly medicine was looking for the next big challenge, their eyes were on SCID.
David Vetter was to be the boy to survive the disease, or so they believed. When he was born he was kept in a man made bubble providing David with the sterile germ free conditions essential for his continued existence.
The principle was simple, keep the germs out, until he was old enough to get a bone marrow transplant from his sister.
However, the time came for the bone marrow transplant which they thought would be a perfect match due to them being siblings. It wasn't.
David was now reliant on the research team to find him a donor match, or to be able to perform a bone marrow transplant that did not match.
Years passed by and the ethical debate on whether Davids isolated existence was 'right' grew by the day.
Finally, they felt confident to perform the procedure to perform the incompatible bone marrow transplant on David.
After the transplant, David soon developed a temperature, suffered from organ hemorrhaging and his condition gradually began deteioriating day by day until he died in 1984.
It was later found that, Davids sisters bone marrow had a dormant disease lurking within it, and once this was transplanted into David it became active and with no immune system to stop it. David stood no chance.

What the world learned from David Vetter?

1. Hematologists were learning about the property of germ free blood

2. Immunologists were learning how SCIP suppressed the immune system

3. As well as that, this was the first link of a virus leading to the cancer

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Types of lymphocytes and their functions: 

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Types of lymphocytes and their functions: 

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Macrophages: found in the lungs, liver and the gut. When infected,  macrophages can engulf the pathogen and use toxic granules to destroy it.
Neutrophil:

Filled with toxic granules.

Found mostly in the blood

Recruited to the site of infection quickly, where they release their toxic granules to kill the bacteria.

Natural Killer Cells:

These cells respond quickly

NK cells receptors are expressed (displayed) on the cell surface.

When cells become stressed (e.g. when cells are infected with a virus) they express certain molecules on their cell surface -otherwise known as stress signals.

This triggers an alert system- where the cells are saying "help me!". NK receptors can recognise these stress signals and kill the entire cell.

Dendritic cell:

These are important for communication between white blood cells.

They are able to recognise pathogens.

These cells are able to take in foreign particles/pathogens, digest them into smaller pieces. These smaller pieces stick to MHC molecules, once bound these MHC molecules then display it on their cell surface.

Once this happens, these cells then migrate to the lymph nodes to activate immune cells that are able to recognise the invading pathogen.

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Monocyte: largest white blood cell with a huge nucleus.
Lymphocyte: Much smaller with a round nucleus.
Neutrophil: Segmented nucleus and contains toxic granules.

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When the immune system is introduced to a new antigen for the first time, the immune system takes a long time to build up the concentration of antibodies (the primary immune response). This could be due to the time taken for the immune cell with the specific receptor to come into contact with the antigen itself and therefore become activated.

However, once exposed to the same antigen a SECOND time, the response time is faster and the concentration of antibodies generated is far greater. This is because of immunological memory - whereby memory T/B cells remember that specific antigen and can mount an immunological response a lot faster and with a greater force.

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The innate immune system:
Includes our chemical and physical defences (stomach acid, saliva and skin)
Inflammation.
Natural killer cells.

The adaptive immune system:
This includes our lymphocytes- Killer T cells, Helper T cells, B lymphocytes and antibodies.
Immunological memory

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Pathogen: a bacterium, virus, or other microorganism that can cause disease.
Hematopoietic stem cell: these are cells that have the ability of multi potency (the ability to differentiate into any blood cell) and self-renewal (ability to give rise to other stem cells of its own kind).
Autoimmune disorder: When our immune system attacks and destroys healthy body tissue by mistake.
Metastatic cancer: This is where the cancer has spread one the place where it started to another area of the body.

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The average healthy human has 500 billion white blood cells in the body.

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Week 1: You Immune system (what is it? What can it do? Can we harness it?)
Week 2: Immune recognition (The challenge and the evidence)
Week 3: New immunotherapies (The changing face of cancer treatment)