. 2015 Jul; 33(51):7415-7422.
doi: 10.1016/j.vaccine.2015.05.105.

In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment

Claire Vanpouille-Box 1 Karsten A Pilones 1 Erik Wennerberg 1 Silvia C Formenti 2 Sandra Demaria 3 
  • PMID: 26148880
  •     96 References
  •     64 citations


Targeting immune checkpoint receptors has emerged as an effective strategy to induce immune-mediated cancer regression in the subset of patients who have significant pre-existing anti-tumor immunity. For the remainder, effective anti tumor responses may require vaccination. Radiotherapy, traditionally used to achieve local tumor control, has acquired a new role, that of a partner for immunotherapy. Ionizing radiation has pro-inflammatory effects that facilitate tumor rejection. Radiation alters the tumor to enhance the concentration of effector T cells via induction of chemokines, cytokines and adhesion molecules. In parallel, radiation can induce an immunogenic death of cancer cells, promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. Newly generated anti-tumor immune responses have been demonstrated post-radiation in both murine models and occasional patients, supporting the hypothesis that the irradiated tumor can become an in situ vaccine. It is in this role, that radiation can be applied to induce anti-tumor T cells in lymphocyte-poor tumors, and possibly benefit patients who would otherwise fail to respond to immune checkpoint inhibitors. This review summarizes preclinical and clinical data demonstrating that radiation acts in concert with antibodies targeting the immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4), to induce therapeutically effective anti-tumor T cell responses in tumors otherwise non responsive to anti-CTLA-4 therapy.

Keywords: Abscopal effect; Immmune checkpoint; Immunotherapy; Radiation-induced vaccination.

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Front Oncol, 2016 Nov 17; 6. PMID: 27847783    Free PMC article.
Highly Cited. Review.
Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone.
Kristian M Koller, Heath B Mackley, +9 authors, Joseph J Drabick.
Cancer Biol Ther, 2016 Dec 03; 18(1). PMID: 27905824    Free PMC article.
Radiotherapy and immunotherapy: a beneficial liaison?
Ralph R Weichselbaum, Hua Liang, Liufu Deng, Yang-Xin Fu.
Nat Rev Clin Oncol, 2017 Jan 18; 14(6). PMID: 28094262
Highly Cited. Review.
Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols.
Matthew T Silvestrini, Elizabeth S Ingham, +12 authors, Katherine W Ferrara.
JCI Insight, 2017 Mar 30; 2(6). PMID: 28352658    Free PMC article.
Following the Preclinical Data: Leveraging the Abscopal Effect More Efficaciously.
Wilfred Ngwa, Zi Ouyang.
Front Oncol, 2017 Apr 28; 7. PMID: 28447024    Free PMC article.
Cancer Vaccines in Ovarian Cancer: How Can We Improve?
Silvia Martin Lluesma, Anita Wolfer, Alexandre Harari, Lana E Kandalaft.
Biomedicines, 2017 May 26; 4(2). PMID: 28536377    Free PMC article.
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.
Narek Shaverdian, Aaron E Lisberg, +5 authors, Percy Lee.
Lancet Oncol, 2017 May 30; 18(7). PMID: 28551359    Free PMC article.
Highly Cited.
Modulating Both Tumor Cell Death and Innate Immunity Is Essential for Improving Radiation Therapy Effectiveness.
Qiuji Wu, Awatef Allouch, +4 authors, Jean-Luc Perfettini.
Front Immunol, 2017 Jun 13; 8. PMID: 28603525    Free PMC article.
Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells.
Nils-Petter Rudqvist, Karsten A Pilones, +7 authors, Sandra Demaria.
Cancer Immunol Res, 2017 Nov 29; 6(2). PMID: 29180535    Free PMC article.
Defining the role of the tumor vasculature in antitumor immunity and immunotherapy.
Marco B Schaaf, Abhishek D Garg, Patrizia Agostinis.
Cell Death Dis, 2018 Jan 27; 9(2). PMID: 29371595    Free PMC article.
Highly Cited. Review.
Radiation effects on antitumor immune responses: current perspectives and challenges.
Thomas Walle, Rafael Martinez Monge, +3 authors, Fernando Lecanda.
Ther Adv Med Oncol, 2018 Feb 01; 10. PMID: 29383033    Free PMC article.
Highly Cited. Review.
Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations-Chances and Challenges.
Marvin Kuske, Ricarda Rauschenberg, +5 authors, Friedegund Meier.
Am J Clin Dermatol, 2018 Feb 09; 19(4). PMID: 29417399    Free PMC article.
Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors.
Jason J Luke, Jeffrey M Lemons, +17 authors, Steven J Chmura.
J Clin Oncol, 2018 Feb 14; 36(16). PMID: 29437535    Free PMC article.
Highly Cited.
Immune modulatory effects of radiotherapy as basis for well-reasoned radioimmunotherapies.
Michael Rückert, Lisa Deloch, +3 authors, Udo S Gaipl.
Strahlenther Onkol, 2018 Mar 04; 194(6). PMID: 29500551
Highly Cited. Review.
Radiotherapy-induced anti-tumor immune response and immune-related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti-PD-1 immunotherapy.
T Finazzi, T Rordorf, +3 authors, H I Garcia Schueler.
BMC Cancer, 2018 Apr 08; 18(1). PMID: 29625593    Free PMC article.
Combination therapy with PD-1/PD-L1 blockade: An overview of ongoing clinical trials.
C Bryce Johnson, Shwe Y Win.
Oncoimmunology, 2018 Apr 11; 7(4). PMID: 29632719    Free PMC article.
Beyond checkpoint inhibition - Immunotherapeutical strategies in combination with radiation.
F Eckert, U S Gaipl, +4 authors, D Zips.
Clin Transl Radiat Oncol, 2017 Feb 04; 2. PMID: 29657997    Free PMC article.
Abscopal effect of radiotherapy combined with immune checkpoint inhibitors.
Yang Liu, Yinping Dong, +3 authors, Jinming Yu.
J Hematol Oncol, 2018 Aug 18; 11(1). PMID: 30115069    Free PMC article.
Highly Cited. Review.
Effective nivolumab sequential thoracic radiotherapy in elderly patients with advanced squamous cell lung cancer: did radiation therapy play a role? A case report.
Grazia Lazzari, Angela Terlizzi, +4 authors, Giovanni Silvano.
Onco Targets Ther, 2018 Aug 21; 11. PMID: 30122953    Free PMC article.
Radiotherapy-Induced Changes in the Systemic Immune and Inflammation Parameters of Head and Neck Cancer Patients.
Katalin Balázs, Enikő Kis, +12 authors, Katalin Lumniczky.
Cancers (Basel), 2019 Sep 11; 11(9). PMID: 31500214    Free PMC article.
Exercise as Adjunct Therapy in Cancer.
Kathleen A Ashcraft, Allison Betof Warner, Lee W Jones, Mark W Dewhirst.
Semin Radiat Oncol, 2018 Dec 24; 29(1). PMID: 30573180    Free PMC article.
Dramatic Response to Concurrent Anti-PD-1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation.
Sameer Tolay, Ranjit Nair, +2 authors, Suresh G Nair.
Oncologist, 2018 Aug 15; 24(1). PMID: 30104290    Free PMC article.
Tumor regression after combination of radiation and PD-1 antibody nivolumab treatment in a patient with metastatic mediastinal leiomyosarcoma: a case report.
Chen Xi, Zhang Wencheng, +7 authors, Wang Ping.
Cancer Biol Ther, 2018 Nov 06; 20(4). PMID: 30388926    Free PMC article.
Immune targets in the tumor microenvironment treated by radiotherapy.
Omer M Ozpiskin, Lu Zhang, Jian Jian Li.
Theranostics, 2019 Mar 15; 9(5). PMID: 30867826    Free PMC article.
Highly Cited. Review.
Combinatorial Approaches With Checkpoint Inhibitors to Enhance Anti-tumor Immunity.
Barbara Seliger.
Front Immunol, 2019 Jun 11; 10. PMID: 31178856    Free PMC article.
Induction of anti-cancer T cell immunity by in situ vaccination using systemically administered nanomedicines.
Geoffrey M Lynn, Richard Laga, Christopher M Jewell.
Cancer Lett, 2019 Jun 12; 459. PMID: 31185250    Free PMC article.
Intratumoral Gene Electrotransfer of Plasmid DNA Encoding shRNA against Melanoma Cell Adhesion Molecule Radiosensitizes Tumors by Antivascular Effects and Activation of an Immune Response.
Simona Kranjc Brezar, Valter Mrak, +3 authors, Maja Cemazar.
Vaccines (Basel), 2020 Mar 25; 8(1). PMID: 32204304    Free PMC article.
Transcriptional Upregulation of NLRC5 by Radiation Drives STING- and Interferon-Independent MHC-I Expression on Cancer Cells and T Cell Cytotoxicity.
Lauren K Zebertavage, Alejandro Alice, Marka R Crittenden, Michael J Gough.
Sci Rep, 2020 May 02; 10(1). PMID: 32355214    Free PMC article.
Engineering nanoparticles to reprogram radiotherapy and immunotherapy: recent advances and future challenges.
Jing Jin, Qijie Zhao.
J Nanobiotechnology, 2020 May 16; 18(1). PMID: 32408880    Free PMC article.
The Impact of Locoregional Treatment on Response to Nivolumab in Advanced Platinum Refractory Head and Neck Cancer: The Need Trial.
Andrea Botticelli, Silvia Mezi, +16 authors, Paolo Marchetti.
Vaccines (Basel), 2020 Apr 25; 8(2). PMID: 32326034    Free PMC article.
In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases.
Paul A Clark, Raghava N Sriramaneni, +16 authors, Zachary S Morris.
J Immunother Cancer, 2020 Jul 22; 8(2). PMID: 32690669    Free PMC article.
Radiation-induced bystander and abscopal effects: important lessons from preclinical models.
Elisabeth Daguenet, Safa Louati, +6 authors, Nicolas Magné.
Br J Cancer, 2020 Jun 26; 123(3). PMID: 32581341    Free PMC article.
Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors.
Magalie Dosset, Elodie Lauret-Marie Joseph, Thaiz Rivera Vargas, Lionel Apetoh.
Cells, 2020 Jul 28; 9(7). PMID: 32707692    Free PMC article.
Combined radiotherapy and immunotherapy in urothelial bladder cancer: harnessing the full potential of the anti-tumor immune response.
Mame Daro-Faye, Wassim Kassouf, +4 authors, Paul Sargos.
World J Urol, 2020 Sep 12; 39(5). PMID: 32915313    Free PMC article.
Targeting MerTK Enhances Adaptive Immune Responses After Radiation Therapy.
Garth W Tormoen, Tiffany C Blair, +10 authors, Marka Crittenden.
Int J Radiat Oncol Biol Phys, 2020 Apr 21; 108(1). PMID: 32311417    Free PMC article.
Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model.
Yiannis Philippou, Hanna T Sjoberg, +16 authors, Richard J Bryant.
Br J Cancer, 2020 Jul 10; 123(7). PMID: 32641865    Free PMC article.
Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death.
Hongzhang Deng, Weijing Yang, +5 authors, Xiaoyuan Chen.
Nat Commun, 2020 Oct 04; 11(1). PMID: 33009382    Free PMC article.
Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations.
Madyson Colton, Eleanor J Cheadle, Jamie Honeychurch, Tim M Illidge.
Radiat Oncol, 2020 Nov 06; 15(1). PMID: 33148287    Free PMC article.
Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment.
Joshua R D Pearson, Stefania Cuzzubbo, +5 authors, Stephanie E B McArdle.
Front Immunol, 2020 Nov 13; 11. PMID: 33178210    Free PMC article.
Combining PARP inhibition, radiation, and immunotherapy: A possible strategy to improve the treatment of cancer?
Mathieu Césaire, Juliette Thariat, +3 authors, François Chevalier.
Int J Mol Sci, 2018 Nov 30; 19(12). PMID: 30487462    Free PMC article.
Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy.
Amy J Wisdom, Yvonne M Mowery, +22 authors, David G Kirsch.
Nat Commun, 2020 Dec 19; 11(1). PMID: 33335088    Free PMC article.
Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers.
Yuehong Kong, Yifu Ma, +3 authors, Liyuan Zhang.
Front Oncol, 2021 Apr 17; 11. PMID: 33859942    Free PMC article.
Systematic Review.
Combination of Bempegaldesleukin and Anti-CTLA-4 Prevents Metastatic Dissemination After Primary Resection or Radiotherapy in a Preclinical Model of Non-Small Cell Lung Cancer.
Amber M Bates, Ryan J Brown, +10 authors, Zachary S Morris.
Front Oncol, 2021 May 04; 11. PMID: 33937052    Free PMC article.
Checkpoint inhibition in combination with an immunoboost of external beam radiotherapy in solid tumors (CHEERS): study protocol for a phase 2, open-label, randomized controlled trial.
Mathieu Spaas, Nora Sundahl, +14 authors, Piet Ost.
BMC Cancer, 2021 May 09; 21(1). PMID: 33962592    Free PMC article.
Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway.
Julie Constanzo, Julien Faget, +2 authors, Jean-Pierre Pouget.
Front Immunol, 2021 Jun 04; 12. PMID: 34079557    Free PMC article.
Prognostic Impact of Sarcopenia and Radiotherapy in Patients With Advanced Gastric Cancer Treated With Anti-PD-1 Antibody.
Nalee Kim, Jeong Il Yu, +6 authors, Kyoung-Mee Kim.
Front Immunol, 2021 Jul 27; 12. PMID: 34305941    Free PMC article.
Revisiting the Radiobiology of Targeted Alpha Therapy.
Jean-Pierre Pouget, Julie Constanzo.
Front Med (Lausanne), 2021 Aug 14; 8. PMID: 34386508    Free PMC article.
Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.
Ravi B Patel, Reinier Hernandez, +19 authors, Zachary S Morris.
Sci Transl Med, 2021 Jul 16; 13(602). PMID: 34261797    Free PMC article.
Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study.
Wencheng Zhang, Cihui Yan, +15 authors, Qingsong Pang.
Oncoimmunology, 2021 Oct 08; 10(1). PMID: 34616588    Free PMC article.
Granzyme B PET Imaging in Response to In Situ Vaccine Therapy Combined with αPD1 in a Murine Colon Cancer Model.
Siddesh V Hartimath, Boominathan Ramasamy, +6 authors, Julian L Goggi.
Pharmaceutics, 2022 Jan 22; 14(1). PMID: 35057046    Free PMC article.
Effective Combinations of Immunotherapy and Radiotherapy for Cancer Treatment.
Siting Yu, Yang Wang, +9 authors, Lei Liu.
Front Oncol, 2022 Feb 25; 12. PMID: 35198442    Free PMC article.
Preoperative Stereotactic Radiosurgery for Glioblastoma.
Eric J Lehrer, Henry Ruiz-Garcia, +6 authors, Daniel M Trifiletti.
Biology (Basel), 2022 Feb 26; 11(2). PMID: 35205059    Free PMC article.
The impact of radiation therapy on the TCR Vβ chain repertoire in patients with prostate cancer.
Maria Goulielmaki, Nikolaos Davanos, +10 authors, Sotirios P Fortis.
Int J Oncol, 2022 Apr 22; 60(6). PMID: 35445738    Free PMC article.