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Combining Radiotherapy and Immunotherapy: Emerging Preclinical Observations of Lymphocyte Costimulatory and Inhibitory Receptor Modulation

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Increasing the Therapeutic Ratio of Radiotherapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

A greater understanding of immune system biology has translated into more effective cancer immunotherapeutics. This has prompted exploration of the combination of these agents with other cancer treatments such as radiotherapy, which has also been shown to promote antitumor immunity independently. This review will present data from reports of immune modulators and radiotherapy and will discuss common themes and observations. Costimulatory molecules including CD40 and CD134/OX40; glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR), CD137/4-1BB; and inhibitory molecules CD152/cytotoxic T lymphocyte-associated protein 4 (CTLA4), lymphocyte activation gene 3 (LAG3), programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1), and T cell immunoglobulin and mucin domain 3 (TIM-3) will be discussed. Observations regarding radiotherapy sequencing, dose, and fractionation will also be addressed. We conclude that a strategy combining immune modulation and radiotherapy is rational and holds promise for future successful translation in clinical trials.

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References

  1. Lee Y et al (2009) Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114(3):589–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Apetoh L et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050–1059

    Article  CAS  PubMed  Google Scholar 

  3. Reits EA et al (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203(5):1259–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Green DR et al (2009) Immunogenic and tolerogenic cell death. Nat Rev Immunol 9(5):353–363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Golden EB, Apetoh L (2015) Radiotherapy and immunogenic cell death. Semin Radiat Oncol 25(1):11–17

    Article  PubMed  Google Scholar 

  6. Sharma A et al (2011) Gamma-Radiation promotes immunological recognition of cancer cells through increased expression of cancer-testis antigens in vitro and in vivo. PLoS One 6(11), e28217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chakraborty M et al (2004) External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 64(12):4328–4337

    Article  CAS  PubMed  Google Scholar 

  8. Matsumura S, Demaria S (2010) Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation. Radiat Res 173(4):418–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Formenti SC, Demaria S (2013) Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 105(4):256–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sharma P, Allison JP (2015) The future of immune checkpoint therapy. Science 348(6230):56–61

    Article  CAS  PubMed  Google Scholar 

  11. Golden EB et al (2012) The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol 2:88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Burnette B, Weichselbaum RR (2013) Radiation as an immune modulator. Semin Radiat Oncol 23(4):273–280

    Article  PubMed  Google Scholar 

  13. Demaria S et al (2004) Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58(3):862–870

    Article  PubMed  Google Scholar 

  14. Vinay DS, Kwon BS (2012) Immunotherapy of cancer with 4-1BB. Mol Cancer Ther 11(5):1062–1070

    Article  CAS  PubMed  Google Scholar 

  15. Shi W, Siemann DW (2006) Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment. Anticancer Res 26(5A):3445–3453

    CAS  PubMed  Google Scholar 

  16. Newcomb EW et al (2010) Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. Radiat Res 173(4):426–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weinberg AD et al (2011) Science gone translational: the OX40 agonist story. Immunol Rev 244(1):218–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yokouchi H et al (2008) Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer. Cancer Sci 99(2):361–367

    Article  CAS  PubMed  Google Scholar 

  19. Gough MJ et al (2010) Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice. J Immunother 33(8):798–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schaer DA, Hirschhorn-Cymerman D, Wolchok JD (2014) Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy. J Immunother Cancer 2:7

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yoshimoto Y et al (2014) Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model. PLoS One 9(3), e92572

    Article  PubMed  PubMed Central  Google Scholar 

  22. Moran AE, Kovacsovics-Bankowski M, Weinberg AD (2013) The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol 25(2):230–237

    Article  CAS  PubMed  Google Scholar 

  23. Honeychurch J et al (2003) Anti-CD40 monoclonal antibody therapy in combination with irradiation results in a CD8 T-cell-dependent immunity to B-cell lymphoma. Blood 102(4):1449–1457

    Article  CAS  PubMed  Google Scholar 

  24. Verbrugge I et al (2012) Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res 72(13):3163–3174

    Article  CAS  PubMed  Google Scholar 

  25. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736

    Article  CAS  PubMed  Google Scholar 

  26. Demaria S et al (2005) Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11(2 Pt 1):728–734

    CAS  PubMed  Google Scholar 

  27. Dewan MZ et al (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15(17):5379–5388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu L et al (2015) Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model. Oncotarget 6(14):12468–12480

    Article  PubMed  PubMed Central  Google Scholar 

  29. Son CH et al (2014) CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model. J Immunother 37(1):1–7

    Article  CAS  PubMed  Google Scholar 

  30. Nirschl CJ, Drake CG (2013) Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clin Cancer Res 19(18):4917–4924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Topalian SL, Drake CG, Pardoll DM (2012) Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24(2):207–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zeng J et al (2013) Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 86(2):343–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sharabi AB et al (2015) Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res 3(4):345–355

    Article  CAS  PubMed  Google Scholar 

  34. Park SS et al (2015) PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res 3(6):610–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Deng L et al (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124(2):687–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dovedi SJ et al (2014) Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74(19):5458–5468

    Article  CAS  PubMed  Google Scholar 

  37. Twyman-Saint Victor C et al (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520(7547):373–377

    Article  CAS  PubMed  Google Scholar 

  38. Belcaid Z et al (2014) Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS One 9(7), e101764

    Article  PubMed  PubMed Central  Google Scholar 

  39. Jing W et al (2015) Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma. J Immunother Cancer 3(1):2

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 275 York Avenue, New York, NY, 10065, USA

    Robert M. Samstein & Christopher A. Barker

  2. Ludwig Collaborative and Swim Across America Laboratory, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Sadna Budhu & Taha Mergoub

Authors
  1. Robert M. Samstein
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  2. Sadna Budhu
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  3. Taha Mergoub
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  4. Christopher A. Barker
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Corresponding author

Correspondence to Christopher A. Barker .

Editor information

Editors and Affiliations

  1. Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Philip J. Tofilon

  2. 1Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Kevin Camphausen

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Samstein, R.M., Budhu, S., Mergoub, T., Barker, C.A. (2017). Combining Radiotherapy and Immunotherapy: Emerging Preclinical Observations of Lymphocyte Costimulatory and Inhibitory Receptor Modulation. In: Tofilon, P., Camphausen, K. (eds) Increasing the Therapeutic Ratio of Radiotherapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-40854-5_7

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  • DOI: https://doi.org/10.1007/978-3-319-40854-5_7

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  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-40852-1

  • Online ISBN: 978-3-319-40854-5

  • eBook Packages: MedicineMedicine (R0)

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