Comment
Local treatment of tumour masses by ionising radiation with additional immune stimulation could result in systemic and immune-mediated anti-tumour responses. The abscopal effect of radiotherapy for malignant lymphoma was described by Nobler1 in 1969 and has had a renaissance in the last decade when immunotherapies made their way into the clinics. Preclinical work has shown that, especially in melanoma, the combination of radiotherapy with immune checkpoint inhibitors such as anti-CTLA-4 and anti-PDL-1 antibodies results in CD8+ T-cell mediated anti-tumour responses far outside of the irradiated area.2 And in a case report of a patient with melanoma treated with radiotherapy and ipilumumab, immune alterations—eg, increased numbers of antigenpresenting cells and decreased numbers of myeloidderived suppressor cells—were noted in the peripheral blood.3 Combining local radiotherapy with further immune stimulation effectively turns the tumour into its own vaccine.4 In The Lancet Oncology, Encouse Golden and colleagues5 have explored the interaction between radiotherapy and immunotherapy for the first time in other solid metastatic tumours such as non-small-cell lung cancer and breast cancer. Combination of radiotherapy with immunotherapy stimulating the innate and adaptive immune system has already been shown to be feasible, but abscopal responses have not been assessed. Local tumour responses can be enhanced by combining radiochemotherapy with immunotherapy. It was believed for a long time that no synergy exists because of the immune suppressive properties of the classical tumour therapies. However, recent data clearly show that radiotherapy and chemotherapy can be combined with immunotherapy.6 In Golden and colleagues’ study,5 the combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) with radiochemotherapy resulted in abscopal responses in four (22%) of 18 patients with non-smallcell lung cancer and five (36%) of 14 patients with breast cancer. These findings emphasise that systemic anti-tumour immunity can be induced by rendering the tumour cells immunogenic. Radiotherapy alone is capable of enhancing MHC-I surface expression on tumour cells, releasing danger signals, and also broadens
the peptide pool.7 However, it is obviously not sufficient to induce abscopal responses, as proven by clinical observation in patients receiving radiochemotherapy. The immunological balance has to be pushed towards anti-tumour immunity, and addition of immunotherapy is the solution.8 Flt3-L and GM-CSF are both strong stimulators of dendritic cells. The Sipuleucel-T vaccine study9 for prostate cancer shows commonalities with the study of Golden and colleagues.5 Since no control group consisting of only GM-CSF was included in the study of Kantoff and colleagues9 the observed increase of median survival with the vaccine might also be due to GM-CSF and not the antigenic peptide. The abscopal anti-tumour responses were accompanied by stable low concentrations of neutrophils. A challenge for future research is to determine whether these stable concentrations, together with increasing amounts of dendritic cells and CD8+ T cells, might be predictors for radio-immunotherapy-induced abscopal responses. Further, correlations with quality of life of responding patients should be assessed, since metastatic lesions are the specific targets of such immune responses. Whether bone and spinal metastases respond differently compared with visceral metastases also needs to be explored, since their accessibility by the immune system is reduced. In patients with a high metastatic tumour burden, the induction of abscopal anti-tumour reactions could be a welcome means to palliate the disease when the immune evasion of the tumour is at a maximum. The continuing rapid development of more precise and sophisticated accelerators for delivery of ionising irradiation should allow us to investigate the immunological consequences of classical fractionated versus hypofractionated or stereotactic high-dose delivery. Current preclinical data are not conclusive. For instance, the combination of anti-CTLA-4 immunotherapy with fractionated but not hypofractionated radiotherapy induced abscopal antitumour responses in a mouse breast cancer model,10 whereas in a mouse model of melanoma, ablative radiotherapy was particularly immunogenic.11 The study by Golden and colleagues shows, for the first time, that abscopal anti-tumour responses can be induced in solid metastatic tumours by
www.thelancet.com/oncology Published online June 19, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00055-8
Larry Mulvehill/Science Photo Library
Radio-immunotherapy: the focused beam expands
Lancet Oncol 2015 Published Online June 19, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00055-8 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(15)00054-6
1
Comment
combining classical radiochemotherapy with simple immunotherapy. Nevertheless, randomised trials are needed for detailed assessment of the efficacy of radio-immunotherapy in inducing abscopal responses, in particular assessing the best combinations and chronology of treatments.
6
Benjamin Frey, Udo S Gaipl
7
Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitaetsstrasse 27, 91054 Erlangen, Germany [email protected]
8
4
5
9
We declare no competing interests. 1 2
3
2
Nobler MP. The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. Radiology 1969; 93: 410–12. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373–77. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366: 925–31.
10
11
Frey B, Rubner Y, Kulzer L, et al. Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 2014; 63: 29–36. 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; published June 19. http://dx.doi.org/10.1016/ S1470-2045(15)00054-6. van der Sluis TC, van Duikeren S, Huppelschoten S, et al. Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death. Clin Cancer Res 2015; 21: 781–94. Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol 2012; 39: 323–39. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58: 862–70. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–22. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not singledose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009; 15: 5379–88. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 2009; 114: 589–95.
www.thelancet.com/oncology Published online June 19, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00055-8
Local treatment of tumour masses by ionising radiation with additional immune stimulation could result in systemic and immune-mediated anti-tumour responses. The abscopal effect of radiotherapy for malignant lymphoma was described by Nobler1 in 1969 and has had a renaissance in the last decade when immunotherapies made their way into the clinics. Preclinical work has shown that, especially in melanoma, the combination of radiotherapy with immune checkpoint inhibitors such as anti-CTLA-4 and anti-PDL-1 antibodies results in CD8+ T-cell mediated anti-tumour responses far outside of the irradiated area.2 And in a case report of a patient with melanoma treated with radiotherapy and ipilumumab, immune alterations—eg, increased numbers of antigenpresenting cells and decreased numbers of myeloidderived suppressor cells—were noted in the peripheral blood.3 Combining local radiotherapy with further immune stimulation effectively turns the tumour into its own vaccine.4 In The Lancet Oncology, Encouse Golden and colleagues5 have explored the interaction between radiotherapy and immunotherapy for the first time in other solid metastatic tumours such as non-small-cell lung cancer and breast cancer. Combination of radiotherapy with immunotherapy stimulating the innate and adaptive immune system has already been shown to be feasible, but abscopal responses have not been assessed. Local tumour responses can be enhanced by combining radiochemotherapy with immunotherapy. It was believed for a long time that no synergy exists because of the immune suppressive properties of the classical tumour therapies. However, recent data clearly show that radiotherapy and chemotherapy can be combined with immunotherapy.6 In Golden and colleagues’ study,5 the combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) with radiochemotherapy resulted in abscopal responses in four (22%) of 18 patients with non-smallcell lung cancer and five (36%) of 14 patients with breast cancer. These findings emphasise that systemic anti-tumour immunity can be induced by rendering the tumour cells immunogenic. Radiotherapy alone is capable of enhancing MHC-I surface expression on tumour cells, releasing danger signals, and also broadens
the peptide pool.7 However, it is obviously not sufficient to induce abscopal responses, as proven by clinical observation in patients receiving radiochemotherapy. The immunological balance has to be pushed towards anti-tumour immunity, and addition of immunotherapy is the solution.8 Flt3-L and GM-CSF are both strong stimulators of dendritic cells. The Sipuleucel-T vaccine study9 for prostate cancer shows commonalities with the study of Golden and colleagues.5 Since no control group consisting of only GM-CSF was included in the study of Kantoff and colleagues9 the observed increase of median survival with the vaccine might also be due to GM-CSF and not the antigenic peptide. The abscopal anti-tumour responses were accompanied by stable low concentrations of neutrophils. A challenge for future research is to determine whether these stable concentrations, together with increasing amounts of dendritic cells and CD8+ T cells, might be predictors for radio-immunotherapy-induced abscopal responses. Further, correlations with quality of life of responding patients should be assessed, since metastatic lesions are the specific targets of such immune responses. Whether bone and spinal metastases respond differently compared with visceral metastases also needs to be explored, since their accessibility by the immune system is reduced. In patients with a high metastatic tumour burden, the induction of abscopal anti-tumour reactions could be a welcome means to palliate the disease when the immune evasion of the tumour is at a maximum. The continuing rapid development of more precise and sophisticated accelerators for delivery of ionising irradiation should allow us to investigate the immunological consequences of classical fractionated versus hypofractionated or stereotactic high-dose delivery. Current preclinical data are not conclusive. For instance, the combination of anti-CTLA-4 immunotherapy with fractionated but not hypofractionated radiotherapy induced abscopal antitumour responses in a mouse breast cancer model,10 whereas in a mouse model of melanoma, ablative radiotherapy was particularly immunogenic.11 The study by Golden and colleagues shows, for the first time, that abscopal anti-tumour responses can be induced in solid metastatic tumours by
www.thelancet.com/oncology Published online June 19, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00055-8
Larry Mulvehill/Science Photo Library
Radio-immunotherapy: the focused beam expands
Lancet Oncol 2015 Published Online June 19, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00055-8 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(15)00054-6
1
Comment
combining classical radiochemotherapy with simple immunotherapy. Nevertheless, randomised trials are needed for detailed assessment of the efficacy of radio-immunotherapy in inducing abscopal responses, in particular assessing the best combinations and chronology of treatments.
6
Benjamin Frey, Udo S Gaipl
7
Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitaetsstrasse 27, 91054 Erlangen, Germany [email protected]
8
4
5
9
We declare no competing interests. 1 2
3
2
Nobler MP. The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. Radiology 1969; 93: 410–12. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373–77. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 2012; 366: 925–31.
10
11
Frey B, Rubner Y, Kulzer L, et al. Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 2014; 63: 29–36. 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; published June 19. http://dx.doi.org/10.1016/ S1470-2045(15)00054-6. van der Sluis TC, van Duikeren S, Huppelschoten S, et al. Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death. Clin Cancer Res 2015; 21: 781–94. Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol 2012; 39: 323–39. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58: 862–70. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–22. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not singledose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009; 15: 5379–88. Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 2009; 114: 589–95.
www.thelancet.com/oncology Published online June 19, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00055-8
