The future of radiotherapy and immunotherapy concomitantly in cancer management

Keywords: cancer, immunotherapy, radiation therapy, radioimmunotherapy, radiotherapy, tumor
Abstract viewed: 687 times
PDF downloaded: 705 times
HTML downloaded: 169 times
EPUB downloaded: 321 times

Abstract

Immunotherapy is a developing field in cancer treatment. Immunotherapy using immune checkpoint inhibitors has been successful in treating patients with metastatic disease, as well as patients who are refractory to standard treatments. Although immunotherapy has yielded considerably positive outcomes, its clinical benefits are limited to a small subset of patients. A combination of radiotherapy and immunotherapy has been shown to provide greater clinical benefits to more patients. Radiation, particularly hypofractionated radiation with stereotactic radiosurgery or stereotactic body radiotherapy, works by priming T cells, upregulating proinflammatory chemokines, and increasing the immunogenicity of tumor cells. Tumor cells develop immunosuppressive mechanisms that protect them from attack by the immune system. Immunotherapy works by disrupting the ability of tumor cells to setup these defenses. When combined with radiotherapy, it can synergistically enhance tumor cell death via cytotoxic T cells, thus causing systemic tumor regression and generating better clinical response.

References

  1. Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer. 2016;4:51. https://doi.org/10.1186/s40425-016-0156-7

  2. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, 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(7):700-12. https://doi.org/10.1016/S1470-2045(14)70189-5

  3. Hiniker SM, Reddy SA, Maecker HT, Subrahmanyam PB, Rosenberg-Hasson Y, Swetter SM, et al. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys. 2016;96(3):578-88. https://doi.org/10.1016/j.ijrobp.2016.07.005

  4. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med. 1996;183(6):2541-50. https://doi.org/10.1084/jem.183.6.2541

  5. Speiser DE, Ho PC, Verdeil G. Regulatory circuits of T cell function in cancer. Nat Rev Immunol. 2016;16(10):599-611. https://doi.org/10.1038/nri.2016.80

  6. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-23. https://doi.org/10.1056/NEJMoa1003466

  7. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-26. https://doi.org/10.1056/NEJMoa1104621

  8. Pai-Scherf L, Blumenthal GM, Li H, Subramaniam S, Mishra-Kalyani PS, He K, et al. FDA approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond. Oncologist. 2017;22(11):1392-9. https://doi.org/10.1634/theoncologist.2017-0078

  9. Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34(32):3838-45. https://doi.org/10.1200/JCO.2016.68.1478

  10. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908-18. https://doi.org/10.1016/S1470-2045(15)00083-2

  11. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-35. https://doi.org/10.1056/NEJMoa1504627

  12. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-13. https://doi.org/10.1056/NEJMoa1510665

  13. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-94. https://doi.org/10.1016/S1470-2045(16)30167-X

  14. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320-30. https://doi.org/10.1056/NEJMoa1412082

  15. Gajewski TF. The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin Oncol. 2016;42(4): 663-71. https://doi.org/10.1053/j.seminoncol.2015.05.011

  16. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3. https://doi.org/10.1186/2051-1426-2-3

  17. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34. https://doi.org/10.1056/NEJMoa1504030

  18. Abuodeh Y, Venkat P, Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer. 2016;40(1):25-37. https://doi.org/10.1016/j.currproblcancer.2015.10.001

  19. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58(3):862-70. https://doi.org/10.1016/j.ijrobp.2003.09.012

  20. Matsumura S, Demaria S. Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation. Radiat Res. 2010;173(4):418-25. https://doi.org/10.1667/RR1860.1

  21. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203(5):1259-71. https://doi.org/10.1084/jem.20052494

  22. Garnett CT, Palena C, Chakarborty M, Tsang KY, Schlom J, Hodge JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res. 2004;64(21):7985-94. https://doi.org/10.1158/0008-5472.CAN-04-1525

  23. Vanpouille-Box C, Diamond JM, Pilones KA, Zavadil J, James JS, Formenti SC, et al. TGFβ is a master regulator of radiation therapy-induced anti- tumor immunity. Cancer Res. 2015;75(11):2232-42. https://doi.org/10.1158/0008-5472.CAN-14-3511

  24. Yovino S, Kleinberg L, Grossman SA, Narayanan M, Ford E. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest. 2013;31(2):140-4. https://doi.org/10.3109/07357907.2012.762780

  25. Wild AT, Herman JM, Dholakia AS, Moningi S, Lu Y, Rosati LM, et al. Lymphocyte-sparing effect of stereotactic body radiation therapy in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2016;94(3):571-9. https://doi.org/10.1016/j.ijrobp.2015.11.026

  26. Nikitina EY, Gabrilovich DI. Combination of gamma-irradiation and dendritic cell administration induces a potent antitumor response in tumor-bearing mice: approach to treatment of advanced stage cancer. Int J cancer. 2001;94(6):825-33. https://doi.org/10.1002/1097-0215(20011215)94:6<825::AID-IJC1545>3.0.CO;2-5

  27. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, 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(17):5379-88. https://doi.org/10.1158/1078-0432.CCR-09-0265

  28. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687-95. https://doi.org/10.1172/JCI67313

  29. 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(137):137ra74. https://doi.org/10.1126/scitranslmed.3003649

  30. Tang C, Welsh JW, de Groot P, Massarelli E, Chang JY, Hess KR, et al. Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T-cells. Clin Cancer Res. 2017;23(6):1388-96. https://doi.org/10.1158/1078-0432.CCR-16-1432

Published
2019-12-13
How to Cite
1.
Sekarutami SM, Handoko. The future of radiotherapy and immunotherapy concomitantly in cancer management. Med J Indones [Internet]. 2019Dec.13 [cited 2024Apr.20];28(4):391-5. Available from: http://mji.ui.ac.id/journal/index.php/mji/article/view/3211
Section
Review Article