Nivolumab plus ipilimumab in advanced renal-cell carcinoma

Gunjur, Ashray

doi:10.1016/s1470-2045(18)30257-2

Cited by 8 publications

(7 citation statements)

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“…Another example of a tumor type with intermediate levels of TMB but a high response rate to ICB is RCC [3, 95, 96]. Recent work by Turajlic et al shows that in addition to single nucleotide variants, frameshift mutations generated by insertion and deletions that result in the generation of an entirely new peptide amino acid chain before a stop codon being reached, also contribute to the generation of potent tumor neoantigens and the overall TMB of cancers [97].…”

Section: Tmb Limitations and Perspectivesmentioning

confidence: 99%

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

et al. 2019

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BackgroundTreatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required.Materials and methodsIn this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity.ResultsHigh TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established.ConclusionsTMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.

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Section: Tmb Limitations and Perspectivesmentioning

confidence: 99%

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

et al. 2019

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“…Tumor mutation burden (TMB) can be used as a biomarker to predict the e cacy of ICBs (26). Some studies have shown that the RCC was sensitive to ICBs, although the TMB in RCC was moderate (27,28). To identify the somatic mutations that were altered by CTLA4 in ccRCC, we performed the mutation analysis and the result showed that overexpressed CTLA4 was correlated with BRCA-associated protein 1 (BAP1) mutation (p<0.05, Figure 3).…”

Section: Genetic Altered By Ctla4 In Ccrccmentioning

confidence: 99%

CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC)

Liu

Wang

Tan

et al. 2020

Preprint

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Background: Cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors have been shown to significantly prolong the overall survival (OS) in a wide range of cancers. However, its application in clear cell renal cell carcinoma (ccRCC) is limited due to the therapy response, and the prognostic value of CTLA4 in ccRCC has not been investigated in detail.Methods: By using immunohistochemistry, Kaplan-Meier (K-M) analysis, uni- and multi-variate Cox analysis, we comprehensively and systematically studied the prognostic value of CTLA4 in ccRCC. Then, we applied Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and CIBERSORT, ESTIMATE algorithm, ssGSEA and somatic mutation analyses to reveal the impact of CTLA4 on the landscape of tumor-infiltrating lymphocytes (TILs) infiltration and genetic mutation. Besides, given current concerns caused by combined immunotherapy, we also investigated the relationship between CTLA4 and other immune checkpoints.Results: In vitro experiment and data mining showed that, CTLA4 was up-regulated in ccRCC tissues and closely related to the disease progression as well as a poor prognosis. Deeper researches demonstrated that CTLA4 regulates T cell activation and was significantly linked to TIL-abundant tumor microenvironment (TME), but was accompanied by an immunosuppressed phenotype. Mutation analysis showed that CTLA4 was associated with more frequent BRCA-associated protein 1 (BAP1) mutation. Moreover, we found that CTLA4 was markedly correlated with multiple immune checkpoints, which suggested that ccRCC patients with high expressed CTLA4 may benefit more from immune checkpoint blockades (ICBs) combined therapy.Conclusion: CTLA4 has a profound impact on the landscape of TILs and genetic mutation, and can be used as the biomarker with high prognosis value in ccRCC.

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“…It exerted its biological function through inhibiting the PD-1/PD-L1 signal pathway and allowing the immune system to scavenge the tumor cells [ 38 ]. Around the world, nivolumab had been used in the treatment of metastatic melanoma, squamous non-small cell lung cancer and renal cell carcinoma [ 39 – 41 ]. Potential therapeutical effect of the drug on SCLC had also been explored.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum soluble programmed cell death ligand 1 concentration as a potential marker for poor prognosis in small cell lung cancer patients with chemotherapy

Jia

Liu

et al. 2018

Respir Res

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BackgroundPotential relationship between serum soluble programmed cell death ligand 1 and prognosis of small cell lung cancer is not well explored. The aim of the study was to reveal the prognostic significance of serum soluble programmed cell death ligand 1 in patients with small cell lung cancer.MethodsA total of 250 small cell lung cancer patients and 250 controls were included. Research information was obtained from their medical records. Blood samples were collected on admission. Serum concentration of programmed cell death ligand 1 was measured using Enzyme-Linked Immunosorbent Assay. The patients underwent cisplatin-etoposide chemotherapy with a maximum of six cycles. Subsequently, they were followed-up for 12 months, and therapeutic response and cancer death were recorded.ResultsSerum concentration of programmed cell death ligand 1 was higher in the patients than in the controls on admission (P < 0.001). After chemotherapy, 112 patients had no response to this therapy. In the 12-month follow up period, 118 patients died due to this cancer. Multivariate Cox regression model revealed that the higher serum concentration of programmed cell death ligand 1 on admission was associated with the higher risk of no response to chemotherapy or cancer caused death (HR: 1.40, 95% CI: 1.05 ~ 1.87; HR: 1.43, 95% CI: 1.08 ~ 1.87).ConclusionElevated serum concentration of soluble programmed cell death ligand 1 might be an independent risk factor for non-response to chemotherapy and cancer caused death in small cell lung cancer patients.

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Nivolumab plus ipilimumab in advanced renal-cell carcinoma

Cited by 8 publications

References 0 publications

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC)

Elevated serum soluble programmed cell death ligand 1 concentration as a potential marker for poor prognosis in small cell lung cancer patients with chemotherapy

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