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Cancer Immunology, Immunotherapy

, Volume 64, Issue 5, pp 551–562 | Cite as

The safety of allogeneic innate lymphocyte therapy for glioma patients with prior cranial irradiation

  • Larisa PereboevaEmail author
  • Lualhati Harkins
  • Shun Wong
  • Lawrence S. Lamb
Original Article

Abstract

The standard treatment of high-grade glioma presents a combination of radiotherapy, chemotherapy and surgery. Immunotherapy is proposed as a potential adjunct to standard cytotoxic regimens to target remaining microscopic disease following resection. We have shown ex vivo expanded/activated γδ T cells to be a promising innate lymphocyte therapy based on their recognition of stress antigens expressed on gliomas. However, successful integration of γδ T cell therapy protocols requires understanding the efficacy and safety of adoptively transferred immune cells in the post-treatment environment. The unique features of γδ T cell product and the environment (hypoxia, inflammation) can affect levels of expression of key cell receptors and secreted factors and either promote or hinder the feasibility of γδ T cell therapy. We investigated the potential for the γδ T cells to injure normal brain tissue that may have been stressed by treatment. We evaluated γδ T cell toxicity by assessing actual and correlative toxicity indicators in several available models including: (1) expression of stress markers on normal primary human astrocytes (as surrogate for brain parenchyma) after irradiation and temozolomide treatment, (2) cytotoxicity of γδ T cells on normal and irradiated primary astrocytes, (3) microglial activation and expression of stress-induced ligands in mouse brain after whole-brain irradiation and (4) expression of stress-induced markers on human brain tumors and on normal brain tissue. The lack of expression of stress-induced ligands in all tested models suggests that γδ T cell therapy is safe for brain tumor patients who undergo standard cytotoxic therapies.

Keywords

Gamma delta T cells Glioblastoma Cancer immunotherapy Irradiation Safety 

Abbreviations

BrdU

Bromodeoxyuridine

CAR

Chimeric antigen receptor

CTL

Cytotoxic T lymphocytes

DAPI

4′,6-diamidino-2-phenylindole, nuclear counterstaining dye

DDR

DNA damage response

E:T

Effector-to-target ratio

FFPE

Formalin-fixed paraffin-embedded specimens

GBM

Glioblastoma multiforme

γδ T

Gamma delta T cells

IHC

Immunohistochemistry

IL

Interleukin

LAK

Lymphokine-activated killer cells

NK

Natural killer cells

TCR

T cell receptor

TMZ

Temozolomide

TNFα

Tumor necrosis factor α

UAB

University of Alabama at Birmingham

ZOL

Zoledronic acid

Notes

Acknowledgments

We thank Dr. Mitchell S. Berger, Department of Neurological Surgery, University of California, San Francisco for making available FFPE samples of human brain tumors. Support from Elsa U Pardee Foundation (Lawrence S. Lamb) is acknowledged and appreciated.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Ishikawa E, Takano S, Ohno T, Tsuboi K (2012) Adoptive cell transfer therapy for malignant gliomas. Adv Exp Med Biol 746:109–120CrossRefPubMedGoogle Scholar
  2. 2.
    Bielamowicz K, Khawja S, Ahmed N (2013) Adoptive cell therapies for glioblastoma. Front Oncol 3:275CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Lamb LS (2009) Gammadelta T cells as immune effectors against high-grade gliomas. Immunol Res 45:85–95CrossRefPubMedGoogle Scholar
  4. 4.
    Vantourout P, Hayday A (2013) Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol 13:88–100CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Beetz S, Marischen L, Kabelitz D, Wesch D (2007) Human gamma delta T cells: candidates for the development of immunotherapeutic strategies. Immunol Res 37:97–111CrossRefPubMedGoogle Scholar
  6. 6.
    Kabelitz D, Wesch D, He W (2007) Perspectives of gammadelta T cells in tumor immunology. Cancer Res 67:5–8CrossRefPubMedGoogle Scholar
  7. 7.
    Preusser M, de Ribaupierre S, Wöhrer A, Erridge SC, Hegi M et al (2011) Current concepts and management of glioblastoma. Ann Neurol 70:9–21CrossRefPubMedGoogle Scholar
  8. 8.
    Mukherjee D, Coates PJ, Lorimore SA, Wright EG (2014) Responses to ionizing radiation mediated by inflammatory mechanisms. J Pathol 232:289–299CrossRefPubMedGoogle Scholar
  9. 9.
    Zhao W, Robbins ME (2009) Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem 16:130–143CrossRefPubMedGoogle Scholar
  10. 10.
    Friedman EJ (2002) Immune modulation by ionizing radiation and its implications for cancer immunotherapy. Curr Pharm Des 8:1765–1780CrossRefPubMedGoogle Scholar
  11. 11.
    Rödel F, Frey B, Gaipl U, Keilholz L, Fournier C et al (2012) Modulation of inflammatory immune reactions by low-dose ionizing radiation: molecular mechanisms and clinical application. Curr Med Chem 19:1741–1750CrossRefPubMedGoogle Scholar
  12. 12.
    Rödel F, Frey B, Multhoff G, Gaipl U (2015) Contribution of the immune system to bystander and non-targeted effects of ionizing radiation. Cancer Lett 356:105–113CrossRefPubMedGoogle Scholar
  13. 13.
    Bryant NL, Gillespie GY, Lopez RD, Markert JM, Cloud GA et al (2011) Preclinical evaluation of ex vivo expanded/activated γδ T cells for immunotherapy of glioblastoma multiforme. J Neurooncol 101:179–188CrossRefPubMedGoogle Scholar
  14. 14.
    Wu KL, Tu B, Li YQ, Wong CS (2010) Role of intercellular adhesion molecule-1 in radiation-induced brain injury. Int J Radiat Oncol Biol Phys 76:220–228CrossRefPubMedGoogle Scholar
  15. 15.
    Spear P, Wu MR, Sentman ML, Sentman CL (2013) NKG2D ligands as therapeutic targets. Cancer Immun 13:8PubMedCentralPubMedGoogle Scholar
  16. 16.
    Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413–441CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Kim SJ, Kim JS, Park ES, Lee JS, Lin Q et al (2011) Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13:286–298PubMedCentralPubMedGoogle Scholar
  18. 18.
    Wang L, Cossette SM, Rarick KR, Gershan J, Dwinell MB et al (2013) Astrocytes directly influence tumor cell invasion and metastasis in vivo. PLoS One 8:e80933CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Moore ED, Kooshki M, Metheny-Barlow LJ, Gallagher PE, Robbins ME (2013) Angiotensin-(1–7) prevents radiation-induced inflammation in rat primary astrocytes through regulation of MAP kinase signaling. Free Radic Biol Med 65:1060–1068CrossRefPubMedGoogle Scholar
  20. 20.
    Lamb LS, Bowersock J, Dasgupta A, Gillespie GY, Su Y et al (2013) Engineered drug resistant γδ T cells kill glioblastoma cell lines during a chemotherapy challenge: a strategy for combining chemo- and immunotherapy. PLoS One 8:e51805CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer immunotherapy. Science 342:1432–1433CrossRefPubMedGoogle Scholar
  22. 22.
    Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM et al (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18:843–851CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Nicol AJ, Tokuyama H, Mattarollo SR, Hagi T, Suzuki K et al (2011) Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours. Br J Cancer 105:778–786CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Gomes AQ, Martins DS, Silva-Santos B (2010) Targeting γδ T lymphocytes for cancer immunotherapy: from novel mechanistic insight to clinical application. Cancer Res 70:10024–10027CrossRefPubMedGoogle Scholar
  25. 25.
    Bryant NL, Suarez-Cuervo C, Gillespie GY, Markert JM, Nabors LB et al (2009) Characterization and immunotherapeutic potential of gammadelta T-cells in patients with glioblastoma. Neuro Oncol 11:357–367CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Coudert JD, Held W (2006) The role of the NKG2D receptor for tumor immunity. Semin Cancer Biol 16:333–343CrossRefPubMedGoogle Scholar
  27. 27.
    Schmudde M, Braun A, Pende D, Sonnemann J, Klier U et al (2008) Histone deacetylase inhibitors sensitize tumour cells for cytotoxic effects of natural killer cells. Cancer Lett 272:110–121CrossRefPubMedGoogle Scholar
  28. 28.
    Rohner A, Langenkamp U, Siegler U, Kalberer CP, Wodnar-Filipowicz A (2007) Differentiation-promoting drugs up-regulate NKG2D ligand expression and enhance the susceptibility of acute myeloid leukemia cells to natural killer cell-mediated lysis. Leuk Res 31:1393–1402CrossRefPubMedGoogle Scholar
  29. 29.
    Poggi A, Catellani S, Garuti A, Pierri I, Gobbi M et al (2009) Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate. Leukemia 23:641–648CrossRefPubMedGoogle Scholar
  30. 30.
    Rosental B, Appel MY, Yossef R, Hadad U, Brusilovsky M et al (2012) The effect of chemotherapy/radiotherapy on cancerous pattern recognition by NK cells. Curr Med Chem 19:1780–1791CrossRefPubMedGoogle Scholar
  31. 31.
    Kim JY, Son YO, Park SW, Bae JH, Chung JS et al (2006) Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation. Exp Mol Med 38:474–484CrossRefPubMedGoogle Scholar
  32. 32.
    Bedel R, Thiery-Vuillemin A, Grandclement C, Balland J, Remy-Martin JP et al (2011) Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res 71:1615–1626CrossRefPubMedGoogle Scholar
  33. 33.
    Xu X, Rao GS, Groh V, Spies T, Gattuso P et al (2011) Major histocompatibility complex class I-related chain A/B (MICA/B) expression in tumor tissue and serum of pancreatic cancer: role of uric acid accumulation in gemcitabine-induced MICA/B expression. BMC Cancer 11:194CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Butler JE, Moore MB, Presnell SR, Chan HW, Chalupny NJ et al (2009) Proteasome regulation of ULBP1 transcription. J Immunol 182:6600–6609CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Riederer I, Sievert W, Eissner G, Molls M, Multhoff G (2010) Irradiation-induced up-regulation of HLA-E on macrovascular endothelial cells confers protection against killing by activated natural killer cells. PLoS One 5:e15339CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Gasser S, Orsulic S, Brown EJ, Raulet DH (2005) The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436:1186–1190CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Hayday AC (2009) Gammadelta T cells and the lymphoid stress-surveillance response. Immunity 31:184–196CrossRefPubMedGoogle Scholar
  38. 38.
    Schwacha MG (2009) Gammadelta T-cells: potential regulators of the post-burn inflammatory response. Burns 35:318–326CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Matsushima A, Ogura H, Fujita K, Koh T, Tanaka H et al (2004) Early activation of gammadelta T lymphocytes in patients with severe systemic inflammatory response syndrome. Shock 22:11–15CrossRefPubMedGoogle Scholar
  40. 40.
    Williams J, Chen Y, Rubin P, Finkelstein J, Okunieff P (2003) The biological basis of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:182–188CrossRefPubMedGoogle Scholar
  41. 41.
    Lee WH, Sonntag WE, Mitschelen M, Yan H, Lee YW (2010) Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain. Int J Radiat Biol 86:132–144CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Rola R, Sarkissian V, Obenaus A, Nelson GA, Otsuka S et al (2005) High-LET radiation induces inflammation and persistent changes in markers of hippocampal neurogenesis. Radiat Res 164:556–560CrossRefPubMedGoogle Scholar
  43. 43.
    Schindler MK, Forbes ME, Robbins ME, Riddle DR (2008) Aging-dependent changes in the radiation response of the adult rat brain. Int J Radiat Oncol Biol Phys 70:826–834CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Greene-Schloesser D, Moore E, Robbins ME (2013) Molecular pathways: radiation-induced cognitive impairment. Clin Cancer Res 19:2294–2300CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Moravan MJ, Olschowka JA, Williams JP, O’Banion MK (2011) Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain. Radiat Res 176:459–473CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Larisa Pereboeva
    • 1
    Email author
  • Lualhati Harkins
    • 2
  • Shun Wong
    • 3
  • Lawrence S. Lamb
    • 4
  1. 1.Division of Hematology and Oncology, School of MedicineUniversity of Alabama at Birmingham (UAB)BirminghamUSA
  2. 2.Division of Hematology and Oncology, School of MedicineUniversity of Alabama at Birmingham (UAB)BirminghamUSA
  3. 3.Department of Radiation Oncology, Sunnybrook Health Sciences CentreUniversity of TorontoTorontoCanada
  4. 4.Division of Hematology and Oncology, School of MedicineUniversity of Alabama at Birmingham (UAB)BirminghamUSA

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