Scientists believe Crispr Cas-9 gene editing could offer the key to improving ground-breaking immunotherapy cancer drugs. Photo / 123rf
Scientists believe Crispr Cas-9 gene editing could offer the key to improving ground-breaking immunotherapy cancer drugs. Photo / 123rf
It’s one of the biggest breakthroughs of our lifetime: clever drugs trained to harness the power of our own immune system and unleash it against cancer cells as they attack us.
But, while immunotherapies like the well-known Keytruda are revolutionising cancer treatment, they’re stillonly effective in about a third of patients - and scientists don’t yet know why.
“When immunotherapies are successful, they’re super-successful - but there’s still a massive 70 per cent of patients who don’t respond to therapy,” said Dr Hilary Sheppard of the University of Auckland’s School of Biological Sciences.
To help solve that mystery, her team plan to turn to another of our generation’s biggest game-changers - Crispr Cas-9 gene editing - to deeper explore an immune cell pathway that most immunotherapies target.
Their new study, just awarded a $940,000 grant from the Marsden Fund, could ultimately help improve the effectiveness of these drugs - with implications that reach well beyond cancer treatment.
“What we’re interested in is this particular pathway, called the PD-1 pathway, that’s activated in any situation of chronic immune stimulation - whether that’s cancer, chronic infection, or autoimmunity,” Sheppard explained.
“If you’re healthy, your immune system can kill rogue cancer cells.
“But cancer cells can also fight back using a suppressive mechanism that we can think of as a lock and key system - that is, locks on the cancer cell, called ligands, that engage with keys on the immune cells, called receptors.”
When the lock and key are engaged, it effectively dampens down the immune system - and the roving hunter-killer T-cells within it - as it tries to stamp out cancer cells spreading in our bodies.
Within the PD-1 pathway, cancer patients have been found to have varying levels of a key molecule - and just how these different levels affect treatment outcomes, or establish lasting immunity, remains a mystery.
“While you’d think that patients whose PD-1 pathways are very active would respond very well to immunotherapy drugs, that isn’t always the case,” Sheppard said.
“Then, in other patients where that pathway doesn’t seem to be as active, the immunotherapy drugs can work - so there’s a lot we don’t understand about it.”
This is where Sheppard and her team planned to employ Crispr Cas-9 – a system that can be used like molecular scissors to splice and snip genes, or insert new ones - on in-vitro samples in the lab.
Keytruda is New Zealand's best-known cancer immunotherapy drug.
“Using the standard techniques that we employ to understand gene expression, we either knock out a gene completely, or we over-express it at wildly high levels, way beyond physiological levels,” she said.
In this case, the team didn’t want to edit out the troublesome pathway completely, as this could cause adverse effects like auto-immunity.
“Rather, what we’re trying to do is fine-tune the system to find that sweet spot that’s going to allow for the specifically targeted killing of the cancer without having any adverse effects.”
As far as Sheppard was aware, this sort of editing had never been performed on endogenous genes before - nor in human T-cells.
But more exciting was the study’s potential to unlock major new insights into a vast range of diseases and disorders involving our immune system - all of which could advance new clinical treatments.
“Understanding this pathway has implications for multiple immune conditions.”
Jamie Morton is a specialist in science and environmental reporting. He joined the Herald in 2011 and writes about everything from conservation and climate change to natural hazards and new technology.
