Emerging evidence for adapting radiotherapy to immunotherapy

• Published in: Nature reviews. Clinical oncology Vol. 20; no. 8; pp. 543 - 557
• Main Authors: Galluzzi, Lorenzo, Aryankalayil, Molykutty J., Coleman, C. Norman, Formenti, Silvia C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2023; Nature Publishing Group
• Subjects: 631/250/580/1884; 631/67/2329; 631/67/580; 692/699/67/1059/2325; 692/699/67/1059/485; Clinical trials; Combined Modality Therapy; Fitness; Humans; Immune response; Immunization; Immunostimulation; Immunotherapy; Malignancy; Medicine; Medicine & Public Health; Neoplasms - radiotherapy; Oncology; Radiation Oncology; Radiation therapy; Radiotherapy; Review Article; Toxicity
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-023-00782-x

Immunotherapy has revolutionized the clinical management of many malignancies but is infrequently associated with durable objective responses when used as a standalone treatment approach, calling for the development of combinatorial regimens with superior efficacy and acceptable toxicity. Radiotherapy, the most commonly used oncological treatment, has attracted considerable attention as a combination partner for immunotherapy owing to its well-known and predictable safety profile, widespread clinical availability, and potential for immunostimulatory effects. However, numerous randomized clinical trials investigating radiotherapy–immunotherapy combinations have failed to demonstrate a therapeutic benefit compared with either modality alone. Such a lack of interaction might reflect suboptimal study design, choice of end points and/or administration of radiotherapy according to standard schedules and target volumes. Indeed, radiotherapy has empirically evolved towards radiation doses and fields that enable maximal cancer cell killing with manageable toxicity to healthy tissues, without much consideration of potential radiation-induced immunostimulatory effects. Herein, we propose the concept that successful radiotherapy–immunotherapy combinations might require modifications of standard radiotherapy regimens and target volumes to optimally sustain immune fitness and enhance the antitumour immune response in support of meaningful clinical benefits. Radiotherapy has several key attributes that make it an attractive combination partner for immunotherapy; however, numerous clinical trials investigating the combination of these two treatment modalities have failed to demonstrate clear improvements in patient outcomes. In this Review, Galluzzi and colleagues discuss the evidence indicating that radiotherapy administered according to standard schedules and target volumes might impair immune fitness and, therefore, propose that adaptation of the radiotherapy regimens to immunotherapy (and not vice versa) might synergistically enhance the antitumour immune response to achieve meaningful clinical benefits. Key points Numerous clinical studies investigating radiotherapy as a combination partner for immunotherapies, particularly immune-checkpoint inhibitors, failed to reveal a therapeutic benefit over either treatment modality alone. In this context, radiotherapy has often been applied according to conventional regimens and/or target volumes, with limited consideration for potential radiotherapy-driven immunomodulation. Conventional radiation doses and fractionation schedules might result in robust immunosuppression in the tumour microenvironment, at least in part reflecting the repeated killing of circulating immune effector cells. Conventional radiotherapy target volumes are also expected to exacerbate local and systemic immunosuppression given that they often include tumour-draining lymph nodes (which are key sites for the initiation of anticancer immunity) and circulating immune cells. Multiple cellular alterations elicited by radiotherapy are temporally dynamic, suggesting that the treatment schedule (relative timing and sequencing) is a major determinant of the efficacy of radiotherapy–immunotherapy combinations. We surmise that improved radiotherapy regimens and target volumes might enable the development of radiotherapy–immunotherapy combinations with superior clinical activity, at least in some patient populations.