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Neuro Oncol. 2019 Jan 22. doi: 10.1093/neuonc/noz015. [Epub ahead of print]

Modulation of temozolomide dose differentially affects T cell response to immune checkpoint inhibition.

Author information

1
Preston A. Wells Jr. Center for Brain Tumor Therapy UF Brain Tumor Immunotherapy Program Lillian S. Wells Department of Neurosurgery University of Florida Gainesville, FL.

Abstract

Background:

The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM.

Methods:

Immune function and anti-tumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25mg/kg x 10 days) or standard dose (SD) temozolomide (50 mg/kg x 5 days) in the GL261 and KR158 murine glioma models.

Results:

SD temozolomide treatment resulted in an upregulation of markers of T cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with PD-1 antibody therapy, MD temozolomide / PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes (TILs) that were not observed in the SD temozolomide /PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone.

Conclusion:

The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.

PMID:
30668768
DOI:
10.1093/neuonc/noz015

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