Abscopal Effects in Metastatic Cancer: Is a Predictive Approach Possible to Improve Individual Outcomes?
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ABSTRACT:
SUBMITTER: Link B
PROVIDER: S-EPMC8584726 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Perinatal asphyxia occurs still with great incidence whenever delivery is prolonged, despite improvements in perinatal care. After asphyxia, infants can suffer from short- to long-term neurological sequelae, their severity depend upon the extent of the insult, the metabolic imbalance during the re-oxygenation period and the developmental state of the affected regions. Significant progresses in understanding of perinatal asphyxia pathophysiology have achieved. However, predictive diagnostics and personalised therapeutic interventions are still under initial development. Now the emphasis is on early non-invasive diagnosis approach, as well as, in identifying new therapeutic targets to improve individual outcomes. In this review we discuss (i) specific biomarkers for early prediction of perinatal asphyxia outcome; (ii) short and long term sequelae; (iii) neurocircuitries involved; (iv) molecular pathways; (v) neuroinflammation systems; (vi) endogenous brain rescue systems, including activation of sentinel proteins and neurogenesis; and (vii) therapeutic targets for preventing or mitigating the effects produced by asphyxia.
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Project description:Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.
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Project description:BackgroundThere are no accepted universal biomarkers capable to accurately predict response to immuno-checkpoint inhibitors (ICI). Although recent literature has been flooded with studies on ICI predictive biomarkers, available data show that currently approved companion diagnostics either leave out many possible responders, as in the case of PD-L1 testing for first-line metastatic lung cancer, or apply to a small subset of patients, such as the recently approved treatment for microsatellite instability-high or mismatch repair deficiency tumors. In this study, we conducted a survey of the available data on ICI trials with matched genomic or transcriptomic datasets in order to cross-validate the proposed biomarkers, to assess whether their prediction power was confirmed and, mainly, to investigate if their combination was able to generate a better predictive tool.MethodsWe extracted clinical information and sequencing data details from publicly available datasets, along with a list of possible biomarkers obtained from the recent literature. After an operation of data harmonization, we validated the performance of all the biomarkers taken individually. Furthermore, we tested two strategies to combine the best performing biomarkers in order to improve their predictive value.ResultsWhen considered individually, some of the biomarkers, such as the ImmunoPhenoScore, and the IFN-? signature, did not confirm their originally proposed predictive power. The best absolute scoring biomarkers are TIDE, one of the ICB resistance signatures and CTLA4 with a mean AUC?>?0.66. Among the combinations tested, generalized linear models showed the best performance with an AUC of 0.78.ConclusionsWe confirmed that the available biomarkers, taken individually, fail to provide a satisfactory predictive value. Unfortunately, also combination of some of them only provides marginal improvements. Hence, in order to generate a more robust way to predict ICI efficacy it is necessary to analyze and combine additional biomarkers and interrogate a wider set of clinical data.
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Project description:Radiation therapy is a mainstay of cancer treatment, with more than 50% of all cancer patients receiving radiation during the course of their disease. Tumor irradiation can activate both innate and adaptive immune responses, and these responses can be pro- or anti-tumor growth . These observations have led to the search for antitumor approaches combining radiotherapy and specific immunotherapies, most commonly strategies promoting the systemic activation of T cells. Thus far, however, many cancer patients still suffer from local recurrence and/or untreatable metastatic disease after radiotherapy. Here we combine radiotherapy with activation of macrophage-mediated phagocytosis via blockade of the ?don?t-eat-me? cell surface molecule CD47 in small-cell lung cancer (SCLC), a highly metastatic form of lung cancer for which treatment options remain limited. We found that irradiation of SCLC cells in culture results in the secretion of inflammatory cytokines that results in increased migration and phagocytosis by macrophages. In vivo, CD47 blockade potently enhances the local antitumor effects of radiation therapy in murine and human pre-clinical models of SCLC. Strikingly, CD47 blockade also stimulates abscopal antitumor effects inhibiting the growth of non-irradiated SCLC tumors in mice receiving radiation. Similar abscopal antitumor effects were observed in colon cancer and lymphoma models. Surprisingly, these abscopal effects are completely independent of T cells but require macrophages that migrate into the non-irradiated tumor sites in response to inflammatory signals mediated by radiation and are locally activated by CD47 blockade to eliminate cancer cells. The systemic activation of antitumor macrophages following radiotherapy and CD47 blockade may be particularly important in cancer patients who suffer from metastatic disease.
2022-09-29 | GSE156106 | GEO