Over the past decade, cancer treatment has been revolutionized by immunotherapy. It is no coincidence that many of the cancers that did not have effective treatments in the past can now be tackled with greater success. There is one though: immunotherapy does not work in all sufferers. This is why research is at work in an attempt to identify new ways to improve its efficiency. At the congress of the American Society of Clinical Oncology, several studies were presented that will trace the future use of immunotherapy: combinations, sequences, new targets and immunomodulating molecules will increasingly contribute to making many of the neoplasms we know today chronic.
Asco 2022
Lung cancer: Immunotherapy before surgery increases the chances of recovery
by Letizia Gabaglio
06 June 2022
The decade of immunotherapy
A little more than ten years have passed since the first historical results, presented at ASCO, on the efficacy of immunotherapy. In that case it was for metastatic melanoma, a tumor that left only a few months to live from diagnosis. “The epochal change – explains Michele Maio, director of the Immuno-Oncology Center at the Policlinico Santa Maria alle Scotte in Siena and president of the NIBIT Foundation – we had when instead of looking at the tumor we began to focus on who could eliminate it. The immune system is a great ally in this but it must be helped “. In fact, tumors have the ability to evade the immune response and grow undisturbed. And this is precisely where immunotherapy made the difference. “By removing the brake on the immune system, it is possible to always keep the response on. This strategy today represents the fourth pillar of cancer treatment together with surgery, chemo and radiotherapy ”continues Maio. Currently used for many cancers, immunotherapy has made it possible to chronicize cancers that previously had very low success rates such as melanoma and lung cancer.
A strategy to improve the efficacy of immunotherapy
by Dario Rubino
01 June 2022
Combinations and new targets
In the golden decade of immunotherapy, ipilimumab – the first immunotherapic in history capable of acting on the CTLA-4 target – was joined by other drugs with different mechanisms of action (against PD-1 and PD-L1) such as pembrolizumab and nivolumab. “Being able to have more immunotherapists capable of exploiting different targets – continues Maio – was very important because unfortunately not all patients respond effectively to therapies. The combinations, that is the administration of more immunotherapics, helped us to raise the share of people who respond. Not only that, the combinations also improved the survival data “. A fact above all: at ASCO the data from the Checkmate-067 study on the combined use of two immunotherapies (ipilimumab plus nivolumab) showed that seven and a half years after diagnosis, 48% of patients are still alive. An epochal result. However, research in the field of immunotherapy is by no means stopped. Over time, numerous other targets have been identified, in addition to the classic CTLA-4 and PD-1 / PD-L1, on which the industry has begun to experiment with possible drugs. Last March, the FDA approved the first immunotherapy (relatlimab) directed against LAG-3, a new target of the immune system. Used in melanoma, it is being tested for other cancers such as multiple myeloma, stomach and esophageal cancer. Not only that, among the other targets being tested there are antibodies against TIM3 and OX40, proteins capable of regulating the immune response.
Change the tumor
But identifying new targets is not the only goal to increase the effectiveness of immunotherapy. “An aspect not to be overlooked at all is the study of the characteristics of the tumor and its microenvironment. In particular, how cancer cells manage to evade the immune response. In recent years we have understood that the use of classic immunotherapies must integrate a strategy to remove that “veil” that the tumor uses to avoid being recognized “. To do this, various approaches are being tested which involve the use of chemotherapy, before administering immunotherapy, in order to change the characteristics of the tumor and make it more easily recognizable. “Another very similar approach is that of using epigenetic drugs such as guadecitabine, a molecule capable of determining changes in the DNA of cancer cells in order to modulate their gene expression. In this way the tumor begins to express molecules on the surface that play a fundamental role in the interaction with the immune system. Subsequently, the tumor, made more visible by guadecitabine, is attacked by the immune system appropriately sitmolated by immunotherapy ”explains Maio.
But there’s more: ASCO was presented with a study by Professor Anna Maria Di Giacomo, from the research group of Michele Maio, in which for the first time in humans an alternative approach was tested to modify the tumor environment. thereby restoring the effectiveness of the immune response against the tumor. “In the study – explains Di Giacomo- we used an experimental molecule (IOA-244) with the aim of interfering with PI3Kδ, an important communication mechanism inside the cell. The molecule in question, in addition to having an antitumor activity, has the characteristic of inhibiting the response of some cells of the immune system that have a negative regulatory function, that is, they switch off the immune response. The first analyzes confirmed the rationale of this approach, namely that inhibiting PI3Kδ could be useful for improving the effect of immunotherapy “.
Learn from failures
The way towards an improvement in immunotherapy therefore seems to have been traced. However, there is a crucial aspect that must not be overlooked and that is research. In recent years it has often happened that for some types of cancer, such as glioblastoma, the path of immunotherapy has been abandoned due to poor results. “I believe that today we need to study more in depth the mechanisms that the tumor puts in place to evade the immune response. Being able to decipher them represents the starting point for the development of new strategies to be associated with immunotherapy. To abandon this approach in certain cancers because studies have shown that it does not work is not correct. It is precisely the study of these failures that will allow us to make immunotherapy work where today it is not yet possible ”concludes Maio.