Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy

Triple negative breast cancer (TNBC) is a high-risk and aggressive malignancy characterized by the absence of estrogen receptors (ER) and progesterone receptors (PR) on the surface of malignant cells, and by the lack of overexpression of human epidermal growth factor 2 (HER2). It has limited therapeutic options compared to other subtypes of breast cancer. There is now a growing body of evidence on the role of immunotherapy in TNBC, however much of the data from clinical trials is conflicting and thus, challenging for clinicians to integrate the data into clinical practice. Landmark phase III trials using immunotherapy in the early-stage neoadjuvant setting concluded that the addition of immunotherapy to chemotherapy improved the pathologic complete response (pCR) rate compared to chemotherapy with placebo while others found no significant improvement in pCR. Phase III trials have investigated the utility of immunotherapy in previously untreated metastatic TNBC, and these studies have similarly arrived at inconsistent conclusions. Some studies showed no benefit while others demonstrated a clinically significant improvement in overall survival in the PD-L1 positive population. It is not yet clear which biomarkers are most useful, and assays for these biomarkers have not been standardized. Given the often serious and severe side effects of immunotherapy, it is important and necessary to identify predictive biomarkers of response and resistance in order to enhance patient selection. In this review, we will discuss both the challenges of traditional biomarkers and the opportunities of emerging biomarkers for patient selection.

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“…88 Consequently, cfDNA is considered a surrogate marker for activation of the cGAS-STING pathway. 89…”

Section: Emerging Biomarkers Of Sensitivity To Immunotherapymentioning

confidence: 99%

“…88 Consequently, cfDNA is considered a surrogate marker for activation of the cGAS-STING pathway. 89 The cGAS-STING pathway is essential for the antitumoral activity of ICIs. Mice that are deficient in this pathway are resistant to the effects of PD-L1 inhibition.…”

Section: Cytoplasmic Dna and The Cgas-sting Pathwaymentioning

confidence: 99%

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: The Search for the Optimal Biomarker

et al. 2022

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“…cfDNA quantification could thus be monitored in order to determine the right timing for ICI initiation and infusion intervals. 83 …”

Section: Face Challenges: How Do We Get There?mentioning

confidence: 99%

The Value of Population Screening in Advancing Personalized Medicine in the Field of Lung Cancer

Mogenet¹,

Greillier²,

Tomasini³

2021

PGPM

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During the past decade, progress has been made in the field of lung cancer molecular biology and onco-immunology, leading to prolonged survival of patients. The combination of increased fundamental knowledge and the pharmaceutical pipeline has allowed the development of various tyrosine kinase inhibitors, targeting numerous molecular alterations. These drugs are now available in daily practice and have transformed survival outcomes for patients harboring EGFR, ALK or ROS1 alterations. Multiple clinical trials are now ongoing in order to increase the number of approved drugs, thus overcoming the issues of rare mutations and tyrosine kinase inhibitors resistance. Immune checkpoint inhibitors development has also changed lung cancer outcomes, but underwhelming response rates highlight the need for immune biomarkers. While PD-L1 expression was the first approved immune biomarker, it has shown several limitations and new biomarkers have to be identified to predict response or resistance to immune checkpoint inhibitors. Testing methods, molecular results and targeted therapeutic schedules will be harmonized in the coming years, with the help of dedicated molecular multidisciplinary boards.

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“…For instance, PD-L1 expression, tumor mutational burden, neutrophils-to-lymphocytes ratio, history of corticoids or antibiotics use, plus rising evidences on the importance of gut microbiota have all been associated with ICI efficacy. However, none of them has emerged as a fully consensual predictive tool thus far [ 1 ]. This lack of available and validated biomarkers for forecasting clinical outcomes is a major concern, especially with respect to the high cost of ICIs.…”

Section: Introductionmentioning

confidence: 99%

Cancer Immunotherapy Dosing: A Pharmacokinetic/Pharmacodynamic Perspective

et al. 2020

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Immune check-point inhibitors are drugs that are markedly different from other anticancer drugs because of their indirect mechanisms of antitumoral action and their apparently random effect in terms of efficacy and toxicity. This marked pharmacodynamics variability in patients calls for reconsidering to what extent approved dosing used in clinical practice are optimal or whether they should require efforts for customization in outlier patients. To better understand whether or not dosing could be an actionable item in oncology, in this review, preclinical and clinical development of immune checkpoint inhibitors are described, particularly from the angle of dose finding studies. Other issues in connection with dosing issues are developed, such as the flat dosing alternative, the putative role therapeutic drug monitoring could play, the rise of combinatorial strategies, and pharmaco-economic aspects.

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Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy

Cited by 5 publications

References 105 publications

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: The Search for the Optimal Biomarker

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: The Search for the Optimal Biomarker

The Value of Population Screening in Advancing Personalized Medicine in the Field of Lung Cancer

Cancer Immunotherapy Dosing: A Pharmacokinetic/Pharmacodynamic Perspective

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