Abstract
Radiation therapy is a longstanding cancer treatment. More recently, it has been demonstrated that radiation therapy (RT) elicits anti-cancer immune response. For this reason, there is a growing interest in combining RT with immunotherapy, specifically with checkpoint inhibitors such as anti-CTLA-4 and anti-PD-L1. In the present paper, we develop a mathematical model of combination therapy with RT and anti-PD-L1. The model is used to compare different schedules in clinical trials. Simulations of the model show that applying both RT and anti-PD-L1 at the same week has more benefits than applying them in separate adjacent weeks. Furthermore, applying anti-PD-L1 before RT has more benefits than applying RT before anti-PD-L1.
Similar content being viewed by others
References
Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol, 1996, 124: 765–772
Azad A, Lim S Y, D’Costa Z, et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med, 2017, 124: 167–180
Brahmer J R, Tykodi S S, Chow L Q, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 2012, 124: 2455–2465
Buttea M J, Pena-Cruzc V, Kima M-J, et al. Interaction of human PD-L1 and B7-1. Mol Immunol, 2008, 124: 3567–3572
Cantelli G, Crosas-Molist E, Georgouli M, et al. TGFB-induced transcription in cancer. Semin Cancer Biol, 2017, 124: 60–69
Chen D, Bobko A A, Gross A C, et al. Involvement of tumor macrophage HIFs in chemotherapy effectiveness: Mathematical modeling of oxygen, pH, and glutathione. PLoS One, 2014, 124: e107511
Cheng X, Veverka V, Radhakrishnan A, et al. Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem, 2013, 124: 11771–11785
Cheng X, Veverka V, Radhakrishnan A, et al. Human PD-L1/B7-H1/CD274 protein. Sino Biological Inc, http://www.sinobiological.com/PD-L1-B7-H1-CD274-Protein-g-533.html
Condamine T, Gabrilovich D I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol, 2011, 124: 19–25
Czarkowska-Paczek B, Bartlomiejczyk I, Przybylski J. The serum levels of growth factors: PDGF, TGF-beta and VEGF are increased after strenuous physical exercise. J Physiol Pharmacol, 2006, 124: 189–189
D’Acunto B. Computational Methods for PDE in Mechanics. Series on Advances in Mathematics for Applied Sciences, vol. 67. Singapore: Word Scientific, 2004
Daly M E, Monjazeb A M, Kelly K. Clinical trials integrating immunotherapy and radiation for non-small-cell lung cancer. J Thorac Oncol, 2015, 124: 1685–1693
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
Dovedi S J, Adlard A L, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res, 2014, 124: 5458–5468
Eckert F, Gaipl U, Niedermann G, et al. Beyond checkpoint inhibition Immunotherapeutical strategies in combination with radiation. Clin Transl Radiat Oncol, 2017, 124: 29–35
Enderling H, Chaplain M A J, Hahnfeldt P. Quantitative modeling of tumor dynamics and radiotherapy. Acta Biotheor, 2010, 124: 341–353
Escorcia F E, Postow M A, Barker C A. Radiotherapy and immune checkpoint blockade for melanoma. Cancer J, 2017, 124: 32–39
Friedman A, Hao W. The role of exosomes in pancreatic cancer microenvironment. Bull Math Biol, 2017, 124: 1111–1133
Hamza T, Barnett J B, Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci, 2010, 124: 789–806
Hao W, Friedman A. Mathematical model on Alzheimer’s disease. BMC Syst Biol, 2016, 124: 1–18
Hu Z I, Ho A Y, Mcarthur H L. Combined radiation therapy and immune checkpoint blockade therapy for breast cancer. Int J Radiat Oncol, 2017, 124: 153–164
Itakura E, Huang R-R, Wen D-R, et al. IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. Mod Pathol, 2011, 124: 801–809
Jafarzadeh A, Minaee K, Farsinejad A-R, et al. Evaluation of the circulating levels of IL-12 and IL-33 in patients with breast cancer: Influences of the tumor stages and cytokine gene polymorphisms. Iran J Basic Med Sci, 2015, 124: 1189–1198
Janco J M T, Lamichhane P, Karyampudi L, et al. Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol, 2015, 124: 2985–2991
Kaminska B, Wesolowska A, Danilkiewicz M. TGF beta signalling and its role in tumour pathogenesis. Acta Biochim Pol, 2005, 124: 329–337
Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer, 2016, 124: 1–20
Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front Onco, 2012, 124: 191
Krüger-Krasagakes S, Krasagakis K, Garbe C, et al. Expression of interleukin 10 in human melanoma. Brit J Cancer, 1994, 124: 1182–1185
Lai X, Friedman A. Combination therapy of cancer with BRAF inhibitor and immune checkpoint inhibitor: A mathematical model. BMC Syst Biol, 2017, 124: 70
Lai X, Stiff A, Duggan M, et al. Modeling combination therapy for breast cancer with BET and immune checkpoint inhibitors. Proc Natl Acad Sci USA, 2018, 124: 5534–5539
Lawrence Y R, Dicker A P. Radiation therapy and the immune system: Learning to live together. Future Oncol, 2014, 124: 777–780
Lee E-J, Lee S J, Kim J-H, et al. Radiation inhibits interleukin-12 production via inhibition of C-rel through the interleukin-6/signal transducer and activator of transcription 3 signaling pathway in dendritic cells. PLoS One, 2016, 124: e0146463
Li H-H, Wang Y-W, Chen R, et al. Ionizing radiation impairs T cell activation by affecting metabolic reprogramming. Int J Biol Sci, 2015, 124: 726–736
Liao K L, Bai X F, Friedman A. Mathematical modeling of interleukin-27 induction of anti-tumor T cells response. PLoS One, 2014, 124: e91844
Liniker E, Menzies A, Kong B, et al. Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. Oncoimmunology, 2016, 124: e1214788
Lisiero D N, Soto H, Liau L M, et al. Enhanced sensitivity to IL-2 signaling regulates the clinical responsiveness of IL-12Cprimed CD8 T cells in a melanoma model. J Immunol, 2011, 124: 5068–5077
Liu S, Sun X, Luo J, et al. Effects of radiation on T regulatory cells in normal states and cancer: Mechanisms and clinical implications. Am J Cancer Res, 2015, 124: 3276–3285
Lo W-C, Arsenescu V, Arsenescu R I, et al. Inflammatory Bowel disease: How effective is TNF-alpha suppression? PLoS One, 2016, 124: e0165782
Lonergan D M, Mikulec A A, Hanasono M M, et al. Growth factor profile of irradiated human dermal fibroblasts using a serum-free method. Plast Reconstr Surg, 2003, 124: 1960–1968
Longoria T C, Tewari K S. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin Drug Metab Toxicol, 2016, 124: 1247–1253
Lowther D E, Goods B A, Lucca L E, et al. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight, 2016, 124: e85935
Ma Y, Shurin1 G V, Peiyuan Z, et al. Dendritic Cells in the Cancer Microenvironment. J Cancer, 2013, 124: 36–44
Maggio F D, Minafra L, Forte G, et al. Portrait of inflammatory response to ionizing radiation treatment. J Inflamm, 2015, 124: 14
Manda K, Glasow A, Paape D, et al. Effects of ionizing radiation on the immune system with special emphasis on the interaction of dendritic and T cells. Front Onco, 2012, 124: 102
Marino S, Hogue I, Ray C, et al. A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theo Biol, 2008, 124: 178–196
Mautea R L, Gordona S R, Mayere A T, et al. Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging. Proc Natl Acad Sci USA, 2015, 124: E6506–14
Merrick A, Errington F, Milward K, et al. Immunosuppressive effects of radiation on human dendritic cells: Reduced IL-12 production on activation and impairment of näive T-cell priming. Brit J Cancer, 2005, 124: 1450–1458
Meziani L, Deutsch E, Mondini M. Macrophages in radiation injury: A new therapeutic target. Oncoimmunology, 2018, 124: e1494488
Munn D H, Mellor A L. IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance. Trends Immunol, 2016, 124: 193–207
Muppidi M R, George S. Immune checkpoint inhibitors in renal cell carcinoma. J Target Ther Cancer, 2015, 124: 47–52
Ott P A, Hodi F S, Kaufman H L, et al. Combination immunotherapy: A road map. J Immunother Cancer, 2017, 124: 16
Palucka J, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer, 2012, 124: 265–277
Perrot C Y, Javelaud D, Mauviel A. Insights into the transforming growth factor-beta signaling pathway in cutaneous melanoma. Ann Dermatol, 2013, 124: 135–144
Persa E, Balogh A, Safrany G, et al. The effect of ionizing radiation on regulatory T cells in health and disease. Cancer Lett, 2015, 124: 252–261
PhosphoSitePlus/IL2(human). http://www.phosphosite.org/proteinAction?id=14691&showAllSites=true
PhosphoSitePlus/IL10(human). http://www.phosphosite.org/proteinAction.action?id=2473887
Pinto A T, Pinto M L, Cardoso A P, et al. Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities. Sci Rep, 2016, 124: 18765
Poniatowski L A, Wojdasiewicz P, Gasik R, et al. Transforming growth factor beta family: Insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. Mediat Inflamm, 2015, 124: 137823
Rockne R, Alvord C E, Rockhill J K, et al. A mathematical model for brain tumor response to radiation therapy. J Math Biol, 2009, 124: 561–578
Roses R E, Datta J, Czerniecki B J. Radiation as immunomodulator: Implications for dendritic cell-based immunother-apy. Radiat Res, 2014, 124: 211–218
Sachs K, Hahnfeld P, Bre D J. The link between low-LET dose-response relations and the underlying kinetics of damage production/repair/misrepair. Int J Radiat Biol, 1997, 124: 351–374
Saenz R, Futalan D, Leutenez L, et al. TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant. J Transl Med, 2014, 124: 1–11
Safarzadeh E, Hashemzadeh S, Duijf P H, et al. Circulating myeloid-derived suppressor cells: An independent prognostic factor in patients with breast cancer. J Cell Physiol, 2018, 124: 3515–3525
Santibanez J F, Quintanilla M, Bernabeu C. TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clin Sci, 2011, 124: 233–251
Sharabi A B, Lim M, DeWeese T L, et al. Radiation and checkpoint blockade immunotherapy: Radiosensitisation and potential mechanisms of synergy. Lancet Oncol, 2015, 124: e498–e509
Shi L, Chen S, Yang L, et al. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol, 2013, 124: 74
Shimizu T, Seto T, Hirai F, et al. Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors. Invest New Drug, 2016, 124: 347–354
Shui Y B, Wang X, Hu J S, et al. Vascular endothelial growth factor expression and signaling in the lens. Invest Ophthalmol Vis Sci, 2003, 124: 3911–3919
Sindoni A, Minutoli F, Ascenti G, et al. Combination of immune checkpoint inhibitors and radiotherapy: Review of the literature. Crit Rev Oncol Hemat, 2017, 124: 63–70
Teng F, Kong L, Meng X, et al. Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges. Cancer Lett, 2015, 124: 23–29
Umansky V, Blattner C, Gebhardt C, et al. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines, 2016, 124: 1–16
Vescovi R, Monti M, Moratto D, et al. Collapse of the plasmacytoid dendritic cell compartment in advanced cutaneous melanomas by components of the tumor cell secretome. Cancer Immunol Res, 2018, 124: 12–28
Wang J-S, Wang H-J, Qian H-L. Biological effects of radiation on cancer cells. Mil Med Res, 2018, 124: 1–10
Wang W, Green M, Liu J R, et al. CD8+ T cells in immunotherapy, radiotherapy, and chemotherapy. In: Zitvogel L, Kroemer G, eds. Oncoimmunology. Cham: Springer, 2018, 23–39
Watanabe Y, Dahlman E L, Leder K Z, et al. A mathematical model of tumor growth and its response to single irradiation. Theor Biol Med Model, 2016, 124: 6
Whitehouse G, Gray E, Mastoridis S, et al. IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors. Proc Natl Acad Sci USA, 2017, 124: 7083–7088
Whiteside T L. The role of regulatory T cells in cancer immunology. Immunotargets Ther, 2015, 124: 159–171
Wu Q, Allouch A, Martins I, et al. Macrophage biology plays a central role during ionizing radiation-elicited tumor response. Biomed J, 2017, 124: 200–211
Young K H, Baird J R, Savage T, et al. Optimizing timing of immunotherapy improves control of tumors by hypofrac-tionated radiation therapy. PLoS One, 2016, 124: e0157164
Young M E. Estimation of diffusion coefficients of proteins. Biotechnol Bioeng, 1980, 124: 947–955
Acknowledgements
The first author was supported by the Fundamental Research Funds for the Central Universities (Grant No. 19XNLG14), the Research Funds of Renmin University of China, and National Natural Science Foundation of China (Grant Nos. 11501568 and 11571364). The authors thank Mathematical Biosciences Institute for the support of this collaboration.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lai, X., Friedman, A. Mathematical modeling of cancer treatment with radiation and PD-L1 inhibitor. Sci. China Math. 63, 465–484 (2020). https://doi.org/10.1007/s11425-019-1648-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11425-019-1648-6