Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies

Garber, Sarah T.; Hashimoto, Yuichi; Weathers, Shiao Pei; Xiu, Joanne; Gatalica, Zoran; Verhaak, Roel G.W.; Zhou, Shouhao; Fuller, Gregory N.; Khasraw, Mustafa; Groot, John de; Reddy, Sandeep K.; Spetzler, David; Heimberger, Amy B.

doi:10.1093/neuonc/now132

Cited by 126 publications

(111 citation statements)

References 38 publications

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“…Glioblastomas contain a greater number of PD‐1+ TILs than lower‐grade gliomas, and the PD‐1 expression on TILs is significantly increased in recurrent tumors compared with initial tumors . Foxp3+ Tregs expressing PD‐1 were also shown to be enriched in human glioblastoma tissue .…”

Section: Discussionmentioning

confidence: 99%

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

et al. 2018

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Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of programmed cell death‐1 (PD‐1)/PD ligand‐1 (PD‐L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD‐1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor‐associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post‐Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long‐term Bev therapy.

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Section: Discussionmentioning

confidence: 99%

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

et al. 2018

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“…Analyzed proteins and antibodies used are listed in Supporting Information Table S2. PD‐L1 staining results are specific for membranous staining, and PD‐1 expression was evaluated by analysis of tumor‐infiltrating lymphocytes as previously described 10. The expression of PD‐L1 was analyzed with B7‐H1 antibody (R&D systems) using automated immunohistochemical methods.…”

Section: Methodsmentioning

confidence: 99%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

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“…A study with a small sample of 10 patients demonstrated that PD-L1 protein expression was detected in all 9 glioblastoma (WHO IV) specimens and in 1 mixed glioma (WHO III) specimen [11]. However, in a large series of human glioma samples involving 345 patients, the rate of PD-L1 expression positivity was found to be only 6.1%; specifically, positivity was found in 0/54 grade I/II, 0/47 grade III, and 21/244 grade IV gliomas (3 gliosarcoma and 18 GBM cases) [13]. However, there were substantial variations in the sample sizes, the ratios of the different pathological grades, the methods of preparing the tumor tissues, the antibodies used, and the diagnosis standards, including the expression patterns and positivity cut-offs, among these studies, which contributed to the biases in the results; these differences are characterized in Table 1.…”

Section: Pd-l1 Expression and Prognosis Value In Gliomasmentioning

confidence: 99%

Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy

et al. 2017

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Gliomas are the most common type of primary brain tumor in adults. High-grade neoplasms are associated with poor prognoses, whereas low-grade neoplasms are associated with 5-year overall survival rates of approximately 85%. Despite considerable progress in treatment modalities, the outcomes remain dismal. As is the case with many other tumors, gliomas express or secrete several immunosuppressive molecules that regulate immune cell function. Programmed death-ligand 1 (PD-L1) is a coinhibitory ligand that is predominantly expressed by tumor cells. The binding of PD-L1 to its receptor PD-1 has been demonstrated to induce an immune escape mechanism and to play a critical role in tumor initiation and development. Encouraging results following the blockade of the PD-1/PD-L1 pathway have validated PD-L1 or PD-1 as a target for cancer immunotherapy. Studies have reported that the PD-1/PD-L1 pathway plays a key role in glioma progression and in the efficacy of immunotherapies. Thus, progress in research into PD-L1 will enable us to develop a more effective and individualized immunotherapeutic strategy for gliomas. In this paper, we review PD-L1 expression, PD-L1-mediated immunosuppressive mechanisms, and the clinical applications of PD-1/PD-L1 inhibitors in gliomas. Potential treatment strategies and the challenges that may occur during the clinical development of these agents for gliomas are also reviewed.

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Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies

Cited by 126 publications

References 38 publications

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

Profiles of brain metastases: Prioritization of therapeutic targets

Blocking the PD-1/PD-L1 pathway in glioma: a potential new treatment strategy

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