Towards a Car-T Therapy Against Colorectal Cancer Metastases

Finding an effective and safe Car-T therapy to treat liver metastases of colorectal cancer, which are one of the main causes of death among patients with this disease. An ambitious goal, given that these cell therapies have proven effective in treating blood tumors, but have given limited results in solid tumors. A goal, however, on which researchers at the IRCCS Ospedale San Raffaele have worked. They have developed and successfully tested - although at the moment only on mice and human tissue - an innovative immunotherapy against these metastases.

Hitting the tumor while sparing healthy cells

The study, published in Science Translational Medicine and coordinated by Monica Casucci , head of the Innovative Immunotherapy research laboratory at the Milanese center and conducted in collaboration with colleagues from the Institut Cochin at the Université Paris-Cité, therefore opens the way to new therapeutic strategies capable of selectively attacking the tumor while sparing healthy cells.

This is how T lymphocytes change

Car-T therapies are based on a particular type of immune system cells, T lymphocytes, which play several key roles in the body's fight against disease. One of these is, for example, killing abnormal cells. However, in cancer patients, T lymphocytes are unable to recognize cancer cells. They must therefore be genetically modified (creating Car-T cells, precisely) so that they produce a protein (a receptor) that recognizes another protein (the antigen) on the surface of tumor cells, to identify and attack them. To counteract the advance of the disease, T lymphocytes are usually taken from the patient, appropriately modified and multiplied, and then reinfused into the same patient. Thanks to this strategy, Car-T cell therapies are now used effectively to treat blood cancers (lymphomas, leukemia and myelomas), but not solid tumors, precisely because of the lack of safe and effective targets.

In search of the ideal target

The study by Italian researchers is therefore based on a question: what could be a suitable target for the development of a Car-T therapy to treat liver metastases of colorectal cancer? “We searched for and identified a protein that is highly present on the surface of tumor cells, but absent or inaccessible in healthy tissues,” explains Beatrice Greco , first author of the study.

The protein in question is called cadherin-17: once this target was identified, adds Rita El Khoury , co-first author of the study, specific Car-T cells were developed to recognize it. The therapy was then verified for efficacy and safety on murine livers, where it was shown to effectively block tumor growth without damaging healthy tissue.

Subsequently, the Car-T cells thus produced were also tested on human tissue, that is, samples from the tumor and healthy tissue of the volunteers who participated in this project. The next step, explains coordinator Casucci, will be to start clinical studies on patients with liver metastases from colorectal cancer, for whom therapeutic options are currently limited and 5-year survival remains low. The positive results could open up new therapeutic prospects also for other tumors that express cadherin-17, such as stomach cancer and neuroendocrine tumors.

The study is part of a large research program that began 6 years ago thanks to the contribution of the Airc Foundation, the Ministry of Health and Education, University and Research and funds from the European Research Council.