An early-stage clinical trial of CRISPR-editing in cancer patients has proven to be safe, with the study participants experiencing no negative side effects.
The phase 1 clinical trial, the results of which were published in Science, also reported that the CRISPR-Cas9-edited T cells remained in patients’ bodies for months.
Subsequent lab tests of the gene-edited T cells taken from the study participants months after they received the treatment confirmed that these cells could still kill cancer.
The trial, which is the first sanctioned study to evaluate the clinical application of multiple CRISPR edits to the human genome, was undertaken by investigators at the Abramson Cancer Center of the University of Pennsylvania, led by Carl June.
June is well-known for his work developing one of the first CAR-T therapies, Novartis’ Kymriah, which he co-invented.
CAR-T therapies extract a patient’s own white blood cells, and modify them to attack malignant cells. The T cells used in these therapies are changed in the lab to identify specific cancer cells by adding a man-made receptor, known as a chimeric antigen receptor (CAR).
One significant side effect of CAR-T therapy treatment is cytokine release syndrome – as CAR T cells multiply, they cause huge amounts of chemicals called cytokines to be released into the bloodstream. This leads to a host of symptoms and while mostly causes only mild cases, it can be fatal.
The researchers of the new study took a different route with their method of gene-editing. Instead of adding a new receptor onto the T cell, they deleted three genes, two of which were for the pre-existing T cell receptor and the third for PD-1.
The PD-1 protein is most well known for a new class of inhibitors which target it, such as Merck & Co’s Keytruda (pembrolizumab). It regulates the immune system’s response to human cells by promoting self tolerance, which suppresses T cell inflammatory activity.
This in turn helps to prevent autoimmune disease, while also preventing the immune system from killing cancer cells. By deleting the PD-1 gene, researchers believe the immune cells will go on to target cancer cells, killing them when originally they wouldn't.
The researchers then added a normal T cell receptor to the modified cells, to help avoid the toxicity side-effects, such as cytokine release syndrome, which are associated with CAR-T therapies.
While the study did not show efficacy, it did avoid those side effects, as well as demonstrating the persistence of the edited immune cells which remained in the patients’ blood nine months after the initial treatment.
Commenting on the results, June said that data from the patients “demonstrate two important things that, to our knowledge, no one has ever shown before.
“First, we can successfully perform multiple edits with precision during manufacturing, with the resulting cells surviving longer in the human body than any previously published data have shown. Second, thus far, these cells have shown a sustained ability to attack and kill tumours.”
In November last year, Vertex and CRISPR Therapeutics revealed initial positive data from the first two patients treated with their investigational CRISPR/Cas9 gene-editing therapy CTX001.
Unlike the Pennsylvania study, Vertex said that its CRISPR therapy was both safe and effective, with the two patients potentially having been cured of their diseases. Both have severe haemoglobinopathies – including transfusion-dependant beta thalassaemia (TDT) and severe sickle cell disease (SCD).