Silvia Formenti, MD

Identifying ways to improve immunotherapy responses so that more patients can benefit from this promising treatment.

Impact

Immunotherapy stimulates a person’s immune system to recognize and destroy cancer cells and is a promising treatment for breast cancer. However, some tumors can evade immune attack. Checkpoint inhibitors (CPI), a type of immunotherapy, work by preventing tumor cells from evading a patient’s immune response. While CPI drugs are approved for treatment of various types of cancers, including some breast cancers, their effectiveness in breast cancer has been disappointing overall. Drs. Formenti and Demaria are investigating ways to improve response to immunotherapies by combining it with radiation treatment. Radiation therapy activates a response in cancer cells that resembles what happens when a cell is infected by a virus, a “viral mimicry” response that generates the immune-activating signals needed for this process. Their research has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into a responsive (immunogenically hot) one. Their work will provide a critical step towards developing precision radiotherapy, facilitating its use in combination with immunotherapy as a successful and durable treatment approach for breast cancer patients.

Progress Thus Far

Drs. Formenti and Demaria have shown that radiotherapy not only kills tumor cells but also recruits the immune system to fight cancer. They discovered that breast cancer cells can respond to radiation in very different ways. While some activate immune signals that mobilize the immune system and attack them, others block this process by disrupting key molecular pathways, a mechanism linked to resistance to immunotherapy. The team is using a cancer organoid culture platform, which allows breast cancer cells isolated directly from a patient’s tumor to be expanded and studied in the lab. Using this platform, they found that some breast tumors partially block the radiation-induced viral mimicry response, and the team has identified one potential therapeutic target aimed at restoring immune recognition in these tumors. The team has also established a system to test in real time how radiation, with or without CPI treatment, regulates the ability of immune cells to kill breast cancer cells. They have also engineered a tumor model that mimics an immune resistance mechanism seen in human tumors, allowing them to test therapeutic interventions aimed at overcoming this resistance. Together, these findings suggest that overcoming immune evasion and tailoring immunotherapy delivery to specific sites in the body may be critical for improving treatment outcomes.

What’s next

Drs. Formenti and Demaria will confirm that experimental drugs targeting the mechanism they identified can prevent the conversion of radiation-induced immune-activating signals into immunosuppressive ones in breast cancer cells. They will then determine whether combining these drugs with radiation therapy favors the activation of immune cells and enhances their ability to kill breast cancer cells in their laboratory models. Looking ahead, the team plans to use their organoid platform to identify and expand patient-matched, tumor-specific T cells directly from a patient’s blood. Using specialized sequencing technology to “barcode” these cells so they can be tracked within the tumor and nearby lymph nodes removed during surgery, the team aims to make new insights into the reservoirs of tumor-specific immune cells in early breast cancer to ultimately design immunotherapies that work more broadly for breast cancer.