Radiation Plus Immunotherapy Produces Abscopal Metastases Response

Immunotherapy induces tumour response in metastases outside of radiotherapy tissue target

medwireNews: A proof-of-principal trial has confirmed that radiotherapy given alongside granulocyte–macrophage colony-stimulating factor (GM-CSF) can induce an abscopal response, defined as immune-mediated tumour regression at sites distant to the irradiated field.

“A strategy to enhance dendritic cell cross-priming contributed to the immunomodulating effects of radiotherapy”, explain Silvia Formenti, from Weill Cornell Medical College in New York, USA, and team.

“Radiation and immunotherapy trials should integrate many strategies to overcome the immunosuppressive setting of established tumours.”

The study, published in The Lancet Oncology, included patients with stable or progressive metastases receiving single-agent chemotherapy or hormone therapy for at least three distinct disease sites.

Patients were assigned to receive 35 Gy of radiation in 10 fractions over 2 weeks targeted at one metastatic site alongside daily GM-CSF injections beginning in the second week of radiotherapy. A second course of treatment was directed at another distinct site.

A partial abscopal response, defined as a decrease of 30% or more in the longest diameter of at least one measurable non-irradiated lesion, was achieved in 27.6% of the first 29 patients treated, and 26.8% of the overall 41 patients accrued (including four patients whose imaging was non-assessable and were counted as non-responders).

Partial abscopal responses were reported for five breast cancer patients and two thymic cancer patients. In addition, two patients with non-small-cell lung cancer achieved complete abscopal responses, with the disappearance of a measureable non-irradiated lesion, and two had partial responses. The majority (72.7%) of patients who responded had three lesions and none had more than six.

Patients with progressive disease had higher white blood cell counts and a greater ratio of neutrophils to lymphocytes than those with stable disease or an objective response. Noting that neutrophils suppress activated T cells and immunosuppressive macrophages, the team suggests that a low baseline ratio could act as a Biomarker for patients most likely to achieve an abscopal response to GM-CSF and radiotherapy.

“Conversely, drivers behind [a] raised neutrophil to lymphocyte ratio might hinder the success of harnessing radiotherapy and GM-CSF to convert a metastasis into an immunising hub”, the researchers comment.

Silvia Formenti and co-authors hypothesise that, based on earlier study findings, combining GM-CSF and radiotherapy with treatment targeting the programed cell death protein 1/programmed death-Ligand 1 pathway or the cytotoxic T lymphocyte-associated protein 4 may enhance the abscopal response.

“In the USA, about 50 clinical studies are currently testing the addition of radiotherapy to various immunotherapeutic strategies in attempts to determine the best dose combinations, fractionation schedule, and patient selection criteria to optimise this treatment paradigm”, they conclude.

Reference

Golden EB, Chhabra A, Chachoua A, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015; Advance online publication 18 June. DOI: dx.doi.org/10.1016/S1470-2045(15)00054-6

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