Double ‘mission’ for killer lymphocytes, thus killing cancer cells

Italian study demonstrates preclinical efficacy as a universal cellular platform for cancer treatment

They are called Natural Killer T lymphocytes, they are soldiers of the immune system that can be ‘trained’ and transformed into increasingly sophisticated anti-cancer ‘hit men’. With a double ‘mission’: to eliminate the cells that suppress the tumor microenvironment, and the new ability to directly kill the neoplastic cells. A team of Italian scientists has demonstrated their effectiveness in preclinical models, as a universal cellular platform to be armed against malignant cells.

In an article published today in the journal ‘Science Immunology’, researchers from the Laboratory of Experimental Immunology of the Irccs San Raffaele Hospital in Milan, under the guidance of Paolo Dellabona and Giulia Casorati, have enhanced the natural antitumor activity of NKT lymphocytes, by arming these cells with a second receptor (Tcr) specific for tumor antigens through genetic engineering methods. In this way, NKT cells have acquired a double function, which consists in their natural ability to modify the neoplastic microenvironment, mediated by their own endogenous Tcr, combined with the new ability to directly kill tumor cells, thanks to the expression of exogenous Tcr. .

The results of the study, supported by the Airc Foundation for Cancer Research, show the potential of NKT cells armed with anticancer receptors (Tcr or even Car) for cancer immunotherapy, applicable to both solid and haematological neoplasms. NKT cells were discovered in the early 1990s, thanks to the contribution of Casorati and Dellabona. What makes the functions of these cells universal is the fact that their antigen receptor and CD1d molecule are identical in all individuals. “Thanks to these characteristics, NKT cells taken from any donor can be used to treat any patient and this means that they represent a universally applicable cellular platform in cellular cancer immunotherapy”, Dellabona and Casorati explain. recent studies have also demonstrated the crucial role of NKT in the antitumor immune response.

The idea of ​​taking them from healthy donors and putting them in the bank and then transferring them to patients

Specifically, these special lymphocytes infiltrate the tumor microenvironment where they promote the immune response directed against cancer cells, through the elimination of particular blood cells, called macrophages, which exert a strong immunosuppressive action that locally supports the progression of the neoplasm. This mechanism of action of NKT cells is considered of particular interest for the treatment of cancer, since the immunosuppression generated at the level of the tumor microenvironment is considered one of the main obstacles to the efficacy of anticancer therapies, in particular for immunotherapy. cell phone.

In the new study, the San Raffaele team further enhanced the antitumor activity of NKT lymphocytes by genetically modifying them to express a specific antigen receptor for a tumor antigen. NKT cells thus acquired two contemporary anticancer functions: on the one hand, to eliminate the cells that suppress the tumor microenvironment, and on the other hand to directly kill the neoplastic cells. The result of this combined antitumor action of NKT cells is the particularly effective control of neoplastic progression in experimental models.

“Once taken from a donor and transferred, these cells have the characteristic of not attacking the recipient’s normal tissues, unlike other T lymphocytes – explains Gloria Delfanti, first author of the study that was the subject of her PhD at Vita-Salute San Raffaele University – This is a huge advantage because it would allow to obtain from a few healthy donors a bank of NKT cells which, once expanded and genetically modified in the laboratory with anticancer receptors, can be subsequently transferred to each patient whose tumor expresses the specific target antigen “.

Nanotechnologies to give specific impulses, aiming to better contrast aggressive and metastatic forms

“With our work – the study coordinators point out – we have identified the mechanisms of action of genetically armed NKT cells against tumor antigens. We have also contributed to providing new information useful for improving their use in adoptive cancer immunotherapy, a practice that in recent years it has been achieving promising clinical results “.

“We have also demonstrated, in experimental models, the possibility of combining this cell therapy with the use of nanotechnologies that specifically stimulate NKT cells – they continue – The combination allows us to further support the antitumor activity of NKT cells over time, to better counteract the most aggressive and metastatic cancers. CAR-modified NKT cells are attracting increasing interest in cancer immunotherapy thanks to the extremely encouraging results obtained in the United States in the experimental treatment of pediatric solid tumors and adult lymphomas. Our future efforts – conclude – they will now be targeted towards the clinical application of the results obtained in this experimental study “.