Could radiotherapy make it possible to go beyond resistance to immunotherapy? This is what researchers from Johns-Hopkins (Baltimore) ‘university in collaboration with a Dutch team in a study conducted in 72 patients with non-small metastatic cells.
Radio-immunotherapy has induced a systemic anti-tumor response, including in cancers usually unavailable to checkpoint inhibitors, which has resulted in longer survival for patients with immunotherapy tumors. The results are published in Nature Cancer.
The ABSCOPAL (that is to say remotely) effect of radiotherapy had already been described when observing the rejection of the irradiated tumor but also of non-irradiated metastatic sites. Radiotherapy would have immunomodlative properties that are expressed remotely: post-radical cell death causes compounds to be released in the micro-environment, which in turn activate the cells of the immune system. Hence the idea of associating radiotherapy and immunotherapy. But if the combination is based on a strong rational, there was little clinical evidence of its effectiveness until then.
A multi-image analysis of remote tumors
In their study, American researchers have combed fine, through multi-ordinary analyzes (notably genomics and transcriptomic), biopsies of non-irradiated tumor tissue and blood samples taken from patients treated with Pembrolizumab, or alone (37), or associated with prior radiotherapy (35). A total of 293 tissue and blood samples were collected, in inclusion and between 3 and 6 weeks of treatment.
The team paid particular attention to so-called immunologically “cold” tumors, that is to say that usually do not respond to immunotherapy. Biomarkers make it possible to identify them: low load of tumor mutations (<300 mutations by exome), zero expression of PD-L1, mutations of the WNT track. The three were studied separately in the study: 43 patients presented a tumor with a low tumor transfer load, 41 one with zero expression of PD-L1 and 10 with WNT mutation.
The researchers first showed the absopal effect of radio-immunotherapy: with radiotherapy, non-irradiated tissues were significantly enriched in gamma interferon, alpha interferon and various antigen presentation sets. Furthermore, the expansion of T cell clones (new and pre -existing) both in remote tumors and in the blood was contemporary with reactive autologies T responses against neoantigens in participants with prolonged survival. “These results go in the direction of systemic immunomodulatory and antitumoral effects of radio-immunotherapy”underline the authors.
An elongated progression survival for cold tumors
What is more, the participants with cold tumors (whatever the biomarkers found) presented a longer progression survival in the group treated with radiotherapy. This observation coincided with an induction of systemic immune responses B and T, suggesting “A potential hot cold conversion of tumor micro-environment with radio-immunotherapy”, We read in the study.
“It was very exciting to complete the loop, said Dr Valsamo Anagnostou, a researcher at Johns-Hopkins and a senior author. We have not only captured the Abscopal effect, we also made the link between the immune response and the clinical prognosis for tumors where we did not expect to see an answer to immunotherapy. »»
The authors thus suggest that the benefits of radio-immunotherapy would be the largest in patients with a tumor resistant to immunotherapy. This would also explain why, until then, clinical trials with unreadmitted patients have given mixed results for radio-immunotherapy. This combination “Opens an opportunity in the therapeutic field to go beyond resistance to immunotherapy”summarize the authors. For the first author, it is even possible that these results, observed in the event of primary resistance, could find themselves “In case of acquired resistance”.
