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Immune checkpoint inhibitors (ICIs) have revolutionized the way we approach lung cancer treatment over the past decade. These lifesaving drugs block the PD-L1 or the CTLA-4 proteins, which inhibit the body’s natural ability to fight tumor cells. Immune checkpoint inhibitors work by removing “the brakes” from the immune system, so that the immune system can kill tumor cells. This approach leads to approximately 20% of patients benefiting from immune checkpoint inhibitor treatment. Researchers are trying a range of approaches to make these drugs effective for more patients living with non-small cell lung cancer (NSCLC).
Rationale Behind Radioimmunotherapy
Immunologically “cold” tumors typically have a low tumor mutational burden, low PD-L1 status, and little immune cell activity within the tumor or in the tumor microenvironment. Taken together, these characteristics make cold tumors poor targets for immune checkpoint inhibitors, which require an active immune system to be effective.
Importantly, radiation therapy has shown promise in activating the immune system. This immune system activation is well-documented at the site of radiation, but the benefits of radiation can extend beyond the area being treated. Known as the abscopal effect, radiation treatment at one tumor site can trigger immune cell responses and shrinkage in distant tumors.
This line of thinking led researchers to try using radiation to activate the immune system in cold tumors and then treat them with immune checkpoint inhibitors.
Pairing immune checkpoint inhibitors with radiation therapy is not a new idea. Studies have shown promise in using radioimmunotherapy to treat metastatic, locally advanced, and resectable NSCLC. However, little is known about the mechanisms of the abscopal effect and how best to optimize radioimmunotherapy for consistent clinical benefit.
Researchers Dig into the Details
A recent study published in Nature Cancer, led by acclaimed physician-scientist Valsamo Anagnostou, MD, PhD, of Johns Hopkins Medicine, explored how radiation combined with immune checkpoint inhibitors may help the immune system fight advanced-stage NSCLC.
Their research focused on using tissue and blood samples from the phase 2 PEMBRO-RT clinical trial which showed that patients with immunologically cold tumors lived longer without disease progression when radiation (stereotactic body radiation therapy or SBRT) was given before pembrolizumab treatment. Dr. Anagnastou’s team aimed to answer the question: Why was this radioimmunotherapy successful?
Her team delved into the cellular details, such as which immune cells were activated, which proteins and chemicals were being released into the blood stream, and which genes were transcribed into RNA, to understand how the abscopal effect worked.
The research team compared the serial tissue samples of abscopal tumors and their tumor microenvironments to understand the changes that occurred over time in the tumor cells, the immune cells and in the tumor microenvironment. The blood sample studies allowed researchers to understand the systemic effects of immune checkpoint inhibitor treatment with and without radiotherapy.
Their analysis identified specific immune signaling molecules, T cell activation, and RNA transcripts that were initiated by radioimmunotherapy. These findings suggest that combining radiation with immunotherapy could be a promising strategy to induce an immune response in cold NSCLC tumors and improve benefit from immunotherapy.
Continuing the Research
This deep understanding of the cellular changes that are caused by radioimmunotherapy offers us promising paths to pursue as we develop this approach into a lifesaving treatment option for patients.
Further studies are already underway to leverage radioimmunotherapy to treat patients. The phase 2 RAD-IO trial aims to use radioimmunotherapy to revive the immune system’s response to immune checkpoint inhibitor treatment in patients whose disease has progressed on immune checkpoint inhibitors alone.
Visit LUNGevity’s Research News page to see more exciting advances like this.