Importance of iatrogenic immunosuppression in the treatment of patients with high-grade glioma with immunotherapy

Treatment-related lymphopenia is a poor prognostic factor for overall survival in patients with high-grade glioma and predicts suboptimal response to immune therapies. Immunotherapy is conceptually an appealing approach in adults with high-grade glioma given that effector lymphocytes are capable of penetrating the blood–brain barrier. However, 40% of these patients develop severe lymphopenia (CD4 counts <200) following concurrent radiation and temozolomide. These low lymphocyte counts are associated with inferior survival. Research suggests that this iatrogenic immunosuppression is attributed to the inadvertent radiation of circulating lymphocytes as they traverse the irradiated field. Lymphocyte subtypes are universally affected by this radiation toxicity. These findings have been reproduced in animal studies, and clinical correlations have been demonstrated in patients with various malignancies. This lymphopenia has been linked with failure to respond to immunologic interventions. Recent insights into the etiology of this radiation-induced lymphopenia have triggered a variety of novel approaches to prevent or restore immunologic function in this patient population. These include altering radiation plans, reducing the number of lymphocytes passing through the radiation field, harvesting lymphocytes before and reinfusing them after radiation, and using growth factors to restore lymphocyte counts. This manuscript reviews critical relationships between treatment-related lymphopenia and immunotherapy outcomes in patients with high-grade gliomas and novel approaches to these issues.