Journal Article
. 2016 Jun; 11(6):e0157164.
doi: 10.1371/journal.pone.0157164.

Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy

Kristina H Young 1 Jason R Baird 1 Talicia Savage 1 Benjamin Cottam 1 David Friedman 1 Shelly Bambina 1 David J Messenheimer 1 Bernard Fox 1 Pippa Newell 2 Keith S Bahjat 1 Michael J Gough 1 Marka R Crittenden 1 
  • PMID: 27281029
  •     39 References
  •     109 citations


The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstrate that the combination of immunotherapy and radiation results in improved therapeutic efficacy, and that the ideal timing of administration with radiation is dependent on the mechanism of action of the immunotherapy utilized.

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Changhoon Choi, Gyu Sang Yoo, Won Kyung Cho, Hee Chul Park.
World J Gastroenterol, 2019 Jun 07; 25(20). PMID: 31171886    Free PMC article.
Radiation and immunotherapy: emerging mechanisms of synergy.
William G Breen, Konstantinos Leventakos, Haidong Dong, Kenneth W Merrell.
J Thorac Dis, 2020 Dec 08; 12(11). PMID: 33282406    Free PMC article.
Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy.
M R Landry, A N DuRoss, +4 authors, C Sun.
Mater Today Bio, 2020 Dec 10; 8. PMID: 33294836    Free PMC article.
Enhancing Combined Immunotherapy and Radiotherapy through Nanomedicine.
C Tilden Hagan, Yu Mi, Nicole M Knape, Andrew Z Wang.
Bioconjug Chem, 2020 Dec 01; 31(12). PMID: 33251789    Free PMC article.
Radiotherapy-Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?
Erminia Romano, Jamie Honeychurch, Timothy M Illidge.
Cancers (Basel), 2021 Feb 04; 13(3). PMID: 33530329    Free PMC article.
Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments.
Adrien Procureur, Audrey Simonaggio, +2 authors, Yann-Alexandre Vano.
Cancers (Basel), 2021 Feb 12; 13(4). PMID: 33567530    Free PMC article.
A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes.
Amit Maity, Rosemarie Mick, +9 authors, John N Lukens.
Oncoimmunology, 2021 Mar 02; 10(1). PMID: 33643689    Free PMC article.
Combined Treatment of Radiotherapy and Immunotherapy for Urological Malignancies: Current Evidence and Clinical Considerations.
Haoran Lei, Ming Shi, +4 authors, Lu Yang.
Cancer Manag Res, 2021 Mar 05; 13. PMID: 33658847    Free PMC article.
Harnessing the potential of multimodal radiotherapy in prostate cancer.
Yiannis Philippou, Hanna Sjoberg, +2 authors, Richard J Bryant.
Nat Rev Urol, 2020 May 03; 17(6). PMID: 32358562
The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy.
Miles Piper, Adam C Mueller, Sana D Karam.
Mol Carcinog, 2020 May 05; 59(7). PMID: 32363633    Free PMC article.
Emerging Trends for Radio-Immunotherapy in Rectal Cancer.
Claudia Corrò, Valérie Dutoit, Thibaud Koessler.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33803620    Free PMC article.
Charged Particle and Conventional Radiotherapy: Current Implications as Partner for Immunotherapy.
Damiënne Marcus, Relinde I Y Lieverse, +4 authors, Ala Yaromina.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33806808    Free PMC article.
The role of radiotherapy in the age of immunotherapy.
Hiro Sato, Sandra Demaria, Tatsuya Ohno.
Jpn J Clin Oncol, 2021 Feb 10; 51(4). PMID: 33561212    Free PMC article.
Radiation for Oligometastatic Lung Cancer in the Era of Immunotherapy: What Do We (Need to) Know?
Stephanie T H Peeters, Evert J Van Limbergen, Lizza E L Hendriks, Dirk De Ruysscher.
Cancers (Basel), 2021 May 01; 13(9). PMID: 33925139    Free PMC article.
An overview of the published and running randomized phase 3 clinical results of radiotherapy in combination with immunotherapy.
Ben G L Vanneste, Evert J Van Limbergen, Kobe Reynders, Dirk De Ruysscher.
Transl Lung Cancer Res, 2021 May 21; 10(4). PMID: 34012813    Free PMC article.
Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma.
Rom Leidner, Marka Crittenden, +13 authors, R Bryan Bell.
J Immunother Cancer, 2021 May 09; 9(5). PMID: 33963014    Free PMC article.
Current Prospects for Treatment of Solid Tumors via Photodynamic, Photothermal, or Ionizing Radiation Therapies Combined with Immune Checkpoint Inhibition (A Review).
Sanjay Anand, Timothy A Chan, Tayyaba Hasan, Edward V Maytin.
Pharmaceuticals (Basel), 2021 Jun 03; 14(5). PMID: 34068491    Free PMC article.
Neoadjuvant Immunotherapy for High-Risk, Resectable Malignancies: Scientific Rationale and Clinical Challenges.
Mithunah Krishnamoorthy, John G Lenehan, Saman Maleki Vareki.
J Natl Cancer Inst, 2021 Jan 13; 113(7). PMID: 33432320    Free PMC article.
Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities.
Ravi B Patel, Claire C Baniel, +3 authors, Zachary S Morris.
Brachytherapy, 2018 Aug 07; 17(6). PMID: 30078541    Free PMC article.
A narrative review of combined stereotactic ablative radiotherapy and immunotherapy in metastatic non-small cell lung cancer.
Zarique Z Akanda, Paul J Neeson, +5 authors, Shankar Siva.
Transl Lung Cancer Res, 2021 Jul 24; 10(6). PMID: 34295676    Free PMC article.
Local Destruction of Tumors and Systemic Immune Effects.
Karl-Göran Tranberg.
Front Oncol, 2021 Jul 27; 11. PMID: 34307177    Free PMC article.
Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy.
Eswari Dodagatta-Marri, Hsiao-Yen Ma, +22 authors, Dean Sheppard.
Cell Rep, 2021 Jul 08; 36(1). PMID: 34233193    Free PMC article.
Local ablative therapies in oligometastatic NSCLC-upfront or outback?-a narrative review.
Michael C Tjong, Alexander V Louie, +3 authors, Shankar Siva.
Transl Lung Cancer Res, 2021 Aug 26; 10(7). PMID: 34430379    Free PMC article.
Concurrent Sorafenib and Radiotherapy versus Radiotherapy Alone for Locally Advanced Hepatocellular Carcinoma: A Propensity-Matched Analysis.
Chieh-Min Liu, Bing-Shen Huang, +6 authors, Jen-Yu Cheng.
J Hepatocell Carcinoma, 2021 Aug 27; 8. PMID: 34434903    Free PMC article.
Radioimmunotherapy: future prospects from the perspective of brachytherapy.
Maximilian Fleischmann, Markus Glatzer, Claus Rödel, Nikolaos Tselis.
J Contemp Brachytherapy, 2021 Sep 07; 13(4). PMID: 34484362    Free PMC article.
Cytoreductive stereotactic body radiotherapy (SBRT) and combination SBRT with immune checkpoint inhibitors in metastatic renal cell carcinoma.
Jonathan Peng, Aly-Khan Lalani, Anand Swaminath.
Can Urol Assoc J, 2021 Jan 08; 15(8). PMID: 33410742    Free PMC article.
The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances.
James R Janopaul-Naylor, Yang Shen, David C Qian, Zachary S Buchwald.
Int J Mol Sci, 2021 Oct 24; 22(20). PMID: 34681719    Free PMC article.
Current advances in immune checkpoint inhibitor combinations with radiation therapy or cryotherapy for breast cancer.
Alice Y Ho, Shervin Tabrizi, Samantha A Dunn, Heather L McArthur.
Breast Cancer Res Treat, 2021 Oct 30; 191(2). PMID: 34714450
Advances in Combining Radiation and Immunotherapy in Breast Cancer.
Anthony T Nguyen, Stephen L Shiao, Heather L McArthur.
Clin Breast Cancer, 2021 Apr 04; 21(2). PMID: 33810972    Free PMC article.
A Rational Approach to Unilateral Neck RT for Head and Neck Cancers in the Era of Immunotherapy.
Re-I Chin, Joshua P Schiff, +3 authors, Alexander J Lin.
Cancers (Basel), 2021 Nov 14; 13(21). PMID: 34771432    Free PMC article.
Bridging Radiotherapy to Immunotherapy: The IFN-JAK-STAT Axis.
Lewis Zhichang Shi, James A Bonner.
Int J Mol Sci, 2021 Nov 28; 22(22). PMID: 34830176    Free PMC article.
Systematic Review.
Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer.
Iosune Baraibar, Oriol Mirallas, +4 authors, Elena Élez.
Cancers (Basel), 2021 Dec 25; 13(24). PMID: 34944931    Free PMC article.
Immune System in Action.
Bettzy Stephen, Joud Hajjar.
Adv Exp Med Biol, 2022 Jan 02; 1342. PMID: 34972961
A Promising Treatment Strategy for Lung Cancer: A Combination of Radiotherapy and Immunotherapy.
Yuhei Miyasaka, Hiro Sato, +3 authors, Tatsuya Ohno.
Cancers (Basel), 2022 Jan 12; 14(1). PMID: 35008367    Free PMC article.
Combination radiation and immunotherapy in gynecologic malignancies-a comprehensive review.
Colton Ladbury, Elizabeth Germino, +4 authors, Scott Glaser.
Transl Cancer Res, 2022 Feb 05; 10(5). PMID: 35116574    Free PMC article.
Immune Response on Optimal Timing and Fractionation Dose for Hypofractionated Radiotherapy in Non-Small-Cell Lung Cancer.
Xianlan Zhao, Jixi Li, +7 authors, Jianguo Sun.
Front Mol Biosci, 2022 Feb 11; 9. PMID: 35141280    Free PMC article.
The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy.
José Antônio Fagundes Assumpção, Gabriel Pasquarelli-do-Nascimento, +2 authors, Kelly Grace Magalhães.
J Biomed Sci, 2022 Feb 16; 29(1). PMID: 35164764    Free PMC article.
Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade.
Alecsandra Gorzo, Diana Galos, +3 authors, Daniel Sur.
Life (Basel), 2022 Feb 26; 12(2). PMID: 35207516    Free PMC article.
Adoptive T-Cell Therapy in Advanced Colorectal Cancer: A Systematic Review.
Damie J Juat, Stephanie J Hachey, +4 authors, Jason A Zell.
Oncologist, 2022 Mar 12; 27(3). PMID: 35274719    Free PMC article.
Systematic Review.
Combinations of radiotherapy with immunotherapy in cervical cancer.
Xiaojing Yang, Hanru Ren, Jie Fu.
J Cancer, 2022 Apr 05; 13(5). PMID: 35371317    Free PMC article.
How to Improve SBRT Outcomes in NSCLC: From Pre-Clinical Modeling to Successful Clinical Translation.
Marina Milic, Michele Mondini, Eric Deutsch.
Cancers (Basel), 2022 Apr 13; 14(7). PMID: 35406477    Free PMC article.
Navigate Towards the Immunotherapy Era: Value of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Patients With Brain Metastases.
Guanqun Yang, Ligang Xing, Xiaorong Sun.
Front Immunol, 2022 Apr 16; 13. PMID: 35422812    Free PMC article.
Assessing the interactions between radiotherapy and antitumour immunity.
Clemens Grassberger, Susannah G Ellsworth, +2 authors, Jay S Loeffler.
Nat Rev Clin Oncol, 2019 Jun 28; 16(12). PMID: 31243334
Mathematical Modeling to Simulate the Effect of Adding Radiation Therapy to Immunotherapy and Application to Hepatocellular Carcinoma.
Wonmo Sung, Theodore S Hong, +2 authors, Clemens Grassberger.
Int J Radiat Oncol Biol Phys, 2021 Nov 15; 112(4). PMID: 34774999    Free PMC article.