Immuno-Radiotherapy for brain glioma: sorting out the immunomodulatory effects of radiotherapy

BACKGROUND. Glioblastoma (GBM) is a fast-growing and aggressive brain tumor. GBM is the most frequent malignant primary brain tumour and it can result in death in three-six months, if untreated. The current standard of care (SOC) therapy consists in maximal safe surgical resection followed by radiation therapy and adjuvant temozolomide (Stupp protocol), with a median overall survival (OS) of 8-10 months. However, more than half of GBM patients die within one year from the diagnosis, and only 5% survive more than 5 years despite aggressive therapies. Research has now shifted additional attention to methods of modulating the innate immune system for the treatment of GBM. Moreover, radiotherapy, that plays a key role in GBM treatment, has the potential to convert immunologically ‘cold’ tumors into ‘hot’ tumors by a combination of distinct mechanisms. Overall, literature data indicate that local radiation produces systemic, immune-mediated anti¬tumour and, potentially, antimetastatic effects. Additionally, the combination of local radiotherapy and immune-modulation can augment local tumour control and cause distant (abscopal) antitumour effects through increased tumour-antigen release and antigen-presenting cell (APC) cross-presentation, improved dendritic-cell (DC) function, and enhanced T cell priming. In order to sort out the immunomodulatory effects of radiotherapy for brain glioma we conducted this project, also in association with immunetherapy. The radiological response has been evaluated as well. METHODS. Radiotherapy treatment in combination with dendritic cell immunotherapy was evaluated. GL261-glioma bearing immune-competent mice were treated by means of RT (3 fractions, 1 fr/day) as exclusive and concomitant immunotherapy (dendritic cells). Two clinical trials were studied as well. The population was GBM patients treated by means of standard therapy plus DC-vaccine therapy. Response assessment of GBM after radio-chemotherapy and during immunotherapy by delayed contrast trams (treatment response assessment maps) was evaluated as well. RESULTS. Survival, CD8+ T, NK cells were significantly and slightly significant different: control vs RT vs RT-IT. We found that activated microglia persists in both tumor and contralateral brain of irradiated mice. Moreover, RT promoted antitumoral M1 polarization and RT contributed to a massive recruitment of Th1 CD4+ T cells; RT and DC combination contributes to a robust infiltrate of CD8+ T cells. CONCLUSION. Our results confirm that RT can modulate the TME creating a specific chemokine gradient involved in T cell homing. RT in combination with IT can induce an anti-tumour systemic long-lasting effector CD8+ T cell response as well as a local infiltration of NK cells and CD8+ T cells. The combinatorial approach seems to be a promising therapy for GBM patients. It might be evaluated trough other clinical trials in order to confirm the preliminary results.