A Trojan horse against cancer

Concealing an attack force inside an apparently innocuous object, such as the Trojan Horse, so that the enemy allows it to be introduced into the target site, is an ingenious military strategy and can also be used in the fight against cancer. .

An ambitious project, led by a team that includes researchers from the Higher Council for Scientific Research (CSIC) in Spain, aims to develop biological capsules that house CAR-T cells (immune cells specifically designed to attack molecules expressed in certain subtypes of tumors). ) with which to treat solid tumors more effectively and specifically. Like a microscopic Trojan horse, these tiny capsules or pills will hide anti-tumor cells inside and thus be able to invade the cancerous area bypassing the protective barriers and kill off the malignant cells from within the tumor.

The Salamanca Cancer Research Center (CIC, a mixed research institute of the CSIC and the University of Salamanca), the Cancer Network Biomedical Research Center (CIBERONC), the University of Santiago de Compostela participate in the project. (USC) and the Center for Advanced Medical Research (CIMA) of Pamplona, ​​all of these entities in Spain.

CAR-T cell therapy is already commonly used in cancer treatments, but its effectiveness with solid tumors is very low. To improve it, the biocapsules that this scientific team will develop will favor the implantation and localized dissemination of CAR-T cells in this type of tumor (or in the region operated on after surgical removal of the tumor). In addition, they will make it possible to include within them different cocktails of molecules that facilitate the activity of these cells in the long term, as well as the modification of the tumor microenvironment so that it is receptive to their antitumor action.

“With this methodology we want to use the Trojan horse tactic: introducing CAR-T cells hidden in a protective capsule into the tumor so that, once released, they cause the destruction of the tumor cells that surround them in the most effective way possible” , explains the CSIC researcher Xosé Bustelo, one of the main researchers of the project. “To do this, he adds, the biocapsules will include cocktails of biological molecules aimed at facilitating the action of the CAR-T cells released inside the tumor. Using a war simile, it is like being able to bomb an entire war zone after having inactivated the anti-aircraft defenses of the tumor”.

The key to the project, technically called “Encapsulation of CART cells in bioactive nanostructured porous systems for their targeted delivery in solid tumors”, is to design the Trojan horses that allow the soldiers inside them to be kept in top shape until the battle and provide them with weapons that allow these soldiers, once they get off the horse, to be as lethal as possible against tumor cells, in the words of José Rivas Rey, coordinator of the project and professor in the Department of Applied Physics at the University of Santiago de Compostela.

CAR-T cells (red and green) surrounding cancer cells (blue). (Image: NIH)

“As a working model, we will use various subtypes of breast cancer, which will be treated with genetically modified CAR-T cells so that they recognize molecules that are specifically expressed in each of these subtypes,” says Sandra Hervás (CIMA), third Principal Investigator of the project.

“In any case, what is important is that the methods optimized in this project will be used, with slight modifications, for other types of solid tumors, regardless of whether they originate in the breast or in other organs,” he adds.

Other applications of these capsules is that they can incorporate magnetic materials that, after external stimulation by patients with appropriate equipment, will allow tumor cells to be destroyed through the generation of high temperatures inside the tumor. The project also contemplates the study of the potential interest of the simultaneous use of this with chemotherapy or targeted therapies.

After its optimization at an experimental level using cell and animal models, this new version of the immunotherapy will be tested in clinical trials, a task that will be carried out by the Galician public health services company GALARIA. “With this approach, we want to close the entire cycle in the project that goes from innovation in the laboratory to the practical implementation of these therapies at the clinical level,” says one of the company’s managers, Alicia Piñeiro.

One of the most successful immunotherapy methods to date is the use of genetically modified T lymphocytes (scientifically known as CAR-T cells), which can recognize molecules specifically expressed in tumor cells and, subsequently, promote their destruction. This type of treatment is already in routine use for patients with tumors derived from blood cells.

Despite this success, these therapies are still far from optimal today due to several problems: the difficulty of developing effective CAR-T cells against solid tumors, the most frequent in cancer patients; the fact that many tumors develop a microenvironment that is hostile to said cells and that promotes their short-term inactivation; a decrease in their long-term efficacy due to the spread of injected CAR-T cells throughout the body of patients and, finally, that some of these therapies may have unwanted side effects because the molecules that are specifically recognized by CAR-T cells are present in some cases in normal cells of our body. (Source: CIC / CSIC)