Anti-PD-1, anti-TIM-3, and radiation in glioma model

Introduction: Checkpoint molecules like programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme (GBM). Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model (1) . However, tumor-infiltrating lymphocytes (TILs) can express multiple checkpoints, and expression of {greater than or equal to}2 checkpoints corresponds to a more exhausted T cell phenotype (2) . We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. Methods: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (1) control, (2) SRS, (3) anti-PD-1 antibody, (4) anti-TIM-3 antibody, (5) anti-PD-1+SRS, (6) anti-TIM-3+SRS, (7) anti-PD-1+anti-TIM-3, and (8) anti-PD-1+anti-TIM-3+SRS. Survival and immune activation were assessed. Results: Dual therapy with anti-TIM-3 antibody+SRS or anti-TIM-3+anti-PD-1 improved survival compared to anti-TIM-3 antibody alone. Triple therapy resulted in 100% OS (p<0.05), a significant improvement compared to other arms. Long-term survivors demonstrated increased immune cell infiltration and activity, and immune memory. Lastly, positive staining for TIM-3 was detected in 7/8 human GBM samples. Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human GBM and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of GBM.

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