Targeting the immune microenvironment in ovarian cancer therapy-mission impossible?
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ABSTRACT:
SUBMITTER: Blanc-Durand F
PROVIDER: S-EPMC10955311 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Targeting the immune microenvironment in ovarian cancer therapy-mission impossible?
Blanc-Durand F F Pautier P P Michels J J Leary A A
ESMO open 20240315 3
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Project description:Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3+ regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments.
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Project description:Antisense oligonucleotides can regulate gene expression in living cells. As such, they regulate cell function and division, and can modulate cellular responses to internal and external stresses and stimuli. Although encouraging results from preclinical and clinical studies have been obtained and significant progress has been made in developing these agents as drugs, they are not yet recognized as effective therapeutics. Several major hurdles remain to be overcome, including problems with efficacy, off-target effects, delivery and side effects. The lessons learned from antisense drug development can help in the development of other oligonucleotide-based therapeutics such as CpG oligonucleotides, RNAi and miRNA.
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Project description:BackgroundCardiovascular disease (CVD) risk prediction models are often used to identify individuals at high risk of CVD events. Providing preventive treatment to these individuals may then reduce the CVD burden at population level. However, different prediction models may predict different (sets of) CVD outcomes which may lead to variation in selection of high risk individuals. Here, it is investigated if the use of different prediction models may actually lead to different treatment recommendations in clinical practice.MethodThe exact definition of and the event types included in the predicted outcomes of four widely used CVD risk prediction models (ATP-III, Framingham (FRS), Pooled Cohort Equations (PCE) and SCORE) was determined according to ICD-10 codes. The models were applied to a Dutch population cohort (n = 18,137) to predict the 10-year CVD risks. Finally, treatment recommendations, based on predicted risks and the treatment threshold associated with each model, were investigated and compared across models.ResultsDue to the different definitions of predicted outcomes, the predicted risks varied widely, with an average 10-year CVD risk of 1.2% (ATP), 5.2% (FRS), 1.9% (PCE), and 0.7% (SCORE). Given the variation in predicted risks and recommended treatment thresholds, preventive drugs would be prescribed for 0.2%, 14.9%, 4.4%, and 2.0% of all individuals when using ATP, FRS, PCE and SCORE, respectively.ConclusionWidely used CVD prediction models vary substantially regarding their outcomes and associated absolute risk estimates. Consequently, absolute predicted 10-year risks from different prediction models cannot be compared directly. Furthermore, treatment decisions often depend on which prediction model is applied and its recommended risk threshold, introducing unwanted practice variation into risk-based preventive strategies for CVD.
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Project description:The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy.
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Project description:ObjectiveIn children many antiepileptic drugs (AEDs) are prescribed off-label due to a lack of well-designed randomized controlled trials (RCTs). We conducted a multicenter RCT in the Netherlands to compare levetiracetam and valproic acid as monotherapy in children with newly diagnosed epilepsy. After 2 years, we had to stop this investigator-initiated trial prematurely because the inclusion rate was too low. We analyzed the reasons for this failure, assessed the various issues involved in performing RCTs in children, and now give recommendations for future studies.MethodsA questionnaire was completed by all investigators involved in the study. It included questions about the motivation to participate and the perceived reasons for recruitment failure. We also studied literature about financial, logistic, legal, and ethical aspects of RCTs in children.ResultsMain reasons for recruitment failure were overestimation of the number of eligible AED-naive children referred by general pediatricians; personal preferences of investigators for specific antiepileptic drugs; and the extensive administrative load due to extra regulations and guidelines for children. Fundraising for investigator-initiated trials is difficult and the majority of RCTs concerning AEDs are sponsored by pharmaceutical companies. Involving children requires balancing between protection and participation; the randomization procedure and obtaining informed consent are complex for both children and parents.SignificancePerforming RCTs with AEDs in children is important but complicated by logistic, regulatory, legal, and ethical restrictions. Based on our recent experience, our advice to colleagues who are planning a similar trial would be to perform a feasibility pilot study; to set up intensive collaboration with referring pediatricians; to arrange support of a clinical trials unit and a local research nurse during the complete trial period; and to incorporate the possibility of extending the recruitment period. Major investments, both financially from governmental organizations and in time, are imperative for independent RCTs in children.
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