Stimulating the immune system to fight cancer naturally

“Over the past years, cancer treatments have improved thanks to the introduction of targeted and immuno-therapies”, says Professor and cancer biologist Elisa Oricchio, “However, tumor relapse and resistance to current treatments prompt to search for new therapeutic targets that could combine the benefits of both approaches.” In 2020, Oricchio’s team identified a key mechanism that tumor cells use to take advantage of and avoid detection by the immune system. Targeting this mechanism offers a new therapeutic strategy for cancers such as Non-Hodgkin lymphoma (NHL). The lab got the support from the enable program to perform additional pre-clinical studies to further put to test the technology they are developing.

The role of the protein cathepsin S

Immunotherapy is one of the most promising treatments for cancer patients. Unlike radio- or chemo- therapies, immunotherapy aims to “switch on” the patient's own immune system to attack and eliminate the tumor. However, tumors, including NHL, often mutate to make themselves invisible to the immune system or even exploit interactions with immune cells to grow.

As explained in an article published on the EPFL website in April 2020, the team of researchers has identified one of the mechanisms used by NHL to hijack the immune system: certain patients with cancer have a mutated and over-activated form of a protein called cathepsin S. This protein is responsible for cutting other proteins into small fragments that are then exposed on the surface of tumor cells. These fragments mediate communications between cancer and immune cells. When cathepsin S is active, cancer cells interact with immune cells called CD4+ T-cells, which help the tumor to grow, while they maintain social distance with CD8+ T-cells, which would attack and kill the tumor. Inhibiting cathepsin S reduces tumor growth by inverting the communication with T-cells: CD8+ T-cells are now attacking the tumor, while CD4+ T-cells are kept at bay. This happens by inducing something called “antigen diversification”, which generates a different population of fragments helping T-cells to identify and kill tumor cells.

A completely novel approach

“It has been known for a few years now that targeting these cathepsins can provide new ways of treating different tumor types”, says Aaron Petruzzella, doctoral assistant who leads the project in Oricchio’s group.“The lab was the first to describe that this is also important in lymphoma, a type of blood cancer; but nobody managed to find a drug that works on these enzymes and that can be delivered efficiently in vivo and work in patients”, he adds. “The clinical trials which have been performed to test small-molecule inhibitors of cathepsins suggest that systemic delivery of such drugs without selectivity for the target tissue gives raise to secondary effects which decrease the therapeutic benefit of these drugs” he emphasizes. “This problem could be overcome by the antibody-peptide conjugate design we are developing, that provides the specificity and efficacy needed to achieve therapeutic effects in patients without severe secondary effects.”

Cathepsin inhibitors developed by Petruzzella and Oricchio could be beneficial, not only for cancer patients but also for those suffering from autoimmune diseases for which cathepsin S or cathepsin B have been shown to play a pathological role. Diseases that could be targeted with cathepsin inhibitors include, among others: lymphoma, breast cancer, colorectal cancer, lupus and Sjogren's syndrome.

enable support

“Thanks to enable support, we are currently performing additional pre-clinical studies to further prove that our antibody-peptide conjugates are highly specific and that they work as expected in vivo”, says Petruzzella. “We have good preliminary results for the experiment we are doing in vivo, which is promising on the clinical side”, adds Oricchio. “The initial goal was to develop a treatment for blood cancer and now we are expanding on solid tumors with a first targer on breast cancer.”

Petruzzella and Oricchio are starting to discuss with different potential partners to find ways of bringing forward the technology. “There are still steps that we can perform in the lab while starting to figure out whether we can collaborate to license the molecule so we can move to the clinical trials.”

Professor Oricchio’s lab is part of the Swiss Institute for Experimental Cancer Research (ISREC) within the School of Life Sciences at EPFL. ISREC@EPFL is part of the Swiss Cancer Center Léman (SCCL), a multidisciplinary alliance pursuing fundamental, translational, and clinical cancer research. The SCCL founding members are the Lausanne University Hospital (CHUV), the Geneva University Hospitals (HUG), the universities of Lausanne (UNIL) and Geneva (UNIGE), and EPFL.