방사선의학 웹진

바로가기  >

Abstract

PURPOSE:

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. 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. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. 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.

EXPERIMENTAL DESIGN:

C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) 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 with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 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 glioblastoma multiforme 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 glioblastoma multiforme.

Translational Relevance

To our knowledge, this is the first preclinical investigation on the antitumor effects of TIM-3 blockade with stereotactic radiosurgery and/or anti-PD-1 in the setting of established glioma. Using a syngeneic orthotopic murine glioma model, we demonstrate that severely exhausted PD-1+TIM-3+ lymphocytes accumulate in intracranial tumors in a time-dependent manner and that combination radiation and dual immune checkpoint blockade results in a significant increase in survival. Our study demonstrates the presence of TIM-3–expressing targets in human glioblastoma multiforme, provides preclinical evidence for a novel treatment combination that has potential to improve the antitumor immune response and result in durable immunity, and has direct implications for a clinical trial.​

​Author information

Kim JE1, Patel MA1, Mangraviti A1, Kim ES1, Theodros D1, Velarde E2, Liu A1, Sankey EW1, Tam A3, Xu H4, Mathios D1, Jackson CM1, Harris-Bookman S1, Garzon-Muvdi T1, Sheu M5, Martin AM1, Tyler BM1, Tran PT2, Ye X1, Olivi A1, Taube JM4, Burger PC1,4,6, Drake CG6, Brem H1, Pardoll DM6, Lim M7.

1Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland.
2Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland.
3Flow Cytometry Core, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
4Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
5Department of Dermatology, Johns Hopkins University, Baltimore, Maryland.
6Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
7Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland. mlim3@jhmi.edu.
​