1. Goodwin, Peter M.

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TURIN, Italy-A phase I clinical trial has been launched following findings from an experimental study in mice showing that radiotherapy combined with the immunocytokine L19 inerleukin-2 (L19-IL2) had a synergistic anti-tumor effect and also brought long-lasting anti-tumor benefits outside the field of radiation-a so-called abscopal effect. The research was reported at the 2016 European Society for Radiotherapy and Oncology Annual Meeting (ABSTRACT OC-0234).

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The study found increases of CD4-positive T cells capable of inhibiting tumor development following irradiation that lead author Nicolle Rekers, MSc, from Maastricht University Medical Centre in the Netherlands, said was "extending immunological memory" creating the durable anti-tumor boost to immunotherapy beyond the field of radiation.


"Radiotherapy creates damage to the tumor and that makes it more easy for the immune system to detect," Rekers told Oncology Times, explaining that this was why they were now looking for this effect in humans with oligometastatic solid tumors in the new phase I clinical study (NCT02086721).


"Seventy-five percent of all the tumors [in the mice] were cured," she said, and she noted these animals were later found to have high expression of CD127 on their T cells-a marker for immunological memory-which explained why they were not able to form new tumors when re-injected with cancer cells 150 days later. She was impressed by the fact that none of the mice cured by the combination therapy developed new tumors while all of the untreated mice of the same age went on to develop cancers.


Rekers said the two arms of the immunoconjugate-IL2 stimulating the immune system and L19 delivering this to the tumor-made it a perfect match with radiotherapy to achieve a durable abscopal effect.


Radiation Plus Immunotherapy

Daniel Zips MD, Chair of Radiation Oncology at the University of Tubingen in Germany, told Oncology Times he thought the findings of an abscopal effect were promising. Patients could potentially be treated in the future with a combination of radiation and immunocytokines such as L19-IL2 that target tumor vasculature.


"It's very exciting because that supports a concept now taken into the clinic that there is a specific synergy between radiation plus immunotherapy," he said, adding that an abscopal effect could extend the synergy to improve responses to immunotherapy afterward and inhibit distant metastases later on.


"So it could be of benefit for the patient to have radiation while receiving immunotherapy," he said.


When Zips was asked how radiation could achieve such an "off-target" effect, he theorized radiation triggers immune response by destroying tumor cells. "So there will be antigens presented to the immune system. And the immune system will then be effective against tumor cells-both in the irradiated site, but also outside the radiation field in the whole body," he explained.


And Zips was confident about the potential for potentiating similar anti-tumor mechanisms in humans using such techniques. "The study results are very promising and definitely support taking this further into a clinical trial," he said, adding there was promise for improving outcomes in both advanced and metastatic disease.


Rekers pointed out that 150 days was a relatively long portion of a mouse's lifespan-typically about 2 years-attesting to the durability of the abscopal effect protecting them from the experimental injections of cancer cells. "[But] these mice are models of human disease and can never be 100 percent comparable with a patient," she said.


She said that, because L19-IL2 was known to be safe in patients, the new clinical trial would test whether combining it with radiation could increase progression-free survival in humans by attacking primary tumors and metastases.


Rekers noted that, although reprogramming the immune system was a new science, it was without damaging long-term effects. "We believe that the risk-to-benefit equation is likely to come down firmly on the side of benefit," she said.


ESTRO President Philip Poortmans, MD, PhD, Professor of Radiation Oncology at Radboud University in Nijmegen, The Netherlands, commented that following the recent breakthroughs of immunotherapy in medical oncology, researchers are on the verge of an exciting new era that combined this with radiation therapy. "This could open the door to shorter treatment durations reducing side effects and costs, as well as to potentially new curative options where we had none before," he concluded.


Peter M. Goodwin is a contributing writer.