rel="nofollow" href="#ulink_0e43c02e-7848-50ab-93f5-22aea5cc7ed0">61–63]. However, irradiation alone only rarely leads to antitumour immune effects in patients, and abscopal effects have only been described in a few case reports. This might be explained by the upregulation of immunosuppressive mechanisms, like the induction of Treg cells and a possible Th2 polarisation after irradiation [64, 65]. Tumours might also be able to upregulate PD-L1 after irradiation [66].
Combination Concepts
Combination of Irradiation and Immune Checkpoint Inhibition
As immune checkpoint inhibition is the most advanced modality for cancer immunotherapy, the combination with irradiation has been evaluated in a number of preclinical and clinical studies. CTLA-4 blockade showed enhanced local and distant control in combination with irradiation in in vivo models of breast cancer, colorectal cancer, and glioma [67–69]. Similar results have been reported for the combination of radiation with PD-1 blockade [70, 71]. However, the first clinical data showed only limited additive or synergistic activity of combination regimens compared to immune checkpoint inhibition alone in melanoma [72] and prostate cancer [73, 74]. The limited success might be due to the selection of patient cohorts, suboptimal radiation regimes, or problems in timing [75]. In vivo studies also suggest that triple combination of CTLA-4 blockade, PD-1 blockade, and radiation might be able to overcome resistance mechanisms [66]. Ongoing clinical trials in different cancer entities (for example CTLA-4 blockade, summarised by Vanpouille-Box et al. [75]) will show whether and how patients might benefit from combination therapies.
Antigen Release through Irradiation and Cancer Vaccines
The immunogenic cell death induced by irradiation can synergise with anticancer vaccines. The combination has been evaluated for dendritic cell vaccines, whole-tumour cell vaccines, and viral vaccines, as well as peptide and nucleic acid vaccines [76].
For virus-induced cancers, irradiation might be combined with vaccines targeting the respective virus. One example is HPV-associated head and neck cancer, where preclinical data have shown pronounced combination effects [77]. RNA-based vaccination in combination with irradiation has been evaluated for a Lewis Lung Cancer model and showed promising results [78], so that the concept has been translated into a clinical phase Ib trial [79]. A poxvirus-based vaccine was evaluated in combination with curative radiotherapy for prostate cancer [80]. However, the long-term follow-up did not show a significant difference to standard treatment concerning prostate-specific antigen control and immune responses [81].
T Cell Effects and T Cell-Engaging Therapy
One of the main immunological effects of irradiation is to facilitate T cell infiltration in tumours. Non-irradiated tumours often have a tumour-suppressive microenvironment with the T cells present located at the borders of the tumour without being able to exert their antitumour function. Irradiation can change this picture and T cells will enter the tumours and begin to be activated [57, 58]. This is the rationale for combining irradiation with T cell-engaging therapies. Chimeric antigen receptor T cells as well as T cell-engaging bispecific antibodies are able to transform every intratumoural T cell into an antitumour T cell irrespective of their T cell receptor specificity [82–84] so that the combination with irradiation might elicit additive or synergistic effects. Yet, the first preclinical data showed a dependency of response on initial tumour size with a negative effect of combination treatment on tumour control for some subgroups [85].
Fig. 1. Antitumour immune responses are dependent on neoantigen presentation by dendritic cells and dendritic cell activation leading to T cell activation and expansion. Tumour-targeting T cells have to enter the tumour and overcome the immunosuppressive tumour microenvironment. Different immunotherapeutic strategies alter this process at different stages and might be beneficial in combination with irradiation based on different conceptual ideas of interaction, as displayed.
Tumour Microenvironment and Cytokine-Based Therapies
The tumour microenvironment engages different tumour-suppressive mechanisms, which might even be more pronounced after irradiation. Immunocytokines are able to overcome this immunosuppression and have shown antitumour effects, also in combination with irradiation. IL-2-based immunocytokines evaluated in combination with irradiation are L19-IL2 and NHS-IL2. L19-IL2 targets the tumour neovasculature and has shown antitumour effects in combination with irradiation preclinically [86, 87], even in an MHC-I-deficient cancer model [88]. NHS-IL2, targeting tumour necrosis by binding to extracellular DNA-histone complexes, achieved synergistic antitumour activity with irradiation preclinically and in a phase Ib study [89]. NHS-IL12 has shown antitumour activity on its own [90, 91] and in combination with different anticancer treatments [42]. Irradiation has been shown to increase intratumoural bioavailability of the construct [92] and to synergise with NHS-IL12 for antitumour activity and abscopal effects [97].
Table 1. Different classes of immunotherapies already utilised in combination with radiotherapy in clinical trials according to Golden et al. [96], with an explanation of the mode of action
