Radiotherapy and immunotherapy: a synergistic effect in cancer care

Turgeon, Guy‐Anne; Weickhardt, Andrew; Azad, Arun A; Solomon, Benjamin; Siva, Shankar

doi:10.5694/mja2.12046

ARTICLE
AUTHORS
REFERENCES

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Neoplasms

Summary

Radiotherapy is an effective treatment modality commonly used in efforts to cure many localised cancers and in the palliation of symptoms in metastatic cancers.
Immunotherapy has revolutionised cancer care by increasing the disease control and overall survival of patients in several cancer types; however, the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors (ICIs). The benefit of those agents is limited to patients who have a pre‐existing active immune microenvironment that can be reactivated by ICIs.
It is now recognised that radiotherapy does not only directly kill tumour cells but it also changes the tumour microenvironment, enhancing tumour cell recognition by the immune system and, therefore, acting as an in situ vaccine.
Radiotherapy increases expression of tumour‐associated antigens, causes the release of cytokines, stimulates recruitment of dendritic cells and, most importantly, stimulates the proliferation and priming of cytotoxic CD8+ T cells in the tumour microenvironment. This immunological cascade specifically generates activated T cells able to induce immunogenic cell death directed against cancer cells bearing those antigens.
By its ability to overcome some tumour immune escape mechanisms, radiation provides a non‐pharmacological and cost‐effective approach to potentially improve the systemic response to immune checkpoints inhibitors.

1 Peter MacCallum Cancer Institute, Melbourne, VIC
2 Olivia Newton‐John Cancer Centre, Austin Health, Melbourne, VIC
3 La Trobe University, Melbourne, VIC
4 Monash Health, Melbourne, VIC
5 Monash University, Melbourne, VIC
6 University of Melbourne, Melbourne, VIC

Correspondence: Shankar.Siva@petermac.org

Competing interests:

Andrew Weickhardt has received consultancy fees from MSD, Novartis and Ipsen. Arun Azad is conducting an investigator‐initiated trial supported by Merck Serono. Benjamin Solomon has an advisory role for AstraZeneca, Roche‐Genentech, Bristol‐Myers Squibb, Merck, Pfizer and Novartis. Shankar Siva has an advisory role for Astellas Pharma and Janssen Pharmaceuticals, and receives research funding from Varian Medical Systems and Merck‐Sharp and Dohme Pharmaceuticals, and received speakers’ bureau, travel and accommodations expenses from Bristol‐Myers Squibb pharmaceuticals and Astellas Pharma.

1. Barton MB, Jacob S, Shafiq J, et al. Estimating the demand for radiotherapy from the evidence: A review of changes from 2003 to 2012. Radiother Oncol 2014; 112: 140–144.
2. Reck M, Rodríguez‐Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD‐L1–positive non–small‐cell lung cancer. N Engl J Med 2016; 375: 1823–1833.
3. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non‐small‐cell lung cancer (OAK): a phase 3, open‐label, multicentre randomised controlled trial. Lancet 2017; 389: 255–265.
4. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second‐line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376: 1015–1026.
5. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal‐cell carcinoma. N Engl J Med 2015; 373: 1803–1813.
6. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long‐term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clini Oncol 2015; 33: 1889–1894.
7. Teng F, Meng X, Kong L, Yu J. Progress and challenges of predictive biomarkers of anti PD‐1/PD‐L1 immunotherapy: a systematic review. Cancer Lett 2018; 414: 166–173.
8. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy‐refractory metastatic Merkel cell carcinoma: a multicentre, single‐group, open‐label, phase 2 trial. Lancet Oncol 2016; 17: 1374–1385.
9. Ansell SM, Lesokhin AM, Borrello I, et al. PD‐1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372: 311–319.
10. Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous‐cell carcinoma of the head and neck. N Engl J Med 2016; 375: 1856–1867.
11. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: 320–330.
12. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331: 1565–1570.
13. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
14. Galon J, Costes A, Sanchez‐Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313: 1960–1964.
15. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor‐infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node‐positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin‐based chemotherapy: BIG 02‐98. J Clini Oncol 2013; 31: 860–867.
16. Nguyen N, Bellile E, Thomas D, et al. Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma. Head Neck 2016; 38: 1074–1084.
17. Siva S, MacManus MP, Martin RF, Martin OA. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett 2015; 356: 82–90.
18. Mole R. Whole body irradiation: radiobiology or medicine? Br J Radiol 1953; 26: 234–241.
19. 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: 925–931.
20. Reynders K, Illidge T, Siva S, et al. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 2015; 41: 503–510.
21. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non‐small cell lung cancer. Cancer Immunol Res 2013; 1: 365–372.
22. Chandra RA, Wilhite TJ, Balboni TA, et al. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology 2015; 4: e1046028.
23. Koller KM, Mackley HB, Liu J, et al. Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther 2017; 18: 36–42.
24. Lugade AA, Moran JP, Gerber SA, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen‐specific effector cells that traffic to the tumor. J Immunol 2005; 174: 7516–7523.
25. Gupta A, Probst HC, Vuong V, et al. Radiotherapy promotes tumor‐specific effector CD8+ T cells via dendritic cell activation. J Immunol 2012; 189: 558–566.
26. Wan S, Pestka S, Jubin RG, et al. Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon‐beta signaling in breast cancer cells. PLoS One 2012; 7: e32542.
27. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006; 203: 1259–1271.
28. Matsumura S, Wang B, Kawashima N, et al. Radiation‐induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol 2008; 181: 3099–3107.
29. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 2013; 105: 256–265.
30. Buchbinder EI, Desai A. CTLA‐4 and PD‐1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39: 98–106.
31. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372: 2006–2017.
32. Antonia SJ, López‐Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small‐cell lung cancer (CheckMate 032): a multicentre, open‐label, phase 1/2 trial. Lancet Oncol 2016; 17: 883–895.
33. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA‐4 blockade in melanoma. N Engl J Med 2014; 371: 2189–2199.
34. Taube JM, Klein A, Brahmer JR, et al. Association of PD‐1, PD‐1 ligands, and other features of the tumor immune microenvironment with response to anti‐PD‐1 therapy. Clin Cancer Res 2014; 20: 5064–5074.
35. Ratcliffe MJ, Sharpe A, Midha A, et al. Agreement between programmed cell death ligand‐1 diagnostic assays across multiple protein expression cutoffs in non‐small cell lung cancer. Clin Cancer Res 2017; 23: 3585–3591.
36. Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD‐1 blockade in non–small cell lung cancer. Science 2015; 348: 124–128.
37. Demaria S, Kawashima N, Yang AM, et al. Immune‐mediated inhibition of metastases after treatment with local radiation and CTLA‐4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005; 11: 728–734.
38. Deng L, Liang H, Burnette B, et al. Irradiation and anti–PD‐L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014; 124: 687–695.
39. 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: 373–377.
40. Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer 2016; 4: 51.
41. Vacchelli E, Bloy N, Aranda F, et al. Trial watch: immunotherapy plus radiation therapy for oncological indications. Oncoimmunology 2016; 5: e1214790.
42. Golden EB, Chachoua A, Fenton‐Kerimian MB, et al. Abscopal responses in metastatic non‐small cell lung cancer (NSCLC) patients treated on a phase 2 study of combined radiation therapy and ipilimumab: evidence for the in situ vaccination hypothesis of radiation. Int J Radiat Oncol Biol Phys 2015; 93: S66–S67.
43. Tang C, Welsh JW, de Groot P, et al. Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T cells. Clin Cancer Res 2017; 23: 1388–1396.
44. Slovin SF, Higano CS, Hamid O, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration‐resistant prostate cancer: results from an open‐label, multicenter phase I/II study. Ann Oncol 2013; 24: 1813–1821.
45. Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clini Oncol 2018; 36: 1611–1618.
46. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small‐cell lung cancer. N Engl J Med 2017; 377: 1919–1929.
47. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non‐small‐cell lung cancer: a secondary analysis of the KEYNOTE‐001 phase 1 trial. Lancet Oncol 2017; 18: 895–903.
48. Aboudaram A, Modesto A, Chaltiel L, et al. Concurrent radiotherapy for patients with metastatic melanoma and receiving anti‐programmed‐death 1 therapy: a safe and effective combination. Melanoma Res 2017; 27: 485–491.
49. Hwang WL, Niemierko A, Hwang KL, et al. Clinical outcomes in patients with metastatic lung cancer treated with PD‐1/PD‐L1 inhibitors and thoracic radiotherapy. JAMA Oncol 2018; 4: 253–255.
50. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J Clini Oncol 2015; 33: 2092–2099.
51. Kwon ED, Drake CG, Scher HI, et al. 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: 700–712.
52. Bang A, Wilhite TJ, Pike LRG, et al. Multicenter evaluation of the tolerability of combined treatment with PD‐1 and CTLA‐4 immune checkpoint inhibitors and palliative radiation therapy. Int J Radiat Oncol Biol Phys 2017; 98: 344–351.
53. Qin R, Olson A, Singh B, et al. Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab. Int J Radiat Oncol Biol Phys 2016; 96: 72–77.
54. Kroeze SG, Fritz C, Hoyer M, et al. Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review. Cancer Treat Rev 2017; 53: 25–37.
55. Sun XS, Sire C, Tao Y, et al. A phase II randomized trial of pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN): first results of the GORTEC 2015‐01 “PembroRad” trial. J Clini Oncol 2018; 36: 6018.
56. Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short‐ versus long‐course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 2005; 97: 798–804.
57. Sundahl N, Rottey S, Decaestecker K, et al. OC‐0682: Phase 1 trial of pembrolizumab with SBRT in metastatic urothelial carcinoma. Radiother Oncol 2018; 127: S357–S358.
58. Dovedi SJ, Adlard AL, Lipowska‐Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD‐L1 blockade. Cancer Res 2014; 74: 5458–5468.
59. Young KH, Baird JR, Savage T, et al. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One 2016; 11: e0157164.
60. Park HJ, Griffin RJ, Hui S, et al. Radiation‐induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res 2012; 177(3): 311–327.
61. Vanpouille‐Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy‐induced tumour immunogenicity. Nat Commun 2017; 8: 15618.
62. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single‐dose radiotherapy induces an immune‐mediated abscopal effect when combined with anti–CTLA‐4 antibody. Clin Cancer Res 2009; 15: 5379–5388.
63. Marconi R, Strolin S, Bossi G, Strigari L. A meta‐analysis of the abscopal effect in preclinical models: is the biologically effective dose a relevant physical trigger? PLoS One 2017; 12: e0171559.
64. Kordbacheh T, Honeychurch J, Blackhall F, et al. Radiotherapy and anti‐PD‐1/PD‐L1 combinations in lung cancer: building better translational research platforms. Ann Oncol 2018; 29: 301–310.

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Radiotherapy and immunotherapy: a synergistic effect in cancer care

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