ABSTRACT: Although it is usually described as an immunosuppressive modality and not thought of as immunotherapy, there are new preclinical evidences suggesting that high-dose ionizing irradiation (IR) results in direct tumour cell death and augments tumour-specific immunity, which enhances tumour control both locally and distantly. Importantly, IR effects exceed the classical cytocidal properties by also causing phenotypic changes in the fraction of surviving cells, markedly enhancing their susceptibility to T cell-mediated elimination. However, not all IR-induced modifications of the tumour and its microenvironment favor immune rejection. The tumour microenvironment is populated by various types of inhibitory immune cells including Tregs, alternatively activated macrophages, and myeloid-derived suppression cells (MDSCs), which suppress T cell activation and promote tumour outgrowth. Chiang et al. showed the accumulation of pro-tumourigenic M2 macrophages in areas of hypoxia present in irradiated tumours. IR then may also induced responses that are inadequate to maintain antitumuor immunity.
Close interaction between IR, T cells, and the PD-L1/PD-1 axis exsit and provide a basis for the rational design of combination therapy with immune modulators and radiotherapy. Deng et al. demonstrate that PD-L1 was upregulated in the tumour microenvironment after IR. Moreover, administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent mechanism. Concomitant with IR-mediated tumour regression, IR and anti-PD-L1 synergistically reduced the local accumulation of tumour-infiltrating MDSCs, which suppress T cells and alter the tumour immune microenvironment. Finally, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumours through the cytotoxic actions of TNF. Sagiv-Barfi et al, also demonstrated in 5 patients receiving atezolizumab and radiation therapy, at least stabilization of systemic progression in all patients and a RECIST partial response at systemic sites in 1 patient. Transient, grade 1-2 inflammatory adverse events (fevers, flu-like symptoms) occurred with no serious immune-related toxicities. Abscopal out-field effects of irradiation has also been described in addition to a reduction in circulating MDSCs in a melanoma patient treated with the anti CTLA-4 ipilimumab and radiotherapy.
Lastly, recent evidence demonstrates that loco-regional curative treatment with stereotactic ablative radiotherapy (SABR) is a good alternative as compared with conventional 3D RT for patients with solid tumour, with durable remissions and a low toxicity profile. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. For colorectal, non-small cell, and renal cell cancers, 1-year metastasis control rates ranged from 67 to 91%. Moreover, abscopal reponses in the setting of immune checkpoints inhibitors and radiotherapy combinations have been made in the setting of metastatic disease event in patients with extensive tumor burden. The goal of SABR is to deliver appropriate metastasis directed radiotherapy while minimizing exposure of surrounding normal tissues. Interestingly, the dose and fractionation employed modulate RT ability to synergize with immunotherapy. Vanpouille-Box et al, showed that immune response genes were differentially expressed in irradiated tumours by 8Gyx3 but not 20Gyx1. This highlight the interest of hypofractionated SABR acting as a "in situ tumour vaccine".
As hypofractionated SABR may, in addition to its good local control, increase the effectiveness of anti PD-L1, investigators aimed to investigate the efficacy and the tolerability of the combination of anti-PD-L1 antibody with SABR.
