Can CRISPR treat cancer?

11 February 2020

Interview with 

Joseph Fraietta, University of Pennsylvania

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Gene Editing CRISPR

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In a world first in humans, scientists in the US have used the gene editing tool CRISPR to treat patients with cancer. In a proof-of-concept study, the team began by harvesting immune “T” cells from 3 patients with advanced tumours. They then edited the T cells’ genes to re-programme the receptor that the T cells use to recognise hostile targets so that they would then regard the patient’s cancer cells as foreign and destroy them. A gene that normally puts the brakes on cell growth was also disabled, so the T cells should be able to grow and expand their numbers in the body, to keep the cancer under control in the long term. The modified cells were then injected back into the patients, and Katie Haylor heard what happened from Joseph Fraietta...

Joseph - We use the molecular scissors to delete the genes that code for the natural T-cell receptor, so that we can insert the tumour specific T-cell receptor, and thus endow these T-cells with the ability to seek out and destroy the tumour so to speak.

Katie - So it's almost like the guards on the outside of the fortress, they can see the enemy and maybe sound the alarm?

Joseph - Absolutely, yes. And expand and mobilise and kill the tumour as well.

Katie - What exactly is a receptor?

Joseph - A receptor is a molecule on the surface of a T-cell that can recognise tumour specific components, in this case, protein fragments. And so that's how a T-cell knows it's a tumour, and it's triggered to attack and as you said, sound the alarm and expand into this massive army. In this paper, those were two edits that we did to the genome and then we did a third, and there's a specific molecule that T-cells overexpress and it's called PD-1: Programmed death ligand one. And this is overexpressed on T-cells in the context of cancer. And what it does is it sort of puts the brakes on the T-cell response. It prevents that expansion of the army to really take care of this tumour and it also shuts down all of those weapons that the T cell has to really fight the tumor. So the third edit that we did was to delete the gene that codes for this PD-1 protein to take the brakes off of that response.

Katie - What was the result then when you transfuse these T-cells back into these people who had cancer?

Joseph - Remarkably these CRISPR edited, reprogrammed T-cells expanded, and they also persisted and that's very key. We really need them to persist, to do battle with the tumour, and also to sort of hang around should the enemy return.

Katie - From what I understand about cancer actually, uncontrolled proliferation is a bit of a hallmark. Is there any worry about having runaway T-cells?

Joseph - That is a very valid point and that has been documented actually, when other therapies were used to target this specific molecule in the context of cancer. So to prevent that, we carefully monitor the patients during the trial and we're going to continue to monitor the patients very carefully during longterm followup, for any signs of these runaway T-cells, as you put it.

Katie - Where do you go from here?

Joseph - I believe that designing new cellular therapies, using better technologies is the most likely path forward. Given the high costs of these clinical trials and the organisational and logistic challenges, we really owe it to the patients to use the best technologies that are available at the current time, and so CRISPR based gene editing and genome editing, it's just moving forward at such an incredibly fast pace. So I think the next frontier is to use some of the new CRISPR based editing approaches to really improve these so-called designer T-cells, that are the patient's own T-cells that we use to treat their cancer. We hope that this study will help really forge a path for developing “best in class” engineered T cells to treat cancer and hopefully a variety of other diseases.

 

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