Study Supports Immunotherapy/Radiation Combo in Head and Neck Cancer

Jonathan D. Schoenfeld, MD

There may be potential synergy between radiation therapy, given with or without chemotherapy, and immune checkpoint inhibitors in patients with squamous cell carcinoma of the head and neck (SCCHN), according to results of a prospective study.

The study, which was presented at the the 2016 Multidisciplinary Head and Neck Cancer Symposium in February 2016, examined blood samples from 16 consecutive patients with SCCHN undergoing curative-intent radiation therapies.

Samples were obtained at week 1 and week 6 to 7. Patients received a median of 70 Gy for disease in the oropharynx (n = 12, 75%), nasopharynx (n = 2, 12%), larynx (n = 1, 6%), or oral cavity (n = 1, 6%). The majority of patients had stage IV disease that was metastatic to regional lymph nodes and received concurrent platinum-based chemotherapy.

The analysis found that, during radiation treatment, circulating CD8-positive T-effector cells increased (P = .01), as did CD4-positive PD-1—positive cells (P = .02), CD8-positive LAG3-positive cells (P = .02), and regulatory T cells (P = .04). sPD-L1 levels also increased, mirroring increases in CD8-positive T cells over the course of therapy (P = .047).

While the extent to which these systemic changes reflect changes in the tumor microenvironment is unknown, the study authors noted that these findings support the “complex immunologic effects of fractionated chemoradiation therapy and mechanisms for potential synergy between chemotherapy, radiation treatment, and immunotherapy in SCCHN.”

OncLive: What were the goals of this study?

To learn more about the impact of the research, OncLive spoke to one of the study’s authors, Jonathan D. Schoenfeld, MD, physician, assistant professor of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, who presented the findings at the meeting.Schoenfeld: Immunotherapy, particularly immune checkpoint blockade, is demonstrating some exciting results in head and neck cancer. Largely, that work has been done in metastatic head and neck cancer. Our goal was to look at the immunologic effects of a treatment that is commonly given to patients with early-stage head and neck cancer: chemotherapy and radiation.

We found that the combination of chemotherapy and radiation—and in some cases, just radiation alone—led to immune effects that we could see not just in the site where we were radiating, but also if we looked at markers in the peripheral blood.

One of the interesting things that we found was that radiation, with or without chemotherapy, has the potential to increase the number of tumor antigens that were targeted by the host immune response. One of the ways that we hope to use radiation in the future is to stimulate an initial immune response.

What immune effects were investigated?

Based on the data that is emerging with PD-1 inhibitors, we know that the majority of patients will not respond to these agents. We need to determine if we can use radiation and chemotherapy to increase the number of responders initially that can then be stimulated even further with immune checkpoint blockade.We looked at a variety of effects. We looked at chemokines, which are cytokines that could mediate effects outside of the radiation treatment field. We looked at circulating T cells, including CD8-positive T cells, CD4-positve T cells, and markers of activated T cells.

What can a community oncologist take away from these findings?

We also looked at potentially inhibitory T cells as well, including T-regulatory cells, T cells that were expressing checkpoint receptors, and myeloid-derived suppressor cells. We also looked, in more detail, at the types of T-cell receptors that were expressed on the surface of these T cells, and it looked like the combination of radiation and chemotherapy could change the clonality of the receptor on these T cells, suggesting that radiation or targeted tumor death could stimulate a more targeted immune response.Chemotherapy and radiation have long been appreciated for their immunosuppressive effects. We all know that when you treat someone with radiation or chemotherapy, you can see a decrease in cytopenia and lymphocytes.

We are now learning that certain types of chemotherapy and radiation, given in the proper circumstance, can cause immunogenic cell death. That can possibly synergize with the newer types of immune checkpoint blockade that are being developed.

One of our study’s findings was that we saw an increase in T cells expressed in the PD-1 receptor. Those could potentially be targeted with new checkpoint inhibitors that target the PD-1 receptor. As we develop these therapies even further, there are exciting new combinations between immunotherapies and some of the traditional therapies that have long been used for head and neck cancer with potential.

In melanoma, there are case reports of patients who have progressed on immune checkpoint blockade and are then treated with high-dose palliative radiation that then began to experience a response outside of the radiation treatment field. That is a very exciting avenue of research for head and neck cancer, as well. Can we take patients who don’t respond to the current checkpoint inhibitors that we have and use radiation in a targeted way to stimulate a broader immune response?

Radiation and chemotherapy are a backbone of some of the definitive treatments currently used for head and neck cancer. There is a lot of interest with the success of PD-1/PD-L1 inhibitors to integrate these into the definitive management, and combine them the proper way with chemotherapy and radiation to better maximize our results.

What impact will immunotherapy will have in head and neck cancer?

Chemotherapy and radiation are still very important for patients with curative head and neck cancer, but perhaps we should be giving these treatments in a different way—different types of radiation and chemotherapy and different targets for radiation. All of these things need to be explored, as new therapies, such as immune checkpoint inhibitors, are developed in this disease.It will have a huge impact. Exciting data are emerging in metastatic head and neck cancer that show that PD-1 inhibitors offer real benefit to patients. Many of these patients had very few other treatment options and could obtain a survival benefit after treatment with PD-1 inhibitors. That opens up a whole new realm of opportunities to study immunotherapy in different settings, in different groups of patients, and in combination with other agents.

Sridharan V, Margalit D, Curreri S, et al. Systemic immunologic effects of definitive radiation in head and neck cancer. Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; February 18-20, 2016; Scottsdale, AZ. Abstract 2.