Predicting efficacy assessment of combined treatment of radiotherapy and nivolumab for NSCLC patients through virtual clinical trials using QSP modeling.

Non-Small Cell Lung Cancer (NSCLC) remains one of the main causes of cancer death worldwide. In the urge of finding an effective approach to treat cancer, enormous therapeutic targets and treatment combinations are explored in clinical studies, which are not only costly, suffer from a shortage of participants, but also unable to explore all prospective therapeutic solutions. Within the evolving therapeutic landscape, the combined use of radiotherapy (RT) and checkpoint inhibitors (ICIs) emerged as a promising avenue. Exploiting the power of quantitative system pharmacology (QSP), we undertook a study to anticipate the therapeutic outcomes of these interventions, aiming to address the limitations of clinical trials. After enhancing a pre-existing QSP platform and accurately replicating clinical data outcomes, we conducted an in-depth study, examining different treatment protocols with nivolumab and RT, both as monotherapy and in combination, by assessing their efficacy through clinical endpoints, namely time to progression (TTP) and duration of response (DOR). As result, the synergy of combined protocols showcased enhanced TTP and extended DOR, suggesting dual advantages of extended response and slowed disease progression with certain combined regimens. Through the lens of QSP modeling, our findings highlight the potential to fine-tune combination therapies for NSCLC, thereby providing pivotal insights for tailoring patient-centric therapeutic interventions.

Dynamical behavior-based approach for the evaluation of treatment efficacy: The case of immuno-oncology.

Sophistication of mathematical models in the pharmacological context reflects the progress being made in understanding physiological, pharmacological, and disease relationships. This progress has illustrated once more the need for advanced quantitative tools able to efficiently extract information from these models. While dynamical systems theory has a long history in the analysis of systems biology models, as emphasized under the dynamical disease concept by Mackey and Glass [Science 197, 287-289 (1977)], its adoption in pharmacometrics is only at the beginning [Chae, Transl. Clin. Pharmacol. 28, 109 (2020)]. Using a quantitative systems pharmacology model of tumor immune dynamics as a case study [Kosinsky et al., J. Immunother. Cancer 6, 17 (2018)], we here adopt a dynamical systems analysis to describe, in an exhaustive way, six different statuses that refer to the response of the system to therapy, in the presence or absence of a tumor-free attractor. To evaluate the therapy success, we introduce the concept of TBA, related to the Time to enter the tumor-free Basin of Attraction, and corresponding to the earliest time at which the therapy can be stopped without jeopardizing its efficacy. TBA can determine the optimal time to stop drug administration and consequently quantify the reduction in drug exposure.

Dynamical systems analysis as an additional tool to inform treatment outcomes: The case study of a quantitative systems pharmacology model of immuno-oncology.

Quantitative systems pharmacology (QSP) proved to be a powerful tool to elucidate the underlying pathophysiological complexity that is intensified by the biological variability and overlapped by the level of sophistication of drug dosing regimens. Therapies combining immunotherapy with more traditional therapeutic approaches, including chemotherapy and radiation, are increasingly being used. These combinations are purposed to amplify the immune response against the tumor cells and modulate the suppressive tumor microenvironment (TME). In order to get the best performance from these combinatorial approaches and derive rational regimen strategies, a better understanding of the interaction of the tumor with the host immune system is needed. The objective of the current work is to provide new insights into the dynamics of immune-mediated TME and immune-oncology treatment. As a case study, we will use a recent QSP model by Kosinsky et al. [J. Immunother. Cancer 6, 17 (2018)] that aimed to reproduce the dynamics of interaction between tumor and immune system upon administration of radiation therapy and immunotherapy. Adopting a dynamical systems approach, we here investigate the qualitative behavior of the representative components of this QSP model around its key parameters. The ability of T cells to infiltrate tumor tissue, originally identified as responsible for individual therapeutic inter-variability [Y. Kosinsky et al., J. Immunother. Cancer 6, 17 (2018)], is shown here to be a saddle-node bifurcation point for which the dynamical system oscillates between two states: tumor-free or maximum tumor volume. By performing a bifurcation analysis of the physiological system, we identified equilibrium points and assessed their nature. We then used the traditional concept of basin of attraction to assess the performance of therapy. We showed that considering the therapy as input to the dynamical system translates into the changes of the trajectory shapes of the solutions when approaching equilibrium points and thus providing information on the issue of therapy.

Brimonidine displays anti-inflammatory properties in the skin through the modulation of the vascular barrier function.

BACKGROUND: Rosacea is a chronic inflammatory skin disease. Characteristic vascular changes in rosacea skin include enlarged, dilated vessels of the upper dermis and blood flow increase. Brimonidine is approved for symptomatic relief of the erythema of rosacea. It acts by selectively binding to α2-adrenergic receptors present on smooth muscle in the peripheral vasculature, resulting in transient local vasoconstriction. OBJECTIVES: To provide further evidence of the anti-inflammatory potential of brimonidine across preclinical models of skin inflammation and its ability to decrease the neutrophil infiltration in human skin after ultraviolet light exposure. METHODS: The anti-inflammatory properties of brimonidine through modulation of the vascular barrier function were assessed using in vivo neurogenic vasodilation and acute inflammatory models and a well-described in vitro transmigration assay. A clinical study assessed the neutrophil infiltration in human skin after exposure to UV in 37 healthy Caucasian male subjects. RESULTS: In vitro, brimonidine affects the transmigration of human neutrophils through the endothelial barrier by modulating adhesion molecules. In vivo, in the mouse, topical treatment with brimonidine, used at a vasoconstrictive dose, confirmed its anti-inflammatory properties and prevented leucocyte recruitment (rolling and adhesion) mediated by endothelial cells. Topical pretreatment with brimonidine tartrate 0.33% gel once a day for 4 days significantly prevented neutrophil infiltration by 53.9% in human skin after exposure to UV light. CONCLUSION: Results from in vitro, in vivo and from a clinical study indicate that brimonidine impacts acute inflammation of the skin by interfering with neurogenic activation and/or recruitment of neutrophils.

Mid-infrared spectral microimaging of inflammatory skin lesions.

Skin is one of the most important organs of the human body because of its characteristics and functions. There are many alterations, either pathological or physiological, that can disturb its functioning. However, at present all methods used to investigate skin diseases, non-invasive or invasive, are based on clinical examinations by physicians. Thus, diagnosis, prognosis and therapeutic management rely on the expertise of the practitioner, the quality of the method and the accessibility of distinctive morphological characteristics of each lesion. To overcome the high sensitivity of these parameters, techniques based on more objective criteria must be explored. Vibrational spectroscopy has become as a key technique for tissue analysis in the biomedical research field. Based on a non-destructive light/matter interaction, this tool provides information about specific molecular structure and composition of the analyzed sample, thus relating to its precise physiopathological state and permitting to distinguish lesional from normal tissues. This label-free optical method can be performed directly on the paraffin-embedded tissue sections without chemical dewaxing. In this study, the potential of the infrared microspectroscopy, combined with data classification methods was demonstrated, to characterize at the tissular level different types of inflammatory skin lesions, and this independently from conventional histopathology.

Transcriptional profiling shows altered expression of wnt pathway- and lipid metabolism-related genes as well as melanogenesis-related genes in melasma.

Melasma is a commonly acquired hyperpigmentary disorder of the face, but its pathogenesis is poorly understood and its treatment remains challenging. We conducted a comparative histological study on lesional and perilesional normal skin to clarify the histological nature of melasma. Significantly, higher amounts of melanin and of melanogenesis-associated proteins were observed in the epidermis of lesional skin, and the mRNA level of tyrosinase-related protein 1 was higher in lesional skin, indicating regulation at the mRNA level. However, melanocyte numbers were comparable between lesional and perilesional skin. A transcriptomic study was undertaken to identify genes involved in the pathology of melasma. A total of 279 genes were found to be differentially expressed in lesional and perilesional skin. As was expected, the mRNA levels of a number of known melanogenesis-associated genes, such as tyrosinase, were found to be elevated in lesional skin. Bioinformatics analysis revealed that the most lipid metabolism-associated genes were downregulated in lesional skin, and this finding was supported by an impaired barrier function in melasma. Interestingly, a subset of Wnt signaling modulators, including Wnt inhibitory factor 1, secreted frizzled-related protein 2, and Wnt5a, were also found to be upregulated in lesional skin. Immunohistochemistry confirmed the higher expression of these factors in melasma lesions.

In vivo reflectance confocal microscopy detects pigmentary changes in melasma at a cellular level resolution.

Melasma is a frequent pigmentary disorder caused by abnormal melanin deposits in the skin. In vivo reflectance confocal microscopy (RCM) is a repetitive imaging tool that provides real-time images of the skin at nearly histological resolution. As melanin is the strongest endogenous contrast in human skin, pigmentary disorders are the most suitable candidates for RCM examination but RCM features of melasma have never been reported. This study investigates the pilot use of RCM in melasma to provide a set of well-described morphological criteria with histological correlations. RCM images were acquired from melasma skin and compared to adjacent control skin in 26 patients. Skin biopsies were obtained from eight patients. In the epidermis, RCM showed in all patients a significant increase in hyperrefractile cobblestoning cells. These cells corresponded to hyperpigmented basal keratinocytes in histology. In six patients, dendritic cells corresponding to activated melanocytes were also found in the epidermis. In the dermis, RCM identified in nine patients plump bright cells corresponding to melanophages. Interestingly, for a given patient, the topographic distribution of melanophages in melasma lesions was very heterogeneous. RCM also showed a significant increase in solar elastosis and blood vessels in the dermis. RCM is a non-invasive technique that detects pigmentary changes in melasma at a cellular level resolution. Therefore, RCM provides an innovative way to classify melasma by pigment changes.