- Email: [email protected]
Combination of radiotherapy and immune treatment: First clinical data
G Model CANRAD-3784; No. of Pages 3
ARTICLE IN PRESS Cancer/Radiothérapie xxx (2018) xxx–xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Review
Combination of radiotherapy and immune treatment: First clinical data Combinaison de la radiothérapie et immunothérapie : premières données cliniques D. De Ruysscher ∗ Maastricht University Medical Center, Department of Radiation Oncology (Maastro clinic), GROW School for oncology and developmental biology, Maastricht, The Netherlands
a r t i c l e
i n f o
Article history: Received 5 June 2018 Received in revised form 13 July 2018 Accepted 18 July 2018 Keywords: Clinique immunotherapy Radiotherapy
a b s t r a c t There is a very strong biological and pre-clinical rationale for combining radiotherapy with immune treatment. Radiation affects all steps in the immune response to antigens and clearly upregulates key-molecules on the cancer cell and in the tumor micro-environment, such as MHC class I antigens, tumor-associated antigens and the creation of neo-antigens as well. In many pre-clinical models, radiation together with the right combination and timing of immune therapy leads to regression of distant metastases, at remote non-irradiated sites of the body, the so-called “abscopal effects”. The combination generally also increases the local tumor control. Although a plethora of clinical trials are ongoing or are being planned, clinical data are sparse and mostly even retrospective. The few published prospective studies nevertheless support a synergy between radiotherapy and immune treatment. At least with checkpoint inhibitors, the side effects of the combined modality treatment do not seem to be significantly higher than of each modality alone. In the coming years, more solid data will surely appear and it is anticipated that radiotherapy will become an integral part of immune therapy. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2018 Societ rights reserved.
r é s u m é Mots clés : Immunothérapie Radiothérapie
Il existe une très forte justification biologique et préclinique pour associer la radiothérapie et un traitement immunologique. Les radiations affectent toutes les étapes de la réponse immunitaire aux antigènes et régulent nettement les molécules-clés sur la cellule cancéreuse et dans le micro-environnement tumoral, comme les antigènes de classe I du Complexe majeur d’histocompatibilité (CMH), les antigènes associés aux tumeurs et la création de néo-antigènes. Dans de nombreux modèles précliniques, la radiothérapie associée à la bonne combinaison et au bon moment de l’immunothérapie conduit à la régression des métastases à distance, sur des sites distants non irradiés du corps, ce qu’on appelle les «effets abscopaux». La combinaison augmente généralement également le taux de contrôle de la tumeur locale. Bien qu’une pléthore d’essais cliniques soit en cours ou planifiée, les données cliniques sont rares et surtout rétrospectives. Les quelques études prospectives publiées soutiennent néanmoins une synergie entre la radiothérapie et le traitement immunitaire. Au moins avec les inhibiteurs de point de contrôle, les effets secondaires de l’association thérapeutique ne semblent pas être significativement plus élevés que pour chaque modalité seule. Dans les années à venir, des données plus solides apparaîtront sûrement et il est prévu que la radiothérapie devienne partie intégrante de la thérapie immunitaire. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2018 Societ ´ ´ droits reserv es.
∗ Maastro clinic, Dr. Tanslaan 12, 6229ET Maastricht, The Netherlands. E-mail address: [email protected] https://doi.org/10.1016/j.canrad.2018.07.128 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: De Ruysscher D. Combination of radiotherapy and immune treatment: First clinical data. Cancer Radiother (2018), https://doi.org/10.1016/j.canrad.2018.07.128
G Model
ARTICLE IN PRESS
CANRAD-3784; No. of Pages 3
D. De Ruysscher / Cancer/Radiothérapie xxx (2018) xxx–xxx
2
1. Background
4. Combining radiotherapy with immune therapy: randomized studies
There is a very strong and reproducible scientific body of evidence that shows the strong influence of radiotherapy on all parts of the immune system. Many excellent reviews have been published recently [1–4]. Radiation induces cell death that may induce an immunological response, the so-called “immunogenic cell death” (ICD). This cell death may through DNA and RNA related pathways result in the production of type I interferons (IFN), which activates dendritic and CD8 T-lymphocytes. Already at this early stage, type I IFNs will induce PD-L1 expression as a negative feedback mechanism. Prolonged IFN I production will also stimulate pro-survival pathways in the tumor. Radiation will also facility the influx of effector T-cells in the tumor, but also here, the negative feedback mechanism leads to the influx of regulatory T-cells (Tregs) and myeloid-derived suppressor cells. Many other known and unknown mechanisms and feedback loops obviously exist. It is therefore obvious that radiotherapy alone would only seldom lead to a sustained anti-cancer immune effect, but with the right combination with immune therapy, its potential is very high because only a localised treatment without harmful side effects could stimulate the immune system in a systematic and reproducible way. In this short review, we will give a short overview over some clinical data on the combination of radiotherapy with immune therapy to combat cancer.
In a randomized study, the role of ipilimumab vs. placebo after one fraction of 8 Gy in hormonal refractory metastatic prostate cancer patients was investigated [10]. The median overall survival was 11.2 months (95% CI 9.5–12.7) with ipilimumab and 10.0 months (8.3–11.0) with placebo (hazard ratio [HR] 0.85, 0.72–1.00; P = 0.053). In the PACIFIC study, fit patients with stage III non-small cell lung cancer without disease progression after concurrent chemotherapy and radiotherapy were randomized between placebo (236 patients) or durvalumab (473 patients) [11]. The median progression-free survival from randomization was 16.8 months (95% CI 13.0–18.1) with durvalumab versus 5.6 months (95% CI 4.6–7.8) with placebo; the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P < 0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Interestingly, the beneficial effect of durvalumab was observed regardless of the PD-L1 expression of the tumor. This may be due to PD-L1 upregulation by chemotherapy and radiotherapy. Many new studies are ongoing or have been recently reported in abstract form, for example the NICOLAS trial (concurrent chemoradiotherapy and nivolumab followed by nivolumab in stage III NSCLC), the STIMULI trial (phase III trial in localized small cell lung cancer, standard concurrent chemo-radiotherapy and prophylactic cranial irradiation followed by observation or ipilimumab and nivolumab) and the PEMBRORAD study (randomized phase II in stage IV NSCLC, pembrolizumab with or without radiotherapy). It is expected that these and other trials will give answers on many relevant questions.
2. Radiotherapy alone There have been a few case reports on abscopal effects of radiotherapy (reviewed in ref. 4 [4]). All are retrospective and given its rarity, it is uncertain what the causal relation was between radiotherapy and the subsequent regression of non-irradiated metastases. An abscopal effect nevertheless seems to be elicited in some patients with an onset which takes a few months to happen and response durations lasting for many months up to years. These time lines are also observed in most studies with pharmacological immune interventions for cancer [5]. However, in view of the very rare occurrence of abscopal effects after radiotherapy and its unpredictability, more robust ways to come to an immune effect are needed.
5. Abscopal responses induced by radiotherapy in patients who progressed under immune treatment An attractive way to demonstrate an immunological response induced by radiotherapy is to irradiate of a single, progressing lesion in patients who responded to immune therapy and subsequently showed progression. In a retrospective study of melanoma patients who progressed after an initial response to ipilimumab and were treated with radiotherapy, more than half of them achieved a new systemic remission that lasted 22 months [12]. This has also been reported in a patient with stage IV non-small cell lung cancer progressing under nivolumab [13]. It is striking that in these retrospective series, abscopal responses were observed after a variety of doses and fractionations
3. Combining radiotherapy with immune therapy: prospective studies As depicted in Table 1, prospective trials suggest an improved outcome when radiotherapy is combined with immune treatment [6–9]. However, because these studies were not randomized, they are primary hypothesis-generating. An exception may be the phase II study of Golden and colleagues [7] with GM-CSF because this growth factor does not have an anti-tumor effect on its own. Randomized studies are therefore needed.
Table 1 Selected prospective studies combining radiotherapy with immune therapy. Study
Type
n
IT
RT
Toxicity
Outcome
Seung [6]
Melanoma RCC Multiple 1-y OS: 51% Melanoma Melanoma
12
IL-2 iv
NI
41
GMCSF
NR
Med OS: 12 Mo 100% PET response Med OS: 13 Mo
29 22
ipi ipi
60 Gy 3 fr 35 Gy 10 fr 30 Gy 24 Gy 3 fr
ipi ipi
Med OS: 39 Mo Med OS: 17 Mo
Golden [7] Barker [8] Twyman-Saint-Victor [9]
Please cite this article in press as: De Ruysscher D. Combination of radiotherapy and immune treatment: First clinical data. Cancer Radiother (2018), https://doi.org/10.1016/j.canrad.2018.07.128
G Model CANRAD-3784; No. of Pages 3
ARTICLE IN PRESS D. De Ruysscher / Cancer/Radiothérapie xxx (2018) xxx–xxx
such as 30 Gy in 10 fractions and 24 Gy in a single fraction, and also after palliative irradiation of brain metastases. 6. Effect of radiation dose per fraction, fractionation and timing of drugs In pre-clinical models, immune responses can be provoked with different schedules of irradiation and timing of drugs (reviewed in 14 [1]). However, the results are highly dependent on the model and the type of drugs. In some models, fractionation is beneficial, whereas in others one single high-dose is the best. When combining anti-PD(L)-1 with radiotherapy, it seems that the concurrent administration may be optimal. In view of the model dependency and the lack of established biomarkers, it should not come as a surprise that the clinical data on the optimal dose, fractionation and sequencing are unclear. Abscopal responses have been reported in lymphoma patients who were treated with a radiation dose as low as 2 × 2 Gy, combined with a TLR9 agonist [14]. In retrospective series where radiotherapy was used and an abscopal effect was observed, a broad range of doses and fractionations were used, such as 5 × 4 Gy, 10 × 3 Gy and 24 Gy in a single fraction. In most trials 3 × 8 Gy is given. At this point in time, no clear answer on the optimal radiotherapy schedule is known and well designed, biomarker-driven trials are needed and ongoing. 7. Conclusions Despite the strong pre-clinical evidence of the immune effects of radiotherapy, at the time of writing, only a few prospective and some retrospective data are available that suggest that radiotherapy may indeed stimulate the immune system and when combined with immune therapy patients may respond better and longer. Preferentially randomized studies are needed to substantiate these data. Biomarkers for response are needed to optimize the combination. We lack data on the optimal timing, dose and fractionation as a function of the characteristics of the tumor microenvironment. Nevertheless, given the reproducibility of the pre-clinical data, the probability is high that radiotherapy may become an integral part of immune therapy against cancer. Funding None.
3
Disclosure of interest Advisory board of Astra Zeneca, Bristol-Myers-Squibb, Roche/Genentech, Merck/Pfizer, Celgene, Noxxon, Mologen and has received investigator initiated grants from Bristol-Myers-Squibb and Boehringer Ingelheim. References [1] Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 2018;18:313–22. [2] Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 2017;14:365–79. [3] Wu Q, Allouch A, Martins I, Brenner C, Modjtahedi N, Deutsch E, et al. Modulating both tumor cell death and innate immunity is essential for improving radiation therapy effectiveness. Front Immunol 2017;8: 613. [4] Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 2015;41:503–10. [5] Marrone KA, Naidoo J, Brahmer JR. Immunotherapy for lung cancer: no longer an abstract concept. Semin Respir Crit Care Med 2016;37: 771–82. [6] Seung SK, Curti BD, Crittenden M, Walker E, Coffey T, Siebert JC, et al. Phase 1 study of stereotactic body radiotherapy and interleukin-2 tumor and immunological responses. Sci Transl Med 2012;4 [137ra74]. [7] Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, 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;16:795–803. [8] Barker CA, Postow MA, Khan SA, Beal K, Parhar PK, Yamada Y, et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res 2013;1:92–8. [9] Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015;520:373–7. [10] Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15: 700–12. [11] Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:1919–29. [12] Grimaldi AM, Simeone E, Giannarelli D, Muto P, Falivene S, Borzillo V, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology 2014;3: e28780. [13] Yuan Z, Fromm A, Ahmed KA, Grass GD, Yang GQ, Oliver DE, et al. Radiotherapy rescue of a nivolumab-tefractory immune response in a patient with PD-L1-negative metastatic squamous cell carcinoma of the lung. J Thorac Oncol 2017;12:e135–6. [14] Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 2010;28:4324–32.
Please cite this article in press as: De Ruysscher D. Combination of radiotherapy and immune treatment: First clinical data. Cancer Radiother (2018), https://doi.org/10.1016/j.canrad.2018.07.128
ARTICLE IN PRESS Cancer/Radiothérapie xxx (2018) xxx–xxx
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Review
Combination of radiotherapy and immune treatment: First clinical data Combinaison de la radiothérapie et immunothérapie : premières données cliniques D. De Ruysscher ∗ Maastricht University Medical Center, Department of Radiation Oncology (Maastro clinic), GROW School for oncology and developmental biology, Maastricht, The Netherlands
a r t i c l e
i n f o
Article history: Received 5 June 2018 Received in revised form 13 July 2018 Accepted 18 July 2018 Keywords: Clinique immunotherapy Radiotherapy
a b s t r a c t There is a very strong biological and pre-clinical rationale for combining radiotherapy with immune treatment. Radiation affects all steps in the immune response to antigens and clearly upregulates key-molecules on the cancer cell and in the tumor micro-environment, such as MHC class I antigens, tumor-associated antigens and the creation of neo-antigens as well. In many pre-clinical models, radiation together with the right combination and timing of immune therapy leads to regression of distant metastases, at remote non-irradiated sites of the body, the so-called “abscopal effects”. The combination generally also increases the local tumor control. Although a plethora of clinical trials are ongoing or are being planned, clinical data are sparse and mostly even retrospective. The few published prospective studies nevertheless support a synergy between radiotherapy and immune treatment. At least with checkpoint inhibitors, the side effects of the combined modality treatment do not seem to be significantly higher than of each modality alone. In the coming years, more solid data will surely appear and it is anticipated that radiotherapy will become an integral part of immune therapy. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Published by Elsevier Masson SAS. All © 2018 Societ rights reserved.
r é s u m é Mots clés : Immunothérapie Radiothérapie
Il existe une très forte justification biologique et préclinique pour associer la radiothérapie et un traitement immunologique. Les radiations affectent toutes les étapes de la réponse immunitaire aux antigènes et régulent nettement les molécules-clés sur la cellule cancéreuse et dans le micro-environnement tumoral, comme les antigènes de classe I du Complexe majeur d’histocompatibilité (CMH), les antigènes associés aux tumeurs et la création de néo-antigènes. Dans de nombreux modèles précliniques, la radiothérapie associée à la bonne combinaison et au bon moment de l’immunothérapie conduit à la régression des métastases à distance, sur des sites distants non irradiés du corps, ce qu’on appelle les «effets abscopaux». La combinaison augmente généralement également le taux de contrôle de la tumeur locale. Bien qu’une pléthore d’essais cliniques soit en cours ou planifiée, les données cliniques sont rares et surtout rétrospectives. Les quelques études prospectives publiées soutiennent néanmoins une synergie entre la radiothérapie et le traitement immunitaire. Au moins avec les inhibiteurs de point de contrôle, les effets secondaires de l’association thérapeutique ne semblent pas être significativement plus élevés que pour chaque modalité seule. Dans les années à venir, des données plus solides apparaîtront sûrement et il est prévu que la radiothérapie devienne partie intégrante de la thérapie immunitaire. ´ e´ franc¸aise de radiotherapie ´ oncologique (SFRO). Publie´ par Elsevier Masson SAS. Tous © 2018 Societ ´ ´ droits reserv es.
∗ Maastro clinic, Dr. Tanslaan 12, 6229ET Maastricht, The Netherlands. E-mail address: [email protected] https://doi.org/10.1016/j.canrad.2018.07.128 ´ e´ franc¸aise de radiotherapie ´ 1278-3218/© 2018 Societ oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: De Ruysscher D. Combination of radiotherapy and immune treatment: First clinical data. Cancer Radiother (2018), https://doi.org/10.1016/j.canrad.2018.07.128
G Model
ARTICLE IN PRESS
CANRAD-3784; No. of Pages 3
D. De Ruysscher / Cancer/Radiothérapie xxx (2018) xxx–xxx
2
1. Background
4. Combining radiotherapy with immune therapy: randomized studies
There is a very strong and reproducible scientific body of evidence that shows the strong influence of radiotherapy on all parts of the immune system. Many excellent reviews have been published recently [1–4]. Radiation induces cell death that may induce an immunological response, the so-called “immunogenic cell death” (ICD). This cell death may through DNA and RNA related pathways result in the production of type I interferons (IFN), which activates dendritic and CD8 T-lymphocytes. Already at this early stage, type I IFNs will induce PD-L1 expression as a negative feedback mechanism. Prolonged IFN I production will also stimulate pro-survival pathways in the tumor. Radiation will also facility the influx of effector T-cells in the tumor, but also here, the negative feedback mechanism leads to the influx of regulatory T-cells (Tregs) and myeloid-derived suppressor cells. Many other known and unknown mechanisms and feedback loops obviously exist. It is therefore obvious that radiotherapy alone would only seldom lead to a sustained anti-cancer immune effect, but with the right combination with immune therapy, its potential is very high because only a localised treatment without harmful side effects could stimulate the immune system in a systematic and reproducible way. In this short review, we will give a short overview over some clinical data on the combination of radiotherapy with immune therapy to combat cancer.
In a randomized study, the role of ipilimumab vs. placebo after one fraction of 8 Gy in hormonal refractory metastatic prostate cancer patients was investigated [10]. The median overall survival was 11.2 months (95% CI 9.5–12.7) with ipilimumab and 10.0 months (8.3–11.0) with placebo (hazard ratio [HR] 0.85, 0.72–1.00; P = 0.053). In the PACIFIC study, fit patients with stage III non-small cell lung cancer without disease progression after concurrent chemotherapy and radiotherapy were randomized between placebo (236 patients) or durvalumab (473 patients) [11]. The median progression-free survival from randomization was 16.8 months (95% CI 13.0–18.1) with durvalumab versus 5.6 months (95% CI 4.6–7.8) with placebo; the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P < 0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Interestingly, the beneficial effect of durvalumab was observed regardless of the PD-L1 expression of the tumor. This may be due to PD-L1 upregulation by chemotherapy and radiotherapy. Many new studies are ongoing or have been recently reported in abstract form, for example the NICOLAS trial (concurrent chemoradiotherapy and nivolumab followed by nivolumab in stage III NSCLC), the STIMULI trial (phase III trial in localized small cell lung cancer, standard concurrent chemo-radiotherapy and prophylactic cranial irradiation followed by observation or ipilimumab and nivolumab) and the PEMBRORAD study (randomized phase II in stage IV NSCLC, pembrolizumab with or without radiotherapy). It is expected that these and other trials will give answers on many relevant questions.
2. Radiotherapy alone There have been a few case reports on abscopal effects of radiotherapy (reviewed in ref. 4 [4]). All are retrospective and given its rarity, it is uncertain what the causal relation was between radiotherapy and the subsequent regression of non-irradiated metastases. An abscopal effect nevertheless seems to be elicited in some patients with an onset which takes a few months to happen and response durations lasting for many months up to years. These time lines are also observed in most studies with pharmacological immune interventions for cancer [5]. However, in view of the very rare occurrence of abscopal effects after radiotherapy and its unpredictability, more robust ways to come to an immune effect are needed.
5. Abscopal responses induced by radiotherapy in patients who progressed under immune treatment An attractive way to demonstrate an immunological response induced by radiotherapy is to irradiate of a single, progressing lesion in patients who responded to immune therapy and subsequently showed progression. In a retrospective study of melanoma patients who progressed after an initial response to ipilimumab and were treated with radiotherapy, more than half of them achieved a new systemic remission that lasted 22 months [12]. This has also been reported in a patient with stage IV non-small cell lung cancer progressing under nivolumab [13]. It is striking that in these retrospective series, abscopal responses were observed after a variety of doses and fractionations
3. Combining radiotherapy with immune therapy: prospective studies As depicted in Table 1, prospective trials suggest an improved outcome when radiotherapy is combined with immune treatment [6–9]. However, because these studies were not randomized, they are primary hypothesis-generating. An exception may be the phase II study of Golden and colleagues [7] with GM-CSF because this growth factor does not have an anti-tumor effect on its own. Randomized studies are therefore needed.
Table 1 Selected prospective studies combining radiotherapy with immune therapy. Study
Type
n
IT
RT
Toxicity
Outcome
Seung [6]
Melanoma RCC Multiple 1-y OS: 51% Melanoma Melanoma
12
IL-2 iv
NI
41
GMCSF
NR
Med OS: 12 Mo 100% PET response Med OS: 13 Mo
29 22
ipi ipi
60 Gy 3 fr 35 Gy 10 fr 30 Gy 24 Gy 3 fr
ipi ipi
Med OS: 39 Mo Med OS: 17 Mo
Golden [7] Barker [8] Twyman-Saint-Victor [9]
Please cite this article in press as: De Ruysscher D. Combination of radiotherapy and immune treatment: First clinical data. Cancer Radiother (2018), https://doi.org/10.1016/j.canrad.2018.07.128
G Model CANRAD-3784; No. of Pages 3
ARTICLE IN PRESS D. De Ruysscher / Cancer/Radiothérapie xxx (2018) xxx–xxx
such as 30 Gy in 10 fractions and 24 Gy in a single fraction, and also after palliative irradiation of brain metastases. 6. Effect of radiation dose per fraction, fractionation and timing of drugs In pre-clinical models, immune responses can be provoked with different schedules of irradiation and timing of drugs (reviewed in 14 [1]). However, the results are highly dependent on the model and the type of drugs. In some models, fractionation is beneficial, whereas in others one single high-dose is the best. When combining anti-PD(L)-1 with radiotherapy, it seems that the concurrent administration may be optimal. In view of the model dependency and the lack of established biomarkers, it should not come as a surprise that the clinical data on the optimal dose, fractionation and sequencing are unclear. Abscopal responses have been reported in lymphoma patients who were treated with a radiation dose as low as 2 × 2 Gy, combined with a TLR9 agonist [14]. In retrospective series where radiotherapy was used and an abscopal effect was observed, a broad range of doses and fractionations were used, such as 5 × 4 Gy, 10 × 3 Gy and 24 Gy in a single fraction. In most trials 3 × 8 Gy is given. At this point in time, no clear answer on the optimal radiotherapy schedule is known and well designed, biomarker-driven trials are needed and ongoing. 7. Conclusions Despite the strong pre-clinical evidence of the immune effects of radiotherapy, at the time of writing, only a few prospective and some retrospective data are available that suggest that radiotherapy may indeed stimulate the immune system and when combined with immune therapy patients may respond better and longer. Preferentially randomized studies are needed to substantiate these data. Biomarkers for response are needed to optimize the combination. We lack data on the optimal timing, dose and fractionation as a function of the characteristics of the tumor microenvironment. Nevertheless, given the reproducibility of the pre-clinical data, the probability is high that radiotherapy may become an integral part of immune therapy against cancer. Funding None.
3
Disclosure of interest Advisory board of Astra Zeneca, Bristol-Myers-Squibb, Roche/Genentech, Merck/Pfizer, Celgene, Noxxon, Mologen and has received investigator initiated grants from Bristol-Myers-Squibb and Boehringer Ingelheim. References [1] Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 2018;18:313–22. [2] Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 2017;14:365–79. [3] Wu Q, Allouch A, Martins I, Brenner C, Modjtahedi N, Deutsch E, et al. Modulating both tumor cell death and innate immunity is essential for improving radiation therapy effectiveness. Front Immunol 2017;8: 613. [4] Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 2015;41:503–10. [5] Marrone KA, Naidoo J, Brahmer JR. Immunotherapy for lung cancer: no longer an abstract concept. Semin Respir Crit Care Med 2016;37: 771–82. [6] Seung SK, Curti BD, Crittenden M, Walker E, Coffey T, Siebert JC, et al. Phase 1 study of stereotactic body radiotherapy and interleukin-2 tumor and immunological responses. Sci Transl Med 2012;4 [137ra74]. [7] Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, 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;16:795–803. [8] Barker CA, Postow MA, Khan SA, Beal K, Parhar PK, Yamada Y, et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res 2013;1:92–8. [9] Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015;520:373–7. [10] Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15: 700–12. [11] Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:1919–29. [12] Grimaldi AM, Simeone E, Giannarelli D, Muto P, Falivene S, Borzillo V, et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology 2014;3: e28780. [13] Yuan Z, Fromm A, Ahmed KA, Grass GD, Yang GQ, Oliver DE, et al. Radiotherapy rescue of a nivolumab-tefractory immune response in a patient with PD-L1-negative metastatic squamous cell carcinoma of the lung. J Thorac Oncol 2017;12:e135–6. [14] Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol 2010;28:4324–32.
Please cite this article in press as: De Ruysscher D. Combination of radiotherapy and immune treatment: First clinical data. Cancer Radiother (2018), https://doi.org/10.1016/j.canrad.2018.07.128