Brachytherapy: Perspectives for combined treatments with immunotherapy.

Combining brachytherapy with immunotherapies, particularly immune checkpoint inhibitors (ICIs), is a promising approach for potentiating both local control of the tumor and fully exploiting the synergies between pharmaceutic immunomodulation and radiotherapy. Compared to other radiotherapy techniques, BT has a potential to better spare lymphatic drainage areas and gut microbiota, thus reducing the immunosuppressive effects of radiation therapy. In addition, it delivers a broad range of doses due to inherent dose inhomogeneity within the implanted volume. This variability increases the probability that immune infiltrates would be activated, particularly since the optimal dose for immune activation is not yet firmly established. Even if preclinical models show that radiotherapy can stimulate immune responses, it can also induce toxic effects on immune effectors and combination trials show conflicting outcomes. There is a need for refining radiation modalities to enhance immune potentiation. The dosimetric specificities of BT may offer various advantages and should be explored further. Scarce clinical data on combining brachytherapy with ICIs in advanced cancer suggest potential benefits, with case reports of complete local responses and abscopal effects. However, validation requires a large number of patients in randomized clinical trials for which ideal design is discussed. In parallel with ongoing clinical developments, there is a need to refine preclinical models in order to better analyze the specific biological effects involved in BT, in light of immunomodulatory systemic treatments.