One goal of cancer research is to mobilize the patient's own immune system against the tumor. For a clinical phase 1 study, researchers have now for the first time genetically modified immune cells from cancer patients using the Crispr/Cas9 gene scissors in such a way that they recognize the individual mutations of the tumor cells in the patient's body. Injections of these adapted T cells produced few side effects in the patients. The researchers were also able to demonstrate that the new immune cells accumulate in the tumor as hoped. How effective this therapy is in fighting cancer must now be shown in follow-up studies.
As part of our immune system, T cells are able to detect and destroy foreign bodies and diseased body cells. In principle, they can also recognize and attack cancer cells, since the surface of the degenerated cells changes as a result of the cancer mutations. In most cases, our immune system eliminates these cells shortly after they form, preventing tumors from forming. However, some cancer cells manage to adapt in such a way that they remain under the radar of the immune system. Tumors can therefore grow from these cells unmolested by the immune system. Cancer immunotherapy aims to direct the immune system back to the cancer cells. In clinical practice, drugs have so far been used that counteract the tumor's strategies of distracting the immune system from itself.
Patient's own T cells
A team led by Susan Foy from the company PACT Pharma in San Francisco has now tested a new approach together with university researchers: With the help of the Crispr/Cas9 gene scissors, they modified the patient's own T cells in such a way that they react specifically to proteins on the surface of cancer cells that are specific to the patient's individual tumor. To do this, they first isolated the corresponding immune receptors from the blood of the patients using a method specially developed for this purpose. Using samples from the patient's tumor tissue, they also determined which mutations are characteristic of the respective tumor.
For each of the 16 patients who took part in the study, the researchers created an individual library of cancer-specific immune receptors and selected those that matched the respective mutations. Using the Crispr/Cas9 gene scissors, they inserted precisely the gene sequences into the genome of the patient's own T cells that enable the T cells to bind to the tumor cells. Previously, this was only possible using viruses as gene carriers. "This is a major step forward in the development of personalized cancer treatment," says co-author Antoni Ribas of the University of California at Los Angeles. "Without the newly developed ability to use Crispr technology to replace the immune receptors in cell preparations in a single step, the development of a personalized cell treatment for cancer would not have been possible."
focus on security
After the researchers had successfully modified the T cells, they injected them into the patients – initially in very small doses for safety reasons. They paid particular attention to possible side effects. As expected, all patients showed side effects of the chemotherapy administered as preparation. The novel immunotherapy, on the other hand, only caused side effects in two of 16 patients: one of the test subjects reacted with fever and chills, another with neurological problems. In both cases, however, the side effects completely disappeared.
During the follow-up examination of the patients, the researchers again took samples from the tumor tissue and examined to what extent the genetically modified T cells had reached their destination. And indeed: The newly infused defense cells had apparently migrated to the tumor and were now among the most frequently represented T cells there. According to the researchers, this indicates that the concept is as promising as hoped.
Limited effectiveness so far
However, since the current study was primarily about testing the safety of the therapy and approaching a possible dosage, the clinical effectiveness was not yet the focus. At the beginning of the study, the patients received very low doses, which the researchers said only led to a very limited spread of the modified T cells in the patient's body - which made a detectable effect unlikely. In fact, despite treatment, the tumor continued to grow in 11 of 16 patients. In five patients, however, the researchers found during the examination after one month that the tumor had at least not grown in the meantime.
"Improvements in manufacturing during the course of the study and in cell doses resulted in better in vivo expansion in patients who were last treated and approached levels that may be considered therapeutic in further studies," they write authors. The current results show that the procedure is basically feasible and probably has a favorable safety profile. This paves the way for further studies in which therapeutic doses are used to test whether the genetically modified T cells are actually capable of destroying the tumours. The researchers also want to continue working on increasing the functionality of the T cells.
Source: Susan Foy (PACT Pharma, South San Francisco, CA, USA) et al., Nature, doi: 10.1038/s41586-022-05531-1