Interview With the Expert
Prof. Dr. Udo Gaipl
1. What are the immune modulating effects of radiation?
The key aim of radiotherapy for tumor treatment is still the induction of damage in the inherited material (DNA) of the tumor cells, which, in the best case, results in tumor cell death. But it has become evident that radiotherapy also impacts on the immune system. However, immune modulation by radiotherapy has to be regarded as a double-edged sword. One the one hand, radiotherapy can induce immunogenic cancer cell death (ICD), resulting in immune activation against the tumor. On the other hand, radiation increases immune suppressive immune-checkpoint molecules (e.g. PD-L1) on the surface of tumor cells, just to mention two prominent examples of immune modulation by radiotherapy.
These facts call for a combination of the classical tumor therapies with immunotherapy that either further enhances immune activation or counteracts therapy-induced immune suppression: push the "throttle control" or "release the break" by immunotherapy!
2. How does hyperthermia contribute to an immune stimulatory micro-environment?
It has been demonstrated, mainly with pre-clinical model systems, that a combination of radiotherapy with hyperthermia fosters the induction of immunogenic cancer cell death. One can conclude that hyperthermia strengthens the radiation-induced immune activation and thereby contributes to the induction of anti-tumor immune reactions. It has to be stressed that the form of heat application also contributes to these processes. Ongoing work is currently investigating the immunogenicity of microwave-induced heat via conventional heating. Initial results point towards advantages of microwave-heating in this context.
3. What is the benefit of radioimmunotherapy?
If the immune system recognizes a tumor (strong endogenous anti-tumor immune response), the tumor tries to escape the immune attack by up-regulation of immune suppressive immune-checkpoint molecules such as PD-L1. Here single therapies with immune-checkpoint inhibitors are often sufficient; however, only about 10-15% of the patients actually respond very well. This calls at this point for better patient stratification in the future.
If a weak, endogenous, anti-tumor immune response dominates, the first therapeutic aim is to increase it. This can be achieved by immunogenic therapeutic agents, by radiation, by vaccination and by immune stimulation with hyperthermia. However, again, the tumor tries to escape the immune attack by up-regulation of immune suppressive immune-checkpoint molecules. This would necessitate the combination of classical tumor therapies with hyperthermia and immune-checkpoint inhibition.
4. What are the prerequisites for these combined therapies – which patients benefit?
Radiotherapy as in situ vaccine can generally work for all patients. However, one should test whether the tumor becomes immunogenic or not. Another term for that is to turn a "cold" tumor into a "hot" one. This means that the infiltration of immune cells that attack the tumor is increased following local treatment by e.g. radiotherapy. This stratification for patients for further combined therapies is currently being followed up on in clinical trials, such as the Checkrad-CD8 trial (NCT03426657) for locally advanced HNSSC. One could speculate that hyperthermia may add to radiotherapy also in the way that "cold" tumors become "hot". However, data on this is still scarce and under current investigation.
5. Which patients do not benefit from radioimmunotherapies?
If the patient’s tumor cannot be turned into an immunogenic one, they do not benefit from radio(chemo)immunotherapies. Another key indicator whether a response can be expected is the tumor mutational burden. Clinical trials have already shown that tumors with higher mutation characteristics respond much better to immunotherapy. This is independent of the tumor entity in many cases. And, as mentioned above, the immune microenvironment is another key predictor as to whether patients might benefit or not.
6. What do clinicians have to consider with radio(chemo)immunotherapies?
The big advantage is that locally applied therapies (such as radiotherapy and hyperthermia) can result in systemic anti-tumor immune responses: the so-called abscopal affects. Therefore, in clinics, not only the primary tumor should be thoroughly monitored, but also the metastatic sites.
Of special note is that, due to increased immune-cell infiltration into the tumors, their size can increase primarily. This "pseudoprogress" has to be distinguished from a "real" progress. For this, a consensus guideline – iRECIST - was developed by the RECIST working group for the use of modified response evaluation criteria in solid tumors (RECIST version 1.1) in cancer immunotherapy trials.
Further, new side effects have to be considered, since by activating the immune system autoimmune reactions also increase. The fear was great, but even though side reactions do increase, very severe ones are seldom observed and normally can be managed by adequate medication.
7. What are the future developments?
Radio(chemo)immunotherapy with checkpoint inhibitors is beneficial, but only about 15-20% of the patients respond well. This is in part due to the fact that checkpoint inhibitors can only restore a pre-existing, but suppressed immune response. To generate a new one, vaccination should be the approach in the future in a multimodal setting. Here, hyperthermia can contribute as in situ vaccine by rendering the tumor micro-environment in sum immunogenic. Even though much pre-clinical data exists on immune stimulatory effects of radiotherapy and hyperthermia, randomized clinical trials are needed in the future to define the most beneficial combinations for the patients. Here, stratification of patients is important, based on genetic (mutational burden) and immunological markers.
Thank you for taking the time to talk to us.
Prof. Gaipl was speaking to Monica Sennewald, Dr. Sennewald Medizintechnik GmbH