DD4

Describe the checkpoint inhibitor strategy?

Point to reconnect the dots between cells and re-engage the immune system so it can correct the cancer

What can be the problem with the checkpoint inhibitor strategy?

The immune system has often already delivered it’s self to the target, immune cells can become exhausted, making difficult to ramp up

Immune system can become over engaged and become inflammatory

What do checkpoint inhibitor targets need to do?

There is priming event in which the cells will traffic to the location

Can the immune cells trafficked there be overcome the inhibitory cytokines produced by the cancer

Can the immune system then engage to induce the killing of the cell

Try to ensure treatment is scaled up to not overwhelm the patients

Define cytokine storm?

immune system gets so engaged that everything in the body becomes a target

Very difficult to stop → whole immune system is engaged

What must be done to engage the immune system?

Be able to turn it off

What mutations are common?

Germline is rare, somatic mutations are common

What two theories of how stem cells become problematic?

Stems end up being part of the original tumour

Primary tumour with a stem cell in it

Describe reversing oncogenesis?

In cancer the cells lose differentiation and do not redifferentiate

This is an idea to force the cells back into differentiated to their original function

Could use growth factors to help reorganise

What is the possible issue with oncogenesis?

Risk of growth factors losing capacity and adding to the cancer

Describe where opportunities with RNA editing?

• To change not kill the cells

• Would need to ensure every cell is changed

• Could induce a gain of function

  • Optimise things for the RNA to work

What are the challenges with RNA therapies?

• High bar of success have to hit all the cells for it to work

  • Complexity of how RNA work normally

Why do most drugs end up in the liver?

As the majority of things are cleared to the liver

Why can RNA therapies be dangerous?

Can last for months

Therefore any ADR will last a long time

Why do RNA therapies cause problems for the immune system?

• Virus do similar things to this therapy so bad will try and fight off the therapy

• Can’t test in advance to see if any of these delivery systems work

How is the cell surface a problem?

Positive charged materials interact with this negatively-charged surface BEFORE they can even reach the lipid bilayer

What are membrane active peptides usually based on?

toxins, venoms, viral and bacterial pathogens, etc.

How can CRISPR-Cas9 be used in therapies?

Modifying cells and then put them back in body to force function

What is the best place to engage the immune system?

• Intradermal vaccinations

• Natural draining system from here to the immune system

Where does immune system collect information?

dendritic cells look for antigen presenting cells,

Dendritic cells have life expectancy -. so when altered and put back in the body does not change immune system forever

What happens to cells when they become metastatic?

Change profile on surface and become hypermutable ang get variations

Why is difficult to produce a vaccine against cancer?

Unethical to find patient population who you think will have cancer and vaccinate

• Vaccine and other treatments can be in conflict → cannot administer together