“Super cells” created at i3S could revolutionalize tumor treatment
CAR T cells genetically edited by researchers at i3S promise to be more effective and resistant in fighting solid tumours.
CAR-T cells are one of the most innovative approaches in immunotherapy for treating tumours. However, their action is quickly depleted against solid tumours. An international team led by Salomé Pinho, from the Institute for Research and Innovation in Health at the University of Porto (i3S), genetically edited these cells, making them more competent and resistant. It created true CAR T super cells to fight solid tumours.
The study, recently published in the American Association for Cancer Research (AACR) journal Cancer Immunology Research, reveals the results of this innovative T cell gene editing strategy.
The researchers showed that, in the early stages of colorectal cancer, T lymphocytes circulating in the tumour undergo significant changes in the composition of complex sugars on the cell surface (glycans). These changes that occur in T lymphocytes during tumour development are associated with greater immune exhaustion and, thus, greater incompetence of these T cells in fighting the tumour.
Researchers Catarina Azevedo, Salomé Pinho, and Ângela Fernandes believe that the discovery “opens up prospects for the development of innovative approaches in cancer immunotherapy.”
Using CRISPR/Cas9 gene editing technology, the team managed to eliminate the MGAT5 gene, responsible for the synthesis of these complex glycans, which impair the immune function of these T cells. The result was surprising: “T cells without this MGAT5 gene showed a greater ability to destroy tumour cells, reversing their state of exhaustion and making them more resistant and more aggressive in fighting tumour cells,” explains Salomé Pinho, leader of the “Immunology, Cancer & GlycoMedicine” group at i3S.
Foreseeing the application of this knowledge in immunotherapy against different types of cancer, the researchers applied this strategy to anti-CD19 CAR-T cells—a cell therapy already used in haematological tumours, but with limited efficacy in solid tumours— and found that CAR-T cells modified not to express MGAT5 (Glyco-CAR T cells) are more effective at inhibiting the growth of solid tumours.
“These innovative results reveal a new molecular target that may have clinical application to enhance the effectiveness of T cell-based immunotherapy, such as CAR-T cells, especially in the challenging context of solid tumours,” said the professor at the Faculty of Medicine (FMUP) and the Abel Salazar Institute of Biomedical Sciences (ICBAS) at the University of Porto.
Catarina Azevedo, first author of the study and student of the Doctoral Program in Biomedical Sciences at ICBAS, under the supervision of Salomé Pinho and co-supervision of Ângela Fernandes, further emphasises that “the study provides proof of concept that manipulating the glycome of T cells may represent a promising strategy for expanding the therapeutic potential of CAR-T cells.”
This new evidence, adds Ângela Fernandes, one of the senior authors of this study, “opens up prospects for the development of innovative approaches in cancer immunotherapy.”
About CAR-T cells
CAR-T cells (Chimeric Antigen Receptor T cells) are one of the most innovative approaches in immunotherapy. These are the patient's own T cells, genetically modified in the lab to express a receptor capable of recognising specific targets on tumour cells.
After being reintroduced into the body, these cells act as “living drugs,” destroying tumour cells with high precision. Although they have already shown revolutionary results in some types of haematological cancer, such as certain leukaemias, their effectiveness in solid tumours remains one of the major challenges in this field.
This study reveals new evidence that could form the basis for a new generation of CAR-T cells (Glyco-CAR T) with greater antitumor efficacy, especially in solid tumours.