For decades radiation oncology clinicians have noted rare instances of abscopal effects, in which tumors outside of a localized irradiated treatment field appear to respond to treatment. Counterintuitively, radiotherapy appears to stimulate some facets of the immune system, and recent research implicates patients’ immune cells in radiation abscopal effects — raising the possibility that combining radiotherapy and immunotherapy could yield previously-untapped treatment synergies to improve tumor control. This research is advancing, most notably in the treatment of metastatic melanoma.

Radiotherapists have noted rare cases of antitumor effects outside of localized irradiated treatment fields — the so-called abscopal effect.1 Radiation-induced abscopal effects were long dismissed as anecdotal curiosities that occur too infrequently to be developed as a potential treatment strategy.1,2 But recent findings suggest that radiation abscopal effects are mediated by patients’ immune systems.

If true, then combined radiation and immune therapy regimens might leverage interactions between the 2 modalities, with radiotherapy helping to overcome tumor immune evasion to improve treatment efficacy.1 Progress is being made in the development of radioimmunotherapy strategies that can do just that, particularly in the management of advanced and metastatic melanoma.3-7 If these regimens improve treatment outcomes in large, well-designed prospective clinical trials, they will usher in a new era in radiotherapy, and with it, a new and unfamiliar constellation of treatment toxicities and patient-management challenges.

Is This Effect Immunological?

Localized adjuvant radiotherapy is used as a component of curative-intent treatment: irradiating the unresected margins around surgically excised tumors to kill residual microscopic tumor cell populations or to slow tumor progression as palliative therapy. Ionizing radiation is cytotoxic; it kills tumor cells via oxidative stress and damage to DNA, which can either halt cellular division or induce apoptosis.

Preclinical research has shown that ionizing radiation improves immune T-cell vigilance against tumors.1,3,4 Separately, preclinical findings among researchers who were developing immune checkpoint blockade and other immunotherapies also suggested that radiation enhanced antitumor immunity.1,3,8-10 As immunotherapies were tested clinically, cases of radiation abscopal effects were reported among patients who had received immunotherapy for advanced melanoma.4,11,12 A retrospective study of 98 patients with non-small-cell lung cancer (NSCLC) enrolled in a clinical trial of pembrolizumab immunotherapy found that those who had previously received radiotherapy saw longer progression-free survival than those who had not undergone radiotherapy.13

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One hypothesis is that radiation abscopal effects result from the creation of in situ anticancer vaccines from irradiated tumor cells, with destroyed malignant cells’ neoantigens being freed as cells break up, making them more apparent to the immune system.1-3 If that is the case, combining radiation and immunotherapy could have considerable potential for treating early-stage cancers by increasing antitumor immunity before progression and metastasis.1