Efficacy of PD-1 Blockade in Tumors with MMR Deficiency

Lee, Valerie; Le, Dung T.

doi:10.2217/imt.15.97

Cited by 66 publications

(59 citation statements)

References 7 publications

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“…Immunotherapy (Nivolumab) combined with stereotactic body radiotherapy showed exceptional results in a patient with advanced, chemotherapy‐refractory large‐cell neuroendocrine carcinoma of the cervix with high mutational burden . As a virally mediated tumour, SmCC‐Cx is likely to harbour high antigenicity, which makes it an amenable target for immune modulation, similar to neoplasms with a high mutational burden . Recent evidence indicates that the tumour suppressor RB1 , which is frequently affected in SmCC, is also involved in immune functions with down‐regulation of a multitude of immune genes in tumours with RB1 loss .…”

Section: Discussionmentioning

confidence: 99%

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

et al. 2019

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Aims Neuroendocrine carcinoma, small cell type, of the uterine cervix (SmCC‐Cx) is a rare human papilloma virus (HPV) related tumour with limited therapeutic options. Merkel cell carcinoma, another virus‐associated neuroendocrine malignancy, has significant programmed death ligand 1 (PD‐L1) expression rates. PD‐L1 expression has been reported in other malignancies of the cervix. We aimed to determine the prevalence of PD‐L1 in the context of mismatch repair protein (MMR) and RB1 expression status in SmCC‐Cx. Methods and results Ten cases of SmCC‐Cx were tested by immunohistochemistry for expression of PD‐L1, MLH1, MSH2, MSH6, PMS2, RB1, CD3, CD20 and for HPV by in‐situ hybridisation (ISH). PD‐L1 expression was scored quantitatively (H‐score) in tumour cells and lymphocytes (tumoral/peritumoral). PD‐L1 positivity was seen in seven cases, focal in most (H‐score range 3–140). Three of nine cases showed MMR deficiency. PD‐L1 expression levels correlated with MMR expression status: all three MLH1/PMS2‐deficient cases had a ≥5% PD‐L1 staining and an H‐score ≥10 (P = 0.01). RB1 was lost in four of nine cases, all PD‐L1 positive, but this correlation was not statistically significant. Seven of nine tumours were positive for HPV‐ISH; two of these had MLH1/PMS2 loss. Of the two HPV‐ISH negative tumours, one had MLS1/PMS2 loss. Conclusions PD‐L1 expression, predominantly focal, is seen in 70% of SmCC‐Cx, while loss of MMR expression is seen in 33% of SmCC‐Cx in our cohort. PD‐L1 expression in more than 10% of tumour cells is seen in a subset of tumours in association with loss of MMR expression. These patients may be amenable to immune checkpoint inhibitor therapy as a promising alternative for this aggressive disease.

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Section: Discussionmentioning

confidence: 99%

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

et al. 2019

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“…In fact, a high mutational burden entails the fact that some neoantigens become visible to the immune system and potential targets of the T cell response. Recently it has been demonstrated that tumors harboring hypermutations may stronger respond to immunotherapy with checkpoint inhibitors, such as the anti-programmed cell death-1 (PD-1) [97,98]. It has been reported that hypoxia can induce MGMT expression in GSCs, promoting chemoresistance [30].…”

Section: Resistance Mechanisms To Alkylating Agentsmentioning

confidence: 99%

Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Annovazzi

Mellai

Schiffer

2017

Cancers

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Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood–brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize the cytotoxicity of chemo- and radio-therapeutic agents, driving resistance and tumor relapse. It seems that a subpopulation of stem-like cells, indicated as glioma stem cells (GSCs), is responsible for tumor initiation, maintenance and recurrence and they appear to be more resistant owing to their enhanced DNA repair capacity. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis and in the modulation of therapeutic treatment effects. In this review, we try to summarize the knowledge concerning the main molecular mechanisms involved in the removal of genotoxic lesions caused by alkylating agents, emphasizing the role of GSCs. Beside their increased DNA repair capacity in comparison with non-stem tumor cells, GSCs show a constitutive checkpoint expression that enables them to survive to treatments in a quiescent, non-proliferative state. The targeted inhibition of checkpoint/repair factors of DDR can contribute to eradicate the GSC population and can have a great potential therapeutic impact aiming at sensitizing malignant gliomas to treatments, improving the overall survival of patients.

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“…Recent meta-analyses have shown that gastric cancers with EBV positivity and microsatellite instability are most likely to overexpress PDL-1 [9]. Microsatellite instability (MSI-high) already serves as a biomarker in predicting utility of immune checkpoint inhibitors [10], where the PD-1 antibody, pembrolizumab, is FDA approved for use in MSI-high gastric cancers that have progressed on standard treatment. Most recently, results from the global phase II KEYNOTE-059 trial [11] showed an improved overall response rate to pembrolizumab in gastric cancer patients with overexpression of PDL-1.…”

Section: Introductionmentioning

confidence: 99%

Outlooks on Epstein-Barr virus associated gastric cancer

Naseem

Barzi

Brezden-Masley

et al. 2018

Cancer Treatment Reviews

166

143

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Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC.

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Efficacy of PD-1 Blockade in Tumors with MMR Deficiency

Cited by 66 publications

References 7 publications

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Outlooks on Epstein-Barr virus associated gastric cancer

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