Implementing Keytruda/Pembrolizumab Testing in Clinical Practice

Ratner, Dmitry; Lennerz, Jochen K.

doi:10.1634/theoncologist.2017-0591

Cited by 6 publications

(10 citation statements)

References 6 publications

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“…DNA MMR-deficient (dMMR) causes an increased rate of mismatch errors, which further triggers microsatellite instability (MSI) (Lynch et al, 2010). Notably, DNA MMR-deficient phenomenon is common in most types of tumors (Ratner and Lennerz, 2018). A previous study found that 42 out of 149 tumor specimens exhibited loss of MMR protein by IHC (Yamashita et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Identification of an Immune-Related Prognostic Predictor in Hepatocellular Carcinoma

Wen

Luo

et al. 2020

Front. Mol. Biosci.

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Liver hepatocellular carcinoma (LIHC) is the most prevalent primary cancer of the liver, and immune-related genes (IRGs) regulate its development. So far, there is still no precise biomarker that predicts response to immunotherapy in LIHC. Therefore, this research seeks to identify immunogenic prognostic biomarkers and explore potential predictors for the efficacy of anti-PD-1/PD-L1 therapies in LIHC. The clinical data and gene expression profiles of patients diagnosed with LIHC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Moreover, IRGs were obtained from the ImmPort database. We discovered 35 IRGs that were differentially expressed between LIHC tissues and corresponding normal tissues. Through univariate Cox regression analysis, eight prognostic differentially expressed IRGs (PDEIRGs) were identified. Further, three optimal PDEIRGs (BIRC5, LPA, and ROBO1) were identified and used to construct a prognostic risk signature of LIHC patients via multivariate Cox regression analysis. The signature was validated by ROC curves. Subsequently, based on gene set enrichment analysis (GSEA) analysis, two out of the three optimal PDEIRGs (BIRC5 and LPA) were significantly enriched in the mismatch repair (MMR) pathway. Moreover, the two PDEIRGs (BIRC5 and LPA) were significantly correlated with the expression of genes related to mismatch repair (MLH1, MSH2, MSH6, and PMS2). Furthermore, correlations between the two PDEIRGs (BIRC5 and LPA) and immune checkpoints of cancer treatment (such as CTLA4, PD-1, and PD-L1) were demonstrated. Hyperprogressive disease (HPD) is a novel pattern of tumor progression which has a close relationship with immune checkpoint inhibitors (ICIs) utilization. MDM2 family amplification might promote the HPD phenomenon. Finally, we found a positive regulatory relationship between HPD related gene (MDM2) and BIRC5. Notably, MDM2 can either interact directly with BIRC5 or indirectly via downstream transcription factors of BIRC5. Overall, our study uncovered a novel 3-immune-related prognostic genes in LIHC.

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Section: Discussionmentioning

confidence: 99%

Identification of an Immune-Related Prognostic Predictor in Hepatocellular Carcinoma

Wen

Luo

et al. 2020

Front. Mol. Biosci.

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“…MSI is detected in about 15% of all colorectal cancers: 3% are associated with Lynch syndrome and about 12% are caused by sporadic, acquired hypermethylation of the promoter of the MLH1 gene, which occurs in tumors with the CpG island methylator phenotype [55]. MMR deficiency is also common in endometrial cancer, and other tumor types [56]. In a recent study, 42 of 149 tumor specimens exhibited loss of MMR protein by IHC.…”

Section: Standard Approved Biomarkers: Pd-l1 and Mmrmentioning

confidence: 99%

“…Studies suggest that IHC-based and MSI-based tests are both equally sensitive, with recommendations to use IHC-testing as a first line of screening because it is inexpensive and readily available [65]. In terms of dMMR testing, both PCR and IHC have ~ 90% sensitivity; combining both tests can increase sensitivity further [56].…”

Section: Standard Approved Biomarkers: Pd-l1 and Mmrmentioning

confidence: 99%

“…Thus, it is essential to identify other tumor DDR defects that produce a similar phenotype as an MMR defect in order to identify suitable candidates for clinical trials with immunotherapy checkpoint inhibitors. Finally, broader application of IHC and/or PCR MMR testing across multiple tumor types and not only colon cancer is warranted based on MMR-specific FDA approval [56]. A recent study in CRC showed that Fusobacterium nucleatum , a bacterium found in the gut, regulates tumor immune response based on the tumor MSI status [68].…”

Section: Standard Approved Biomarkers: Pd-l1 and Mmrmentioning

confidence: 99%

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Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors

et al. 2019

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In the last few years, immunotherapy has transformed the way we treat solid tumors, including melanoma, lung, head neck, breast, renal, and bladder cancers. Durable responses and long-term survival benefit has been experienced by many cancer patients, with favorable toxicity profiles of immunotherapeutic agents relative to chemotherapy. Cures have become possible in some patients with metastatic disease. Additional approvals of immunotherapy drugs and in combination with other agents are anticipated in the near future. Multiple additional immunotherapy drugs are in earlier stages of clinical development, and their testing in additional tumor types is under way. Despite considerable early success and relatively fewer side effects, the majority of cancer patients do not respond to checkpoint inhibitors. Additionally, while the drugs are generally well tolerated, there is still the potential for significant, unpredictable and even fatal toxicity with these agents. Improved biomarkers may help to better select patients who are more likely to respond to these drugs. Two key biologically important predictive tissue biomarkers, specifically, PD-L1 and mismatch repair deficiency, have been FDA-approved in conjunction with the checkpoint inhibitor, pembrolizumab. Tumor mutation burden, another promising biomarker, is emerging in several tumor types, and may also soon receive approval. Finally, several other tissue and liquid biomarkers are emerging that could help guide single-agent immunotherapy and in combination with other agents. Of these, one promising investigational biomarker is alteration or deficiency in DNA damage response (DDR) pathways, with altered DDR observed in a broad spectrum of tumors. Here, we provide a critical overview of current, emerging, and investigational biomarkers in the context of response to immunotherapy in solid tumors.

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“…In August 2019 a further open label Phase I-II clinical trial investigating the efficacy and the safety of the combination of ataluren with pembrolizumab for the treatment of metastatic mismatch repair deficient and proficient colorectal adenocarcinoma and metastatic mismatch repair deficient endometrial carcinoma was sponsored by the University of Amsterdam (NCT04014530). Pembrolizumab (commercially available as Keytruda ® ) is a clinically approved humanized monoclonal antibody able to block the interaction between the programmed cell death protein (PD)-1 and its ligands which is currently used for the treatment of non-small-cell lung carcinoma (NSCLC) and other solid tumors [223]. Ataluren combination with Pembrolizumab was hypothesized because many deficient metastatic mismatch repair cancers often possessout-of-frame PTCs.…”

Section: Ataluren and Analoguesmentioning

confidence: 99%

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

Bezzerri

Api

Allegri

et al. 2020

IJMS

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Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS.

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Implementing Keytruda/Pembrolizumab Testing in Clinical Practice

Abstract: This Commentary addresses the FDA approval of pembrolizumab and the changes necessary in clinical practice to identify patients who would benefit from such treatment.

Cited by 6 publications

References 6 publications

Identification of an Immune-Related Prognostic Predictor in Hepatocellular Carcinoma

Identification of an Immune-Related Prognostic Predictor in Hepatocellular Carcinoma

Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

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