Elsevier

The Lancet Oncology

Volume 16, Issue 7, July 2015, Pages 795-803
The Lancet Oncology

Articles
Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial

https://doi.org/10.1016/S1470-2045(15)00054-6Get rights and content

Summary

Background

An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer.

Methods

Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 μg/m2 subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simon's optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186.

Findings

From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simon's two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7–47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2–42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3–4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient.

Interpretation

The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area.

Funding

New York University School of Medicine's Department of Radiation Oncology and Cancer Institute.

Introduction

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

Section snippets

Study design and participants

Eligible patients were aged 18 years or older with histologically confirmed solid metastatic cancer and at least three distinct measurable sites of disease (≥1 cm). Eligible patients had adequate baseline organ and marrow function as defined by an absolute neutrophil count greater than 1500 cells per μL, platelet concentration of greater than 50 000 per μL, total bilirubin less than 1·5 times the upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase less than 2·5

Results

Patients were enrolled between April 7, 2003, and April 3, 2012. In stage 1 of the Simon's two-stage design, ten patients were enrolled, of whom eight were assessable with PET-CT, one patient was assessed clinically (skin lesions), and one patient was assessed with PET only. Four out of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled.

Two protocol amendments were made during the study. The first

Discussion

Abscopal responses rarely occur with radiotherapy alone. However, in an era when novel immunotherapeutics are being incorporated into cancer treatments, abscopal responses have been more frequently reported.12, 13, 18 However, a better understanding of the underlying mechanisms responsible for abscopal responses and that of its clinical value are warranted.

Overall, our study met its prespecified margin for activity, with more than 20% of patients having an abscopal response. When patients were

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