Recently, the top academic journal Science published the latest progress of a clinical trial of cancer immunotherapy online. Three patients with refractory cancer received a new T-cell therapy combined with gene editing technology. It is noteworthy that this is the first time in the United States to test cell therapy modified based on CRISPR gene editing in cancer patients.
This new T-cell therapy is similar to car-t cells we often hear. It is to fight cancer by transforming the patient's own immune system. Researchers need to collect T cells from patients' blood and insert therapeutic T cell receptor (TCR) through genetic engineering in vitro to identify the typical protein NY-ESO-1 of cancer cells. This cancer antigen provides a target with high specificity and weak toxic and side effects for T cell therapy. Compared with car-t cell therapy, tcr-t cell therapy has fewer life-threatening adverse events such as cytokine release syndrome.
On the basis of T cell therapy, crispr-cas9 gene editing technology further provides a powerful tool to enhance the natural anticancer ability of T cells.
Before inserting TCR, the researchers used CRISPR technology to knock out three genes in T cells. Two of them are TCR genes carried by T cells, which can avoid wrong pairing or competition between natural TCR and genetically engineered inserted receptors, and improve the role of therapeutic TCR. The third gene is the gene encoding PD-1 receptor. Just as immune checkpoint inhibitors that inhibit the function of PD-1 protein can help T cells remove the "brake", gene editing and knockout of PD-1 receptor can also enhance T cell activity and avoid T cell depletion.
In order to test the practical feasibility and safety of this concept, the researchers conducted a phase 1 clinical trial. "This trial mainly focuses on three questions: can we edit T cells in this special way? Do the T cells still function? Can these cells be safely reinfused into the patient?" said Dr. Edward stadtmauer, the lead author of the study and presiding over the clinical trial. "Early data show that the answer to these three questions is yes."
In the published results, T cells edited by these genes did not lead to serious treatment-related adverse reactions, and showed long-lasting survival and expansion ability. Among the three cancer patients involved in the trial, two were refractory advanced myeloma and one was refractory metastatic sarcoma. The standard therapies they had received in the past were ineffective. After receiving T cell reinfusion, engineered T cells with gene editing can still be detected in patients for up to 9 months. Moreover, when researchers isolated genetically edited T cells from patients and brought them back to the laboratory for testing, they found that they still had the ability to kill cancer cells.
"Previous studies have shown that these cells will lose their function within a few days, but now the results show that CRISPR edited cells can maintain anti-cancer function for a long time after a single injection," Professor June said.
The researchers also mentioned that the preliminary clinical results have acceptable safety, but it still needs more patients and longer observation before it can fully evaluate the safety of this new method. In addition, whether the genetically edited engineered T cells are effective for advanced cancer is also an important question to be answered in follow-up research.
The researchers said that the new data will open the door for later research and continue to study whether this new method can be extended to a wider range in cancer treatment. It is expected that gene editing technology can benefit more cancer patients in the near future.
