MODIFY the tumor micro-environment to target therapies even in tumors that resist the most innovative treatments. Such as ductal adenocarcinoma of the pancreas, an aggressive and difficult to treat disease, of which over 13,000 new cases are registered in Italy every year. An Italian experimental study published in the Journal of Immunotherapy of Cancer has shown that with an immunomodulator, that is a drug that regulates the immune response, it is possible to prepare the ground for immunotherapy, which in this way works: it hits the target. The research was conducted by the Policlinico Gemelli IRCCS Foundation in collaboration with the Universities of Verona and Turin and with the Institute for system analysis and computer science “Antonio Ruberti” (IASI) -CNR, and carried out thanks to the contribution of the AIRC Foundation for Cancer Research.
Ductal adenocarcinoma of the pancreas is the fourth leading cause of cancer death in industrialized countries and could become the second largest by 2030. It is such an aggressive disease because most patients are diagnosed when the cancer is already in an advanced stage, and only 15-20% of them can have surgery right away. Relapses are also common in operated patients, which occur in 80% of cases within two years of surgery. For this form of cancer, the response to treatments, including immunotherapy, is today unsatisfactory and this is because the tumor environment acts as a sort of protective barrier for cancer cells: as cancer were a small ecosystem that protects itself.
From a hostile environment …
“After categorizing different subtypes of pancreatic cancer on the basis of immunological, genomic and molecular characteristics, we selected those potentially most sensitive to a treatment that modulates the hostile tumor microenvironment”, say Carmine Carbone and Geny Piro, both biologists of the University Policlinico Foundation. Agostino Gemelli IRCCS and first authors of the research. The next step was to ‘prepare the ground’ for immunotherapy, by directly injecting an immunomodulator – a TLR9-agonist called IMO-2125 – directly into the tumor transplanted into mice – either alone or in combination with anti-PD1 immunotherapy. Later the authors went to see what had happened both in the tumor tissue and at the level of systemic immunity in the animals.
… to a permissive environment
Well: the injection of IMO-2125 alone triggered the immune response against both local and distant tumor cells in some cancer subtypes with immunogenic capacity (ie able to stimulate the immune response). In addition, associated with immunotherapy (administered systemically), it has triggered an important anti-tumor effect, evident both at the injection site and at a distance, and also in less immunogenic tumors.
What happened on the cellular level? The treatment had made the environment ‘immuno-permissive’, that is, it had allowed the entry into the cancerous mass of dendritic cells and T lymphocytes, the ‘soldiers’ that immunotherapy recruits to destroy diseased cells.
In essence, the study shows that the combination of IMO-2125 injected directly into the tumor tissue and systemically administered anti-PD1 immunotherapy exerts a powerful anti-tumor activity in laboratory animals with ductal adenocarcinomas of the pancreas that normally do not respond to immunotherapy. And that the immunomodulator prepares the tumor microenvironment to respond to treatment.
Next step: human studies
“This is the first demonstration, for now preclinical, of the possibility of reconditioning the tumor micro-environment of the pancreas through a local injection of an immunomodulator, of which my group had discovered some mechanisms of action in the past, and which is already object of clinical trials in patients suffering from different types of tumors ”, underlines Giampaolo Tortora, Director of the Comprehensive Cancer Center of the Agostino Gemelli IRCCS University Hospital Foundation, coordinator of the study. “In light of the new results, we have now designed a Phase I / II clinical trial, which we hope will start next year.”
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