Tumors, the secret to improving immunotherapy is in the genes
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Immunotherapy is a powerful tool in the fight against cancer, especially in the case of tumors that are still difficult to treat with chemotherapy, radiotherapy and surgery. The idea of stimulating the patient’s immune response to fight the tumor has substantially improved the survival of a growing number of patients suffering from different types of cancer. However, it is necessary to continue to study new possible molecular targets for immunotherapy, given that a fraction of patients still do not receive benefit from currently available treatments. The study recently published in the Journal of Translational Medicine by the research group led by Antonio Facchiano, an oncologist specializing in the study of melanomas, goes precisely in this direction. Research suggests looking into genes to find new immunological therapies. That’s how.
The “checkpoints” of the immune system
Facchiano and his team studied the gene expression levels of nine receptors, the so-called “immune checkpoints”, which under normal conditions reveal to the cells of our immune system whether the other cells they encounter in the body are harmful and must therefore be attacked (as in the case of pathogens or, indeed, cancer cells), or if instead they belong to our body and must therefore be left intact. In short, they act like real checkpoints. However, some tumors “learn” to exploit this mechanism in their favor, in order to go unnoticed at the “checkpoint” and continue to proliferate uncontrollably.
Immunotherapy is based precisely on drugs that act at this level, with the aim of unblocking our natural immune response against cancer cells, with so-called immune checkpoint inhibitors. The intuition that it was possible to exploit the immune system to indirectly fight tumors was revolutionary, to the point that studies on immune checkpoints earned James P. Allison and his colleague Tasuku Honjo the Nobel Prize in 2018.
The study suggests that it is possible to use these widely studied receptors and some of which, such as CTLA, PD-1, already targets of “historical” immunotherapy drugs – as disease markers. “We compared the expression levels of the genes related to these nine immune checkpoints in cancer patients and healthy people, for a total of over 15,000 individuals taken into consideration – explains the researcher – For many of the 31 types of tumor analysed, the expression of these nine molecules are altered in sick patients compared to healthy people”. Furthermore, the analysis provides numerical, quantitative values linked to the levels of normal or, vice versa, potentially pathological expression of the nine indicators. This range of values would be an important aid in making the diagnosis increasingly objective and less based on qualitative observations. “Obviously – Facchiano points out – the pathologist’s analysis remains essential as far as the diagnosis is concerned. But having numbers to refer to can certainly be a great help”.
This study opens new perspectives not only for the use of these receptors as disease markers but also for extending their use as therapeutic targets. “We analyzed the expression of these targets in patients as a function of their survival to the disease. In particular, it has been seen that for some types of tumors all nine of these genes are associated with survival. For melanoma, for example, high expression values of these genes are associated with a significant improvement in survival, while the opposite is true for other types of tumours”.
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A combined approach
Despite the possible implications in diagnostic and therapeutic fields – such as the possibility of using already existing drugs for other types of tumors – the more immediate purpose of the work is to speed up trials. Our data is obtained in silico, by analyzing the values we have with mathematical and statistical models – explains the researcher – The final demonstration of the efficacy of a certain therapy must certainly be carried out through a clinical study. However, with our study we think we can speed things up a lot, giving clear indications as to which of the already existing drugs should be immediately tested in the clinic, potentially leading to useful results in a few months”. The next steps will be to include data such as gender, sex, age, stage of the tumor and specific therapies that patients have undergone in the studies. “This – concludes Facchiano – will allow us to have an even more precise classification of new possible therapeutic options”.
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