Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Radiation Oncology and Immune Stimulation

In this episode of OncChats: Moving the Needle in Undifferentiated Pleomorphic Sarcoma, the following experts discuss the potential of radiation therapy to enhance immune response in soft tissue sarcomas, exploring how dose fractionation and emerging techniques like spatially fractionated radiotherapy (SFRT) may optimize immunostimulation in combination with immunotherapy:

• J. Dominic Femino, MD, an orthopaedic surgeon with Keck Medicine of USC and chief of the USC Musculoskeletal Oncology Center
• Lee Zuckerman, MD, an orthopaedic surgeon with Keck Medicine of USC
• Mark Agulnik, MD, a medical oncologist with the USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC
• Andrew Lim, MD, a radiation oncologist with Keck Medicine of USC

Femino: I want to move on to some of the radiation oncology issues. Dr Lim, radiation therapy has traditionally been used for the treatment of soft tissue sarcomas, but now, with the addition of immunotherapy, what are the potential mechanisms for radiation therapy–induced immune stimulation for these patients?

Lim: It’s really important to know that we’re still unraveling the intricacies of this interaction, and what we’ve seen is that radiation can play both an immunostimulant effect as well as [an] immunosuppressant [effect]. The balance between these 2 states depends on a lot of variables. Focusing on the immunostimulatory side, we can really identify a few key mechanisms. First off, we have immunogenic cell death, so when radiation goes in and kills a cancer cell, it can release danger signals like tumor-associated antigens, thereby alerting the immune system to the presence of dying cells. Then, secondly, radiation has been shown to alter the tumor microenvironment, really increasing the expression of MHC class I [molecules], as well as death receptors on the tumor cells. So there are just a couple of mechanisms that are currently being investigated as being the underlying mechanism of radiation stimulation of the immune system.

Femino: Does the radiation dose fractionation influence the cooperative activity of radiation with immune checkpoint blockade?

Lim: You’re absolutely right. Dose fractionation can play a significant role in determining whether radiation is immunostimulant or immunosuppressive. Standard fractionation, which has been the standard of care for sarcomas for decades and used in Stand Up to Cancer SARC 032, can independently kill the cancer cell. But interestingly, what we’re finding is that standard fractionation may actually have an immunosuppressive effect overall, decreasing tumor CD8 T cells and increasing CD4 T regulatory cells. So, we know that 50 Gy in 20 fractions kills the cancer cells, but now some early preclinical studies have [suggested] that it has a more immunosuppressant effect.

Femino: So traditionally, for soft tissue sarcomas, we’ve used 50 Gy in 25 fractions. Because this study was conducted during COVID-19, there were a few patients who received hypofractionation of their radiation with their immunotherapy. Could this possibly improve the outcomes using hypofractionation?

Lim: Absolutely. In some studies, we’ve showed that both hypofractionation, so very high doses per session as well as very low doses of radiation, may be the future if our goal is immunostimulation. So interestingly, very low doses of radiation have been associated with increasing antitumoral immunity. Here, at the University of Southern California, we’re actually the lead investigators of a radiation technique called SFRT, which is spatially fractionated radiotherapy, and this may be the future of immunostimulation. SFRT has the ability to deliver high doses in some areas of the tumor, therefore, killing the cancer cell and releasing these tumor-associated antigens, as well as other areas of the tumor may receive low doses, activating the immune system.

Check back tomorrow for the next episode in the series.