Beyond CAR-T: towards a new cell therapy against leukemia, thanks to an Italian research
by Simone Valesini
Discovery of “corrupted” cells of the immune system that help tumors
From today we know a new mechanism by which a tumor can inhibit the immune system, causing some cells to switch sides, thus facilitating the spread of the disease. In fact, a new name is added to the list of “corrupt cops” already known: that of some neutrophil white blood cells, capable of making even CAR-T therapies inactive. It is the result of a series of studies (the latest published in the Journal of Hematology and Oncology) conducted by the Bambino Gesù pediatric hospital on infantile neuroblastoma, the most common solid tumor of early childhood, but the mechanism has also been identified in adult lung cancer. The research was carried out thanks to a grant from the AIRC Foundation.
The suppressor cells
To counteract external threats, the immune system uses different types of cells, such as natural killer (nk), T lymphocytes, macrophages and neutrophil white blood cells, which are concentrated near the tumor and act by killing cancer cells and looking for to prevent metastases.
In the case studied by the researchers of the Cancer Immunology Laboratory in collaboration with that of Oncohematology, some cells belonging to the neutrophil white blood cell family – called Pmn-Mdsc – were found circulating in the blood, therefore far from the tumor environment. These cells had differentiated from normal cells, becoming suppressive: instead of working in concert with the other defensive cells to counter the advancement of the disease, they were doing exactly the opposite.
“Normally the cell differs to become a mature neutrophil serving the defense system,” explains a Health Lorenzo Morettaimmunologist who coordinated the study and director of the Cancer Immunology Laboratory of the Bambino Gesù hospital: “A bit like a kid influenced by the wrong companies, these cells influenced by the tumor cells become inhibitors of the activity of the others in the immune system . They are called suppressor cells precisely because they limit the functionality of other cells that are important to fight the disease, such as natural killer cells “.
Studies on leukemia and neuroblastoma patients
These “new” suppressor cells were first found in a group of small patients with very aggressive leukemia who received a blood stem cell transplant in the Oncology Department. Survival, while very good, was around 70%.
In an attempt to save more children and investigating the reasons, a massive presence of Pmn-Mdsc suppressor cells was noted in the peripheral blood, in a proportion even ten times higher than natural killers (essential for eliminating residual leukemia cells after transplantation). The investigation was also extended to the case of other childhood cancers, and in particular to metastatic neuroblastoma. Again, there were numerous suppressor cells in the peripheral blood.
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“For neuroblastoma patients, the Infant Jesus is treated with anticancer therapies using engineered cells called Car-T: they derive from T-lymphocytes to which a specific receptor is added in the laboratory”, explains Moretta. “What we noticed is, first of all, that if the suppressor cells were present from the beginning, the Car-T therapy was not going very well, but most of all that the patients who received Car-T and had a tumor relapse also showed an increase of those cells. In other words, following the trend of their number in the peripheral blood it is possible in a certain sense to predict whether the Car-T will work or not. The presence of Pmn-Mdsc therefore seems to correlate with the severity of the disease and with the possibility of relapse. We then demonstrated in the laboratory that these cells in vitro were indeed able to block the function of Car-T “.
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Not just in children
Since the tumors that affect children are about 3% of total cancers, the researchers immediately wondered if this mechanism could also be found in other aggressive and frequent tumors among adult patients. Thanks to a collaboration with the San Martino Hospital and the University of Genoa, over 50 patients with lung cancer (one of the most aggressive and frequent) have been studied. Many Pmn-Mdsc cells could also be found in their peripheral blood. Also in this case, according to what emerges from this study, their presence correlates with the severity of the disease and could have a prognostic value.
The discovery opens up new possible therapies
“The fact that Pmn-Mdsc cells are found in the peripheral blood means that there are so many of them, and they are not limited only to the tumor environment,” Moretta says. “It also means something else, though: that we can identify them with a normal blood sample rather than having to search for them with more complex and less accessible techniques. We have identified markers that allow us to recognize these cells, and in particular one that has turned out to be very specific and that we are patenting “.
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One of the possible solutions to the “corruption” of Pmn-Mdsc cells is to act on the process with molecules that induce the correct differentiation and, in so doing, prevent the development of the suppressor capacity. Another strategy is to identify them very precisely with specific markers, and then target them in a targeted way and eliminate them.
“The road is still long – concludes Moretta – but I find it very promising, also due to the fact that it could be a generalizable therapeutic strategy to many adult cancers. The evidence we now have concerns lung cancers, but we are also moving towards to other cancers “.
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