“IN THIS era of immunotherapy, it is highly possible, and potentially probable, that radiation therapy may become not just a form of locoregional and palliative treatment, but an essential component of our systemic treatments of cancer,” according to Zachary S. Morris, MD, PhD, Vice-Chair, Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison. Radiation therapy may play a role in overcoming some of the typical barriers to preventing or curing metastatic disease, particularly tumor heterogeneity, he told participants at the 2018 Multidisciplinary Head and Neck Cancer Symposium, sponsored by the Robert H. Lurie Comprehensive Cancer Center and Feinberg School of Medicine, Northwestern University, Chicago.1
Zachary S. Morris, MD, PhD
Dr. Morris related that he and other members of the radiology community are excited about the possibility of radiation therapy playing a role in converting functionally immunologically “cold” tumors—those with low mutational burden, few tumor-infiltrating immune cells, and other factors making them unresponsive to immunotherapy—into functionally immunologically “hot” tumors that do respond to immunotherapy.
Effects of Radiotherapy
“RADIATION THERAPY has immediate effects on the inflammatory state of the tumor microenvironment, causing local cytokine release. It also temporarily eliminates many of the immune cells in the radiation target field, particularly those of lymphocyte origin, and that can create a window of opportunity to more effectively reconstitute the microenvironment,” Dr. Morris explained.
“In addition, we see increased immune infiltration after radiation therapy,” he continued. “Finally, the cells that escape the killing effects of radiation do not escape unscathed.” Many of the tumor cells “upregulate factors that make them more recognizable to the immune system,” he noted. Consequently, there are better presentation of antigens and diversification of T-cell response to recognize more features of cancer. “Time, dose, and fractionation may impact these mechanisms in different ways,” Dr. Morris noted.
According to Dr. Morris, the end result is that radiation therapy may serve as the mechanism of an in situ vaccine. “This is really a powerful concept,” he stated. “The idea is to destroy tumor cells in a patient so as to enable them to function as a personalized immune stimulus. We don’t need to necessarily tell the immune system what to recognize. We allow it to recognize the tumor in an environment that we have modified.”
The Rare Abscopal Effect
LOCAL RADIATION therapy alone can trigger a systemic antitumor response in the setting of metastatic disease. A patient receiving radiation for one tumor site not only has the expected local response, but also a systemic response against other tumor sites. This is known as the abscopal effect. The abscopal effect has been well documented for many years, said Dr. Morris, “but it is also exceedingly rare,” with just 46 abscopal cases reported between 1969 and 2014 and only 5 of them included immunotherapy.
“It is not a type of phenomenon that is an effective therapeutic strategy alone,” Dr. Morris noted. “We haven’t had mechanisms of overcoming immune suppression and immune tolerance prior to this current era. Now that we have the opportunity to combine radiation therapy with immune checkpoint blockade, we may uncover these effects in a new way that makes them currently viable as a therapeutic strategy,” Dr. Morris said.
Supporting Clinical Data
“FOR THE first time, we have clinical data to support this phenomenon,” Dr. Morris said. For instance, radiation therapy and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blockade induced systemic antitumor T cells in chemorefractory metastatic non–small cell lung cancer (NSCLC), where anti–CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy, according to a study reported late in 2018 in Nature Medicine.2 “Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system,” the study authors concluded.
“Our concepts of how we think about delivering radiation may need to be reconceptualized in the era of immunotherapy.”— Zachary S. Morris, MD, PhD
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“This led to a lot of excitement in our field about combining radiation and checkpoint inhibitors,” Dr. Morris commented. “There have been a number of retrospective studies,” he noted, with “minimal suggestion of any added or increased toxicity, except in the setting of radiosurgery, so caution is still warranted.”
Dr. Morris briefly mentioned an “exciting” study presented at the 2018 ASCO Annual Meeting. In this trial, 74 patients with advanced NSCLC were randomly assigned to receive pembrolizumab alone or with stereotactic body radiotherapy to a single site of metastasis within 7 days of starting pembrolizumab.3 “The response rate in those who received radiation therapy was 41% compared with 19% in those who received the checkpoint inhibitor alone,” Dr. Morris reported, providing some prospective data to support the concept of radiation serving as an in situ vaccine. “This suggests that we can take immunologically cold tumors in patients who would not have responded and render them responsive.”
Sorting the Results
ANOTHER STUDY presented at the 2018 ASCO Annual Meeting looked at stereotactic body radiotherapy together with nivolumab vs nivolumab alone in patients with head and neck cancer.4 “This study did not show a benefit as of yet in terms of survival. Response rates did not appear to be different, whether patients seek radiation therapy or not. So, this is clearly not a black-and-white answer clinically yet,” Dr. Morris noted.
“We still have, much to learn, and I think it is fair to expect we would see negative studies coming out. This will take a while to sort out,” Dr. Morris said, noting the many variations in how to administer radiation therapy, new and emerging immunotherapeutic agents, and various potential combinations.
WITH RADIATION therapy alone, there are several variables to be considered. They include timing of treatment, the ideal dose and how much to fractionate, as well as the type of radiation therapy (ie, protons, brachytherapy, or any other type that may be more or less beneficial). Dr. Morris raised several related questions: “Is it beneficial to try to tap into different mechanisms by giving very high doses to a portion of the tumor and moderate to low doses to other portions of the tumor? How much of the target do we need to cover, and what organs may be at risk? Do we need to avoid blood pooling and bone marrow?”
“The number of tumors we treat as well as the dose used may have profound impacts on the in situ vaccine effect.”— Zachary S. Morris, MD, PhD
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Dr. Morris pointed out that lymphocytes are among the most sensitive cells in the body to radiation, and “the percentage of immune cells that are exposed to radiation increases with the number of fractions given.” Data suggest that a more fractionated approach may increase the likelihood of lymphopenia. “Our concepts of how we think about delivering radiation may need to be reconceptualized in the era of immunotherapy,” Dr. Morris said.
“The different tumors we treat may interact with one another,” he continued. “If we give radiation to a single tumor, we may see changes in the relative rate of effector to suppressor immune cells over time. However, an unradiated tumor essentially acts as a reservoir of tumor-specific suppressor cells, and they can migrate to and repopulate the targeted tumor. We don’t see those changes in effector/suppressor ratios in untreated tumors. We can overcome that by giving low-dose radiation to those distant sites. So, the number of tumors we treat as well as the dose used may have profound impacts on the in situ vaccine effect.” ■
DISCLOSURE: Dr. Morris is an advisor for and has equity in Archeus Technology LTD, and research agreements with AstraZeneca, Bristol-Myers Squibb, Nektar, Innocrin, Seneca Therapeutics, and Apeiron.
1. Morris ZS: Combining immunotherapy with radiotherapy. 2018 Lurie Cancer Center Multidisciplinary Head and Neck Cancer Symposium. Presented November 11, 2018.
2. Formenti SC, Rudqvist NP, Golden E, et al: Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 24:1845-1851, 2018.
3. Theelen W, Peulen H, Lalezari F, et al: Randomized phase II study of pembrolizumab after stereotactic body radiotherapy versus pembrolizumab alone in patients with advanced non-small cell lung cancer: The PEMBRO-RT study. 2018 ASCO Annual Meeting. Abstract 9023. Presented June 3, 2018.
4. McBride SM, Sherman EJ, Tsai CJ, et al: A phase II randomized trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma. 2018 ASCO Annual Meeting. Abstract 6009. Presented June 1, 2018.