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Potential Biomarkers for the Efficacy of PD-1-PD-L Blockade in Cancer.

ABSTRACT: A decade ago, immune checkpoint blockade emerged as a major breakthrough in oncology, proposing a novel approach by which immune brakes could be released to enhance antitumor responses. Despite apparently modest improvement of the median duration of response, a spectacular doubling of long-term responses as compared to the available standard of care was seen, for instance, in metastatic melanoma. It soon became obvious that the percentage of patients responding to these novel approaches is relatively small, and the importance of an accurate prediction of responders became more and more clear. Strong predictive markers would allow for the administration of immune checkpoint blocker therapy to the patients most likely to benefit from it, and sparing the potential non-responders of a treatment which is far from innocuous, being associated with significant side-effects and, not least, an important price tag. A number of potential response predictors have already been investigated and partly validated, but they do not cover the major unmet need encountered in the current clinical setting. Here, we review biomarkers for immune checkpoint blockade efficacy, either clinically validated and currently in use, or which have been proposed as candidates and are currently under investigation.

SUBMITTER: Grecea M

PROVIDER: S-EPMC8627113 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Potential Biomarkers for the Efficacy of PD-1-PD-L Blockade in Cancer.

Grecea Miruna M Soritau Olga O Dulf Daniel D Ciuleanu Tudor Eliade TE Zdrenghea Mihnea M

OncoTargets and therapy 20211117

A decade ago, immune checkpoint blockade emerged as a major breakthrough in oncology, proposing a novel approach by which immune brakes could be released to enhance antitumor responses. Despite apparently modest improvement of the median duration of response, a spectacular doubling of long-term responses as compared to the available standard of care was seen, for instance, in metastatic melanoma. It soon became obvious that the percentage of patients responding to these novel approaches is relat ...[more]

PMID: 34848970

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Project description:BackgroundThe activity of PD-1/PD-L1 inhibitors in the treatment of advanced bladder cancer (BC) is promising for many patients. However, a subset of patients do not benefit from treatment, thus leading to an effort to better identify predictive molecular biomarkers of response.ObjectiveTo conduct a systematic review of the literature on predictive molecular biomarkers associated with response to PD-1 and PD-L1 inhibitors in advanced bladder cancer, defined as locally-advanced, unresectable, or metastatic (mBC) disease.MethodsA search of the literature was performed using Embase (1947 - January 2019), Medline (1946 - January 2019), and EBM Reviews for Cochrane Central Register of Controlled Trials (as of December 2018). Studies examining the association of molecular biomarkers with clinical outcome in BC treated with PD-1 or PD-L1 monotherapy were included. Outcomes of interest were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), duration of response, and objective response rate (ORR).ResultsUsing the study search criteria, 899 unique abstract citations were found, of which 834 did not meet the eligibility criteria. Full text of the remaining 65 citations were screened, and 50 studies excluded, including 18 review articles. Eight additional studies from the bibliography of the review papers were included, making a total of 23 studies. Five PD-1 / PD-L1 antibodies have been tested in BC immunohistochemistry (IHC). These studies used different expression scoring criteria and generally had poor ability to discriminate likelihood for response. Overall, the data suggests CD8+ T cell infiltration is necessary to mediate an antitumor immune response, but other immune cell populations, such as neutrophils may suppress T cell-mediated immunity and efficacy of PD-1/PD-L1 blockade. An IFNγ signature is a promising predictor, but there needs to be consensus on the optimal gene panel composition, and prospective validation. Tumor mutation burden (TMB) is a promising predictor in six studies reporting on 1200 patients, but there is not a consensus on the optimal definition of "high TMB". Detection of T cell receptor (TCR) clonal expansion has only been conducted in small studies and so its predictive value remains inconclusive. Epithelial-mesenchymal transformation (EMT) and transforming growth factor β (TGFβ) are associated with poor prognosis and possibly intrinsic resistance to PD-1/PD-L1 checkpoint blockade, but more work needs to be done to build upon and confirm the initial findings.ConclusionsCurrently no molecular biomarker is sufficiently mature for routine clinical use, while some candidates, or a combination show great promise and need further study.

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Dataset Information

Potential Biomarkers for the Efficacy of PD-1-PD-L Blockade in Cancer.

Publications

Potential Biomarkers for the Efficacy of PD-1-PD-L Blockade in Cancer.

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