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

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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.

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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

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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.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, School of Medicine, University of Alabama at Birmingham (UAB), 1824 6th Ave S, WTI 510C, Birmingham, AL, 35294, USA

    Larisa Pereboeva

  2. Division of Hematology and Oncology, School of Medicine, University of Alabama at Birmingham (UAB), 1824 6th Ave S, WTI 530, Birmingham, AL, 35294, USA

    Lualhati Harkins

  3. Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada

    Shun Wong

  4. Division of Hematology and Oncology, School of Medicine, University of Alabama at Birmingham (UAB), 1824 6th Ave S, WTI 510F, Birmingham, AL, 35294, USA

    Lawrence S. Lamb

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  1. Larisa Pereboeva
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  2. Lualhati Harkins
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  3. Shun Wong
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  4. Lawrence S. Lamb
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Correspondence to Larisa Pereboeva.

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Pereboeva, L., Harkins, L., Wong, S. et al. The safety of allogeneic innate lymphocyte therapy for glioma patients with prior cranial irradiation. Cancer Immunol Immunother 64, 551–562 (2015). https://doi.org/10.1007/s00262-015-1662-z

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  • DOI: https://doi.org/10.1007/s00262-015-1662-z

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