Attacking the tumor from within the body: this is the therapy that aims to revolutionize cancer treatment

BarcelonaStimulating the immune system to distinguish tumor cells from healthy cells and selectively attack them has revolutionized the way some cancers are treated. This revolution began with personalized medicines called CAR-T(from the English Chimeric Antigen Receptor T-cells), a therapy in which the patient is their own donor. In this strategy, the patient's T lymphocytes (which are natural defenses) are extracted, genetically reprogrammed in the laboratory to kill cancer cells, and then reintroduced into the bloodstream so that they can attack the tumor. Now, scientists at the University of California are proposing a reprogramming method that avoids having to manufacture the cells outside the human body and has allowed for the successful treatment of aggressive leukemia, multiple myeloma, and even a solid tumor, so far in mice transplanted with human cells.

CAR-T therapies have shown great success in some blood cancers and myelomas, but their implementation is complex, requires weeks to prepare—the cancer can progress during this time—and is very expensive, costing around €300,000 per patient, depending on the healthcare center or pharmacy. All of this makes them inaccessible to all hospitals or impossible for all healthcare systems to cover their cost. This is where the work of the San Francisco researchers comes in; they are the first in the world to have successfully integrated a large DNA sequence into a specific location on human T lymphocytes without having to extract them from the body and process them in the laboratory, as they described in an article published this Wednesday in the journal NatureDNA, a giant instruction manual, dictates what each cell does and how it behaves. Until now, when the scientific community wanted to alter cellular function, it used viruses as "messengers," a process known as the standard method of random integration of DNA with viruses. But this approach struggled to introduce the modification at the precise point of alteration. This American team—in collaboration with scientists from the Gladstone Institutes, Duke University, and the Innovation Genomics Institute—has taken a further step and managed to insert the change exactly where it needs to be. And more importantly, they didn't need to remove cells from the body and manipulate them in the laboratory; all the changes were made within the organism. Specifically, the team designed a two-particle system—created to avoid immediate destruction by the immune system—to directly transport the CRISPR-Cas9 gene-editing machinery (the molecular scissors needed to alter the genes of the lesions). against CD3, a protein found exclusively on the surface of T cells, ensuring that the editing affects only the intended targets. The second particle carries new DNA encoding the anticancer CAR, along with instructions for inserting it into a specific location in the T cell's genome. This space contains a kind of molecular switch that is only activated in T cells, and only when the gene is lodged in this exact spot.

"Democratizing access"

"I believe this is just the beginning of a great wave of new therapies that will be truly transformative and save many lives," explains Justin Eyquem, associate professor of medicine at UCSF and lead author of the article. "I'm incredibly excited to be a part of it," he adds. The researcher emphasizes that this finding opens the door to potentially allowing not only large cancer centers "to offer these life-saving therapies" and "democratizing access to them."

The method described in Nature It was tested on mice implanted with an aggressive human cell leukemia, and with a single injection, it eliminated all detectable cancer in almost all the animals within two weeks. In fact, this second wave of CAR-T therapy made up as much as 40% of the immune cells in some organs and successfully eliminated multiple myeloma cancer. Surprisingly, the new method was also successful with a solid sarcomatous tumor. Solid tumors account for 85% of cancers, and cell therapy is not adept at recognizing and attacking tumor cells, as they are more diverse, partly because it is difficult to identify specific targets and, therefore, to clearly differentiate between the cells that cause the tumor and those of healthy tissue. According to the American researchers, unexpectedly, these genetically modified T cells within the body also outperformed those manufactured in the laboratory. "We believe that when cells are removed from the body and grown in the laboratory, they lose some of their mother capacity "And they don't proliferate as easily, and that doesn't happen here," says Eyquem. The technology, however, still needs to be updated and scaled up for human use, and clinical trials will be necessary to assess its safety and efficacy. "Inside the body, we can't perform this post-manufacturing quality control, so we really needed to optimize the approach from the outset to avoid disturbing other cells," says Eyquem. He and his collaborators have founded a company called Azalea Therapeutics to advance the platform. Now, if these new CAR-T cells are successful, they could dramatically reduce costs and eliminate patient wait times. in vivo T-cell therapy could eliminate the need to subject patients to heavy preparatory chemotherapy, a process that is particularly punishing for elderly or frail patients who cannot tolerate it well.