PD-1/PD-L1 and immune-related gene expression pattern in pediatric malignant brain tumors: clinical correlation with survival data in Korean population

Hwang, Kihwan; Koh, Eun Jung; Choi, Eun Jin; Kang, Tae Hee; Han, Jung Ho; Choe, Gheeyoung; Park, Shin Young; Yearley, Jennifer H.; Annamalai, Lakshmanan; Blumenschein, Wendy M.; Sathe, Manjiri; McClanahan, Terri; Jung, Hun; Wang, Kyu Chang; Kim, Seung Ki; Kim, Chae Yong

doi:10.1007/s11060-018-2886-5

Cited by 24 publications

(18 citation statements)

References 25 publications

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“…The effects of PD-L1 expression on survival in pediatric brain tumors has been recently reported by a number of groups and shows considerable variability depending on tumor type. 7,[21][22][23] Larger clinical trials are needed to further explore this relationship, as our findings did not achieve statistical significance, possibly because of the small number of patients studied or lack of uniform diagnosis.…”

Section: Resultsmentioning

confidence: 76%

“…Nivolumab was discontinued in <6 weeks because of the radiographic evidence of disease progression in 6 patients, without making a distinction between true progression and pseudoprogression. [15][16][17][18][19][20][21][22][23][24] Five of these patients died shortly after discontinuation of the treatment, favoring true disease progression in those patients. Future studies involving checkpoint blockers should account for pseudoprogression in the disease evaluation and consider continuing the treatment despite radiographic evidence of progression early on, if patient remains clinically stable.…”

Section: Resultsmentioning

confidence: 99%

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Nivolumab in the Treatment of Recurrent or Refractory Pediatric Brain Tumors: A Single Institutional Experience

Gorsi

Malicki

Barsan

et al. 2019

Journal of Pediatric Hematology/Oncology

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Successful use of immune checkpoint inhibitors in a variety of cancers has generated interest in using this approach in pediatric brain tumors. We performed a retrospective review of 10 consecutive children (6 boys, 4 girls; ages, 2 to 17 y), with recurrent or refractory pediatric brain tumors (5 high-grade glioma, 1 lowgrade glioma, pineoblastoma, medulloblastoma, ependymoma, and CNS embryonal tumor, NOS) treated at Rady Children's Hospital San Diego from 2015 to 2017 with the immune checkpoint inhibitor nivolumab (3 mg/kg every 2 wk). Eight of 10 patients received prior chemotherapy and 9 radiation therapy. Nine patients had radiographic disease progression (median, 2.5 doses). Median time to progression was 5.5 weeks (1.6 to 24 wk). Three patients (2 with high-grade glioma, 1 with CNS embryonal tumor NOS) showed a partial response to treatment at the primary tumor site and 2 of 3 had progression of metastatic disease. Grade 2 toxicities were observed without dose limiting side effects. Tumor mutation burden (TMB) was low to intermediate (median, 1.3; range, 0 to 6.3). Median survival for PD-L1 positive patients was 13.7 weeks versus 4.2 weeks for PD-L1 negative patients (ρ = 0.08) nivolumab was well tolerated in our series of pediatric recurrent brain tumors with some transient partial responses in patients with positive PD-L1 expression and higher TMB. Our findings suggest that the use of immune checkpoint inhibitors in pediatric brain tumor patients should be limited to those with elevated PD-L1 expression and TMB.

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Nivolumab in the Treatment of Recurrent or Refractory Pediatric Brain Tumors: A Single Institutional Experience

Gorsi

Malicki

Barsan

et al. 2019

Journal of Pediatric Hematology/Oncology

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“…Recent pre-clinical evidence suggests that activation of the programmed cell death (PD-1) pathway within the tumor microenvironment plays a role in the pathogenesis of adult and pediatric high-grade gliomas [17][18][19][20][21][22]. In murine glioma models, PD-1 blockade prolongs survival and leads to durable responses [23,24].…”

Section: Introductionmentioning

confidence: 99%

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience

et al. 2018

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“…One study with 89 patients in Korea showed that 0% of medulloblastoma patients demonstrated expression of PD-L1 (0 out of 28 patients). 89 This was in direct contrast to other pediatric brain tumors including 40% of atypical teratoid/rhabdoid tumor (8 out of 20), 20% of ependymoma (4 out of 20), and 19% of high-grade glioma (4 out of 21) that demonstrate expression of PD-L1. This study concluded that medulloblastoma may not be a suitable candidate for PD-1 checkpoint blockade.…”

Section: Checkpoint Inhibitors In Medulloblastomamentioning

confidence: 72%

<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

Kabir¹,

Kunos²,

Villanó³

et al. 2020

ITT

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Background: Immune-mediated therapies have transformed the treatment of metastatic melanoma and renal, bladder, and both small and non-small cell lung carcinomas. However, immunotherapy is yet to demonstrate dramatic results in brain tumors like medulloblastoma for a variety of reasons. Recent pre-clinical and early phase human trials provide encouraging results that may overcome the challenges of central nervous system (CNS) tumors, which include the intrinsic immunosuppressive properties of these cancers, a lack of antigen targets, antigenic variability, and the immune-restrictive site of the CNS. These studies highlight the growing potential of immunotherapy to treat patients with medulloblastoma, a disease that is a frequent cause of morbidity and mortality to children and young adults. Methods: We conducted an inclusive review of the PubMed-indexed literature and studies listed in clinicaltrials.gov using combinations of the keywords medulloblastoma, immunotherapy, CNS tumors, brain tumors, vaccines, oncolytic virus, natural killer, and CAR T to identify trials evaluating immunotherapy in preclinical experiments or in patients with medulloblastoma. Given a limited number of investigations using immunotherapy to treat patients with medulloblastoma, 24 studies were selected for final analysis and manuscript citation. Results: This review presents results from pre-clinical studies in medulloblastoma cell lines, animal models, and the limited trials involving human patients. Conclusion: From our review, we suggest that cancer vaccines, oncolytic viral therapy, natural killer cells, and CAR T therapy hold promise against the innate immunosuppressive properties of medulloblastoma in order to prolong survival. There is an unmet need for immunotherapy regimens that target overexpressed antigens in medulloblastoma tumors. We advocate for more combination treatment clinical trials using conventional surgical and radiochemotherapy approaches in the near-term clinical development.

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PD-1/PD-L1 and immune-related gene expression pattern in pediatric malignant brain tumors: clinical correlation with survival data in Korean population

Cited by 24 publications

References 25 publications

Nivolumab in the Treatment of Recurrent or Refractory Pediatric Brain Tumors: A Single Institutional Experience

Nivolumab in the Treatment of Recurrent or Refractory Pediatric Brain Tumors: A Single Institutional Experience

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience

<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

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