Research ArticleCancer

Anti–PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM

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Science Translational Medicine  21 Dec 2016:
Vol. 8, Issue 370, pp. 370ra180
DOI: 10.1126/scitranslmed.aag2942

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Combining drugs as the doctor ordered

Cancer immunotherapy is rapidly increasing in prominence and being applied for a growing number of cancer types. Chemotherapy is still the mainstay of cancer treatment, however, and it can be difficult to find good ways to combine the two approaches. Mathios et al. addressed this problem by systematically evaluating the effectiveness of local or systemic chemotherapy given before or after immune checkpoint inhibition in mouse models of glioblastoma. The authors demonstrated that local chemotherapy was particularly effective in combination with checkpoint inhibition, whereas systemic chemotherapy was too damaging to the immune system to make for useful combinations.

Abstract

The immunosuppressive effects of chemotherapy present a challenge for designing effective cancer immunotherapy strategies. We hypothesized that although systemic chemotherapy (SC) exhibits negative immunologic effects, local chemotherapy (LC) can potentiate an antitumor immune response. We show that LC combined with anti–programmed cell death protein 1 (PD-1) facilitates an antitumor immune response and improves survival (P < 0.001) in glioblastoma. LC-treated mice had increased infiltration of tumor-associated dendritic cells and clonal expansion of antigen-specific T effector cells. In comparison, SC resulted in systemic and intratumoral lymphodepletion, with decreased immune memory in long-term survivors. Furthermore, adoptive transfer of CD8+ cells from LC-treated mice partially rescued SC-treated mice after tumor rechallenge. Last, the timing of chemo- and immunotherapy had differential effects on anti–PD-1 efficacy. This study suggests that both mode of delivery and timing have distinct effects on the efficacy of anti–PD-1. The results of this work could help guide the selection and scheduling of combination treatment for patients with glioblastoma and other tumor types.

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