Editors' ChoiceImmunotherapy

The ultimate combination immunotherapy

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Science Translational Medicine  18 Mar 2015:
Vol. 7, Issue 279, pp. 279ec44
DOI: 10.1126/scitranslmed.aaa9868

Cancer therapy typically involves some combination of surgery, radiation, and drugs. The latter includes chemotherapy agents that disrupt cell division, targeted therapies like small molecules that block a signaling pathway, and immunotherapy-like checkpoint blockade, which takes the brakes off the immune system to allow it to recognize and reject tumor cells. Combining these modalities is often a matter of clinical judgment or data obtained from large clinical trials.

Now, Twyman-Saint Victor et al. present data from a human trial combining radiation of an index lesion with one form of checkpoint blockade, anti-CTLA-4, and replicate it in a mouse trial of the same combination. Most patients and mice with widespread melanoma did not respond to the combination of anti-CTLA-4 and radiation, but examination of the resistant tumors in mice and humans demonstrated an overexpression of PD-L1. Mice treated with a combination of two checkpoint inhibitors, directed at both CTLA-4 and PD-L1/PD1, plus radiation, had greatly improved responses. Mechanistically, the authors discovered that each modality has a nonredundant mechanism of action on the immune system: Radiation increased the diversity of the repertoire of responding T cells, anti-CTLA-4 decreased the immunosuppressive Treg cells, and PD-1 blockade reinvigorated exhausted T cells and allowed them to expand. All three modalities were required for optimal responses in mice, which directly informs the optimal design of the next human trial.

The abscopal effect of radiation, whereby irradiation of a single lesion causes regression of distant tumor lesions, is an intriguing phenomenon with an unclear mechanism of action; even now, the radiation-induced widening of the T cell repertoire is not completely clear. Given this new understanding of the effects of radiation and checkpoint blockade on the immune system, there is hope that inducing the abscopal effect will become much more common for patients with melanoma and perhaps for patients with other cancers as well.

C. Twyman-Saint Victor et al., Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 10.1038/nature14292 (2015). [Abstract]

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