The results of a clinical trial that tested the safety of the CRISPR gene editing tool for editing T cells to treat cancer have been released and the results are promising. This was the first clinical trial to evaluate multiple edits to the human genome using CRISPR. The clinical trial saw this new technique used on three patients with refractory cancer. One of the patients had sarcoma, the other two patients had multiple myeloma.
In a paper recently published in Science, immunotherapy physician Carl June, MD reports that patients who received the treatment had no side effects and the CRISPR engineered T cells survived in the patients for months. Several months after introducing the engineered T cells, samples were taken and some of the engineered T cells were recovered and were found to still be active and capable of detecting and killing cancer cells.
The trial combined CRISPR-Cas9 with a new immune system therapy that has been developed to target cancer: T cell therapy. T cells in the immune system track down and kill foreign material, which could be cells that have come from a different person via a transplant or cells that have been infected with viruses or bacteria.
T cells can attack cancer cells, but they typically do not. T cell therapy involves harvesting T cells from patients, engineering them in the lab to attack cancer cells, and then re-introducing them into patients. For the clinical trial, CRISPR was used to alter the T cells before they were re-introduced to improve the efficiency at which the T cells attack cancer cells
CRISPR was used to make edits to three genes. The first stage involved targeting a gene that codes for a protein called PD1 that reduces the ability of the immune system to attack cancerous cells. Studies in mice showed that using antibodies to block the protein produced by the gene improved the ability of the immune system to attack cancer cells. CRISPR was used to delete part of the gene that coded for the protein.
Normal T cells recognize foreign material via a T cell receptor (TCR), which consists of two related proteins that bind together to form a receptor complex. By editing the protein of the TCR, T-cells can be reprogrammed to kill cancer cells. While these engineered TCRs will allow the cells to attack cancer cells, TCR genes are also active and the result is T cells with hybrid TCRs, which reduces their ability to attack cancer cells.
The researchers used CRISPR to knock out the two TCR genes to remove the T-cells’ natural receptors so that the T cells would only express the synthetic TCR. Once the genes were knocked out, a lentivirus was used to insert the synthetic TCR which instructs the T cells to target an antigen called NY-ESO-1 and attack cancer cells. The modified T cells were then reintroduced into patients.
The rates of successful editing varied for each gene, ranging from around 15% to 50%. The reintroduced T cells therefore contained some of the intact genes. There were also some off-target effects from the CRISPR edits, so some refinement is required, but the off-target effects were considered to pose an acceptable risk in patients with refractory cancer at an advanced stage of disease progression.
One of the patients has since died from cancer and the two other patients have deteriorated, but the clinical trial was a success as it showed that the combination of CRISPR and T cell therapy is both feasible and safe. The engineered T cells also survived for longer in patients than any previously published study.
You can read more about the study in the paper – CRISPR-engineered T cells in patients with refractory cancer – which was recently published in the journal Science. DOI: 10.1126/science.aba7365