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The CRISPR-Cas9 genetic editing tools have given another twist to the immune cells used to treat cancer. The results of a preliminary clinical study, conducted with three patients, show that it is safe to modify the genome of their own T cells at three points and then introduce them. This complex manipulation not only did not end the cells, but they remained in the body of the sick for months. In addition, they did not cause negative side effects . The research, which is published today in 'Science', is a pioneering proof of concept of a new use of CRISPR technology against cancer.

As Carl June, lead author of the study and architect of CAR-T therapies, has explained to this newspaper, "it is likely that most forms of cancer may benefit in the future from T cells edited with CRISPR," although Remember wisely that "many more trials will be needed" to determine the types of tumors in which this strategy may work best.

June, who heads the Cellular Immunotherapies Unit at the Abramson Cancer Center at the University of Pennsylvania, believes that this trial demonstrates two things for the first time: it is possible to successfully perform multiple precision editions to prepare T-cell lymphocytes resulting "survive for longer in the human body than previously published data" -; on the other hand, "the cells have demonstrated a sustained ability to attack and kill tumors ."

The three treated patients were over 60 years old and had advanced cancer . June notes that "the first patient had received eight different lines of chemotherapy and three bone marrow transplants before the T lymphocytes edited with CRISPR. She died due to her cancer last December. The other two patients are still alive and are now receiving other types of chemotherapy. "

The doctor who treated them in this study, Edward A. Stadtmauer, head of Malignant Hematology at the University of Pennsylvania , writes in an email that "all these patients had metastatic refractory cancer. None of them had realistic options with currently approved treatments. by the FDA. This is just a small sample of patients to determine the safety and feasibility of this new approach. It is necessary to treat many more patients to determine efficacy. "

'Intensive training'

What exactly has this triple gene edition of immune cells consisted of? In a very simplified way, once patients' T cells have been removed, scientists have used the genetic editor CRISPR-Cas9 to eliminate three genes that can interfere with the ability of lymphocytes to attack cancer. In a second step, they added through a viral vector a receptor that recognizes a certain protein present in some tumor cells (something similar to what is done by adding the CD19 chimeric antigen receptor in the CAR-T). Specifically, it recognizes the NY-ESO-1 antigen. The cells obtained -which, playing with this acronym soup, the authors have named NYCE- were introduced into the patients, where they could be detected at nine months. In fact, after several months, the researchers drew blood and isolated the NYCE cells and found that they still maintained antitumor activity .

Juan Roberto Rodríguez Madoz, a researcher at the Top Adoptive Cell Therapy Program at the University of Navarra , details that T lymphocyte receptors (TCR) are the molecules that allow these immune cells to recognize viruses or tumors, among other elements that do not they are characteristic of the organism, and thus in the defense against pathogens or tumors. Each T lymphocyte has a specific one. "The University of Pennsylvania group has eliminated with CRISPR the genes that express TCR-alpha and TCR-beta from patients' T cells." They have also eliminated a third gene, the one that encodes PD-1, an immune checkpoint known for its role as a brake on these immune cells. "Then, using a lentiviral vector, they introduced a transgenic TCR that specifically recognizes the NY-ESO-1 antigen."

New trials at the end of the year

In view of the results of this study, June states that " we plan to start trials using CRISPR technology in CAR-T cells later this year ." And he emphasizes: "This treatment is in the most initial stages of evaluation and it will take time before it is widely available in out-of-trial patients ."

In an article that accompanies this study in 'Science', researchers from the University of California, Berkeley, Jennifer Hamilton and Jennifer Doudna - the latter one of the mothers of CRISPR-Cas9 technology - write that "the big question that It remains unanswered in this study is whether the genetically modified and edited T cells are effective against advanced cancer, "while pointing out that the work has used the editing protocols available in 2016 , bringing the genetic editing obtained in those cells It is probably less effective than could be achieved now.

Antonio Pérez, a hematologist at La Paz Hospital and a member of the Spanish Society of Hematology and Hemotherapy (SEHH) , comments that this study opens the door to using modified cells in solid tumors. "NY-ESO-1 has been identified in certain testicular cancers, but it is expressed in very different ones, such as childhood neuroblastoma, sarcoma and ovarian cancer, among others."

The limitation of this strategy is that NYCE cells require the cooperation of an immune molecule that only appears in a subset of patients. "In some ways, this case shows us that the strategy with CAR is not brown for everyone and needs imaginative interventions that allow generating very individualized treatments, which is what will end childhood cancer, and in general." Without detracting from the progress proposed by this work, which the specialist describes as "exciting", he also recognizes that "we must be attentive to the possible off-tumor effects of the treatment, since NY-ESO-1 is also expressed in healthy tissue" .

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