Interview – Exploring interactions between radiotherapy and the immune system

Maarten Lambrecht, MD, PhD, Department of Oncology, KU Leuven – University of Leuven, Belgium

The modulation of molecular pathways that determine the patient response to radiotherapy might contribute to improving patient outcomes. What insights have been gained to date in this field of research that may be relevant in the years to come?

There is indeed a growing interest in the field of radiobiology and interactions between radiotherapy and molecular biology. In the last couple of years, there is a focus on the interaction between ionizing radiation and the immune system. We have observed that by exploiting the synergy between irradiation and the immune system, we can improve the treatment response. Furthermore, there is growing interest into the effect the immune system has on the specific toxicities caused by radiotherapy.

How can immunotherapy and radiotherapy be expected to interact?

Although radiotherapy is local treatment, it has been known for decades that there is an interaction between radiotherapy and the immune system. We know that an intact immune system is necessary for radiotherapy to be successful. In rare instances, even so-called abscopal responses can be observed where tumor responses are seen, located outside of the radiation field. However, it has been very difficult to harness this synergy. Over the last years, however, our understanding of the basic biology of this synergy has increased considerably. Now we know that radiotherapy has synergistic effects on the immune system through immunogenic cell death, release of cytokines and upregulation of major histocompatibility complex class I molecules that increase antigen presentation. On the other hand, irradiation can also have an immunosuppressive effect on the tumor microenvironment through upregulation of regulatory T cells or upregulation of the PD-L1 expression. The combination of agents such as checkpoint inhibitors with ionizing radiation is very promising because it can actually counteract the immunosuppressive features that are sometimes found in tumors. This way, radiotherapy can be used to prime the immune system like a sort of in-situ tumor vaccination in combination with different types of immunotherapy.

What is new with respect to non-invasive imaging biomarkers in oncology?

Generally, the major evolution in non-invasive imaging biomarkers in oncology over the last years has been the introduction of artificial intelligence. There is a lot of research going on in an attempt to identify non-invasive imaging biomarkers for both tumor response and the prediction of toxicity. Many promising data are emerging. So far, the big problem has been the validation of these results. For this we need a lot of data. Finding a standardized way to obtain these data and using all clinically relevant data to confirm certain imaging biomarkers will be the challenge in the years to come. However, these efforts can result in improving the prediction of patient outcomes.

What are your personal highlights from ESMO 2020?

For me as a radiation oncologist specializing in thoracic oncology, the ESMO Congress held three highlights. The first one was the presentation of the 4-year overall survival data of the PACIFIC trial that assessed the value of durvalumab as consolidation therapy in patients with stage III, unresectable NSCLC [1]. According to the analysis, the addition of durvalumab increased OS, with a 4-year rate of nearly 50 % which is unprecedented in this patient population. This finding, together with manageable toxicity, is good news for this population that generally has a dismal outcome. It serves as an example where we see that the interaction between radiotherapy and immunotherapy has increased OS in patients without metastatic disease.

The second important abstract revealed rather disappointing results. The phase II STIMULI trial evaluated consolidation with nivolumab and ipilimumab in patients with limited-disease SCLC [2]. Similar to the PACIFIC trial, STIMULI tested a very promising combination of double immunotherapy with radiotherapy. However, the study failed to show any PFS benefit. This was very disappointing, as while checkpoint inhibition has demonstrated some activity in SCLC stage IV disease, the investigators did not observe the same effect in the limited-disease population. What they did see was an excess in toxicity in the consolidation arm. However, only a very limited proportion of patients in the experimental arm actually received sufficient immunotherapy, so the combination treatment was not completed in the majority of cases.

The third highlight was the LungART trial, which is an important study for radiation oncologists as it deals with the addition of postoperative radiotherapy in patients with stage III (N2), resectable NSCLC [3]. Patients were randomized to postoperative radiotherapy versus observation. We saw that this population did not derive any survival advantage from the addition of postoperative radio­therapy to standard treatment.

REFERENCES

1. Faivre-Finn C et al., Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase PACIFIC trial. ESMO 2020, LBA49
2. Peters S et al., Consolidation nivolumab and ipilimumab vs observation in limited stage SCLC after chemo-radiotherapy – results from the randomized phase II ETOP/IFCT 4-12 STIMULI trial. ESMO 2020, LBA84
3. Le Péchoux C et al., An international randomized trial comparing post-operative radiotherapy (PORT) to no PORT, in patients with completely resected NSCLC and mediastinal N2 involvement. ESMO 2020, LBA3_PR

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