An abscopal (from Latin ab-scopus, away from the target) response describes tumour regression at sites distant to an irradiated field, and is a rare event seen in patients with various types of metastatic tumours receiving palliative radiotherapy to a single metastasis.1 To better understand the underlying mechanisms behind these observations, we established reproducible syngeneic murine models of metastases and studied whether adding immunotherapy to localised radiotherapy could result in abscopal responses, either in a distant non-irradiated tumour or in spontaneously developing metastases.2, 3
Dendritic cells have a pivotal role in the development of immunity.4 The differentiation of distinct subsets of dendritic cells from bone marrow precursor cells was previously shown to be induced by the growth factors Flt3-L and granulocyte-macrophage colony-stimulating factor (GM-CSF).5, 6 Thus, our first in-vivo proof-of-principle experiment consisted of treating mice with Flt3-L in combination with radiotherapy in a syngeneic mammary carcinoma model with bilateral 67NR flank tumours.2 We recorded abscopal responses in the non-irradiated tumours when radiotherapy was combined with Flt3-L. Abscopal responses were found to be effector T-cell mediated and tumour-specific.2 Hence, this and subsequent studies provided evidence that, when combined with immunotherapy, local radiotherapy can induce an immunogenic type of tumour cell death that contributes to pro-inflammatory signalling, improves dendritic cell cross-priming of effector T cells, increases T-cell repertoire diversity, enhances lymphocyte trafficking, and helps to overcome the immunosuppressive tumour microenvironment.7, 8, 9, 10 Most notably, abscopal responses emerged as valid surrogates for the establishment of radiation-induced anti-tumour immunity.2, 3, 9, 11, 12, 13
Research in context
Evidence before this study
We searched PubMed for the terms “abscopal”, “granulocyte/macrophage colony-stimulating factor (GM-CSF)”, “radiation and immunity”, and “tumor vaccine”, before the start of this study on April 7, 2003. No language restriction was used. We identified several trials using GM-CSF to stimulate dendritic cell activity. Additionally, we identified several case reports of abscopal responses to radiotherapy. However, no trials of combining radiotherapy with GM-CSF to elicit immune-mediated abscopal responses were previously reported.
Added value of this study
In a proof-of-principle clinical trial, we show that the combination of radiotherapy with GM-CSF can produce objective abscopal responses in patients with metastatic solid tumours.
Implications of all the available evidence
A strategy to enhance dendritic cell cross-priming contributed to the immunomodulating effects of radiotherapy. Radiation and immunotherapy trials should integrate many strategies to overcome the immunosuppressive setting of established tumours.
Similar to Flt3-L, GM-CSF is a potent immune adjuvant to dendritic cell maturation tested in several dendritic cell-based tumour vaccine trials.14 For example, in a murine melanoma model, vaccination with irradiated melanoma cells engineered to secrete GM-CSF, stimulated a robust and long-lasting anti-tumour immunity.14, 15 Likewise, sipuleucel-T (the first clinically successful dendritic cell-based vaccine, containing GM-CSF) improved overall survival in patients with castration-resistant prostate cancer, when compared with placebo (hazard ratio [HR] 0·78, 95% CI 0·61–0·98; p=0·03).16
Recent interest in cancer immunotherapeutics includes testing combinations with radiotherapy.17 For instance, the concurrent administration of low-dose radiotherapy (4 Gy divided in two fractions) with the intratumoral injection of the TLR9 agonist, PF-3512676 (a dendritic cell activator that contributes to the presentation of engulfed tumour antigens to T cells), established an in-situ vaccine that contributed to the systemic regression of low-grade B-cell lymphoma.18
Anecdotal clinical cases of abscopal responses to immunotherapy and radiation have been reported.12, 13, 18, 19, 20 These reports have fuelled dozens of prospective trials testing the combined effects of radiotherapy with various immunotherapies, with the overarching aim of enhancing individual anti-tumour immunity.21 This is reflected by the identification of several key immune-intervening sites targeted by conventional treatments together with immunotherapies to potentiate anti-tumour immunity, including the controlled release of cryptic antigens from dying tumour cells, the improvement of dendritic cell antigen presentation, the production of anti-tumour T-cell responses, the reversal of tumour-associated immune suppression, tumour cytoreduction, regulatory T-cell depletion, and the enhancement of tumour cell immune susceptibility.22, 23
About 13 years ago, we hypothesised that local radiotherapy and improved dendritic cell activation can contribute to the generation of abscopal responses. Herein, we report our long-term results of a proof-of-principle clinical trial, testing whether local radiotherapy and the subcutaneous administration of GM-CSF might induce abscopal responses in metastatic solid tumours.24, 25