Triple combination therapy before surgery increases immunity against aggressive soft tissue sarcomas: Study

Early results from preclinical studies and a clinical trial led by researchers at the UCLA Health Jonsson Comprehensive Cancer Center and Stanford Medicine suggest that combining targeted radiation therapy with an experimental immune-boosting drug called BO-112 and anti-PD-1 therapy before surgery may help the immune system fight aggressive soft tissue sarcomas. The findings, published in Cancer Discovery, a journal of the American Association for Cancer Research, show that the approach can reshape the tumor microenvironment to activate the body’s immune cells against cancer.

Why it matters

Soft tissue sarcomas are a rare and often hard-to-treat group of cancers that typically require a combination of surgery, radiation therapy and other systemic treatments. However, these tumors may still be resistant to standard therapies, highlighting the need for new treatment strategies.

This study highlights a new approach that targets both the tumor and the immune system at the same time. By combining radiation therapy with BO-112, an experimental therapy, the approach aims to trigger an immune response by engaging immune cells called myeloid cells. This activation can be further enhanced by anti-PD-1 therapy. Understanding how radiation therapy, BO-112, and anti-PD-1 work together to prime the immune system offers a blueprint for developing more effective therapies for patients whose tumors are otherwise resistant to treatment.

What the study did

Although T cells are immune cells that target and kill cancer cells, myeloid cells are another group of immune cells that can both facilitate and disrupt T cell activity. The researchers first tested whether engaging myeloid cells with BO-112 could indirectly promote T cell activity and enhance the effects of radiation therapy and anti-PD-1 therapy in mouse models. In a phase 1 clinical trial of 14 patients with soft tissue sarcoma, patients were treated with BO-112 injected directly into tumors while receiving a condensed five-day radiation treatment with or without nivolumab, an FDA-approved immunotherapy, before surgery.

What they found

Researchers found that combining BO-112 with radiation therapy, with or without nivolumab, activated the immune system in both mouse models and patients to fight the cancer. After combination treatment, myeloid cells within the tumor switched from a state that helps tumors survive to one that supports the anti-cancer activity of T cells. Over time, tumors were repopulated by newly arriving and more resilient T cells. These immune changes were associated with fewer cancer cells, suggesting a more effective anti-tumor response. In fact, the triple combination was potent enough to cause unexpected immune-related side effects in patients, but these were eliminated by adjusting the doses of BO-112 and nivolumab.

What this means for patients

“Tumors may not respond well to current immunotherapies because they do not have the right types of immune cells within the tumor to support a strong anti-cancer response,” said Dr. Jie Deng, an assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA and first author of the study. “Our findings show that by designing a combination therapy that engages myeloid cells already present in the tumor, we can activate these cells and trigger broader immune responses. This approach can activate immunity not only within the treated tumor but also more broadly.”

What’s next

Future work will further explore how radiation therapy can be combined with immunotherapy approaches that engage myeloid cells to enhance anti-tumor immune responses. This includes studying similar strategies in other types of cancer.

Reference:

Jie Deng, Stefano Testa, Jingyu W. Xu, Linh M. Tran, Danielle S. Graham, Aviv Hargil, Ajay Subramanian, Katie M. Campbell, Neoadjuvant BO-112 and hypofractionated radiation therapy with or without nivolumab in soft tissue sarcoma: preclinical and phase 1 results, Cancer Discovery, DOI:10.1158/2159-8290.CD-25-1132