Redefining the standard of care for low-grade serous ovarian cancer.

Low-grade serous carcinoma is a rare epithelial ovarian cancer subtype with distinct clinical, histologic, and molecular features. Improved understanding of this disease subtype has prompted recent advances in treatment options. Although low-grade serous carcinoma historically has been treated following a high-grade serous carcinoma paradigm, new data have called into question the utility of platinum retreatment, addressed the possibility of first-line hormonal treatment, and brought forth therapeutic options targeting the MAPK pathway and cyclin D kinase in low-grade tumors. Ongoing research efforts seek to leverage the unique features of low-grade serous carcinoma to refine treatment options for patients with this rare tumor subtype.

Oncogenic Pathways and Targeted Therapies in Ovarian Cancer.

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments.

Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives.

Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.

Deregulated circRNAs in Epithelial Ovarian Cancer With Activity in Preclinical In Vivo Models: Identification of Targets and New Modalities for Therapeutic Intervention.

Epithelial ovarian cancer (EOC) is associated with a dismal prognosis due to development of resistance to chemotherapy and metastasis in the peritoneal cavity and distant organs. In order to identify new targets and treatment modalities we searched the literature for up- and and down-regulated circRNAs with efficacy in preclinical EOC-related in vivo systems. Our search yielded circRNAs falling into the following categories: cisplatin and paclitaxel resistance, transmembrane receptors, secreted factors, transcription factors, RNA splicing and processing factors, RAS pathway-related components, proteolysis and cell-cycle regulation, signaling-related proteins, and circRNAs regulating proteins in additional categories. These findings can be potentially translated by validation and manipulation of the corresponding targets, inhibition of circRNAs with antisense oligonucleotides (ASO), small interfering RNAs (siRNA) or small hairpin RNA (shRNA) or by reconstituting their activity.

Impact of FRAilty screening and Geriatric assessment and INtervention in older patients with epithelial Ovarian Cancer: A multicenter randomized clinical trial protocol (FRAGINOC).

INTRODUCTION: Radical surgery combined with chemotherapy is the only potential curative treatment of patients with advanced epithelial ovarian cancer (EOC). However, 43% of older Danish patients with EOC are not referred to surgery due to frailty, age, or fear of complications. Comprehensive geriatric assessment (CGA) has demonstrated ability to reduce frailty in older patients, but there is a knowledge gap regarding its effect before or during treatment in older adults with EOC. This protocol presents a randomized controlled trial (RCT), which evaluates the effect of CGA-based interventions including individualized physical exercise therapy in older adults with EOC during neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: This RCT will include patients aged ≥70 years with primary EOC referred to NACT. Patients will be randomized 1:1 to intervention or standard of care, along with neoadjuvant antineoplastic treatment. Stratification for performance status and center of inclusion will be performed. In the intervention arm, a geriatrician will perform CGA and corresponding geriatric interventions and patients will undergo an individualized home-based exercise program managed by a physiotherapist. All patients will be evaluated with Geriatric-8, modified Geriatric-8, clinical frailty scale, and physical tests at randomization. Predictive values (positive/negative) will be evaluated for CGA detected impairments. The primary endpoint is the proportion of patients referred to interval debulking surgery (IDS). Secondary endpoints include the proportion who complete oncological treatment, improvements in physical tests, quality of life measured by European Organization for Research and Treatment of Cancer-Quality of Life questionnaires at inclusion, after three cycles of chemotherapy, and at end of chemotherapy treatment. Furthermore, the association between results of geriatric screening tests, CGA, and physical tests with complication rate and progression free survival will be examined. The primary outcome will be analyzed with logistic regression in the intention-to-treat population. Power calculations reveal the need to enroll 216 patients. DISCUSSION: The present study examines whether CGA-based interventions including individualized physical exercise can increase the referral rate for potential curative IDS in older patients with EOC. If successful, this will result in more patients undergoing surgery and completing chemotherapy, preventing complications, and ultimately improving quality of life and survival. The study setup may establish the basis for direct clinical implementation if proven effective.

From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer.

Ovarian clear-cell cancer is a rare subtype of epithelial ovarian cancer with unique clinical and biological features. Despite optimal cytoreductive surgery and platinum-based chemotherapy being the standard of care, most patients experience drug resistance and a poor prognosis. Therefore, novel therapeutic approaches have been developed, including immune checkpoint blockade, angiogenesis-targeted therapy, ARID1A synthetic lethal interactions, targeting hepatocyte nuclear factor 1ß, and ferroptosis. Refining predictive biomarkers can lead to more personalized medicine, identifying patients who would benefit from chemotherapy, targeted therapy, or immunotherapy. Collaboration between academic research groups is crucial for developing prognostic outcomes and conducting clinical trials to advance treatment for ovarian clear-cell cancer. Immediate progress is essential, and research efforts should prioritize the development of more effective therapeutic strategies to benefit all patients.

Germline and somatic testing for ovarian Cancer: An SGO clinical practice statement.

Germline and somatic genetic testing have become critical components of care for people with ovarian cancer. The identification of germline and somatic pathogenic variants as well as homologous recombination deficiency can contribute to the prediction of treatment response, prognostic outcome, and suitability for targeted agents (e.g. poly (ADP-ribose) polymerase (PARP) inhibitors). Furthermore, identifying germline pathogenic variants can prompt cascade genetic testing for at-risk relatives. Despite the clinical benefits and consensus recommendations from several organizations calling for universal genetic testing in ovarian cancer, only about one third of patients complete germline or somatic genetic testing. The members of the Society of Gynecologic Oncology (SGO) Clinical Practice Committee have composed this statement to provide an overview of germline and somatic genetic testing for patients with epithelial ovarian cancer, focusing on available testing modalities and options for care delivery.

Front-line chemoimmunotherapy for treating epithelial ovarian cancer: Part II promising results of phase 2 study of paclitaxel-carboplatin-oregovomab regimen.

In the Part I, we have discussed the background of CA125 and the development of anti-CA125 monoclonal antibody (MAb) to highlight the potential role of CA125 and anti-CA125 MAb in the management of women with advanced stage epithelial ovarian cancer (EOC). Glycosylation change either by N-link or by O-link of CA125 is supposed to play a role in the modification of immunity. Anti-CA125 MAb, which can be classified as OC 125-like Abs, M11-like Abs, and OV197-like Abs, is often used for diagnosing, screening, monitoring and detecting the mesothelin-related diseases of the abdominal cavity, particular for those women with EOC. Additionally, anti-CA125 MAb also plays a therapeutic role, named as OvaRex MAb-B43.13 (oregovomab), which has also been extensively reviewed in the Part I review article. The main mechanisms include (a) forming CA125 immune complexes to activate the antigen-presenting cells; (b) triggering induction of CA125-specific immune responses, including anti-CA125 Abs against various epitopes and CA125-specific B and T cell responses; and (c) triggering CD4 and CD8 T-cell responses specific for B43.13 to produce specific and non-specific immune response. With success in vitro, in vivo and in primitive studies, phase II study was conducted to test the effectiveness of chemoimmunotherapy (CIT) for the management of EOC patients. In the 97 EOC patients after optimal debulking surgery (residual tumor <1 cm or no gross residual tumor), patients treated with CIT had a dramatical and statistically significant improvement of both progression-free survival (PFS) and overall survival (OS) compared to those treated with chemotherapy alone with a median PFS of 41.8 months versus 12.2 months (hazard ratio [HR] 0.46, 95 % confidence interval [CI] 0.28-0.7) and OS not yet been reached (NE) versus 42.3 months (HR 0.35, 95 % CI 0.16-0.74), respectively. The current review as Part II will explore the possibility of using CIT as front-line therapy in the management of advanced-stage EOC patients after maximal cytoreductive surgery based on the evidence by many phase 2 studies.

Confirmation of the utility of the CA-125 elimination rate (KELIM) as an indicator of the chemosensitivity in advanced-stage ovarian cancer in a "real-life setting".

OBJECTIVE: The modeled CA-125 ELIMination rate constant K (KELIM) has been validated as a marker of response to chemotherapy in >12,000 patients with advanced epithelial ovarian carcinoma (EOC) treated in first-line setting enrolled in >12 clinical trials. Patient KELIM is calculable online https://www.biomarker-kinetics.org/presentation. The objective was to investigate the prognostic value of KELIM in a large real-life national cancer registry with non-selected patients. METHODS: We investigated 4,025 EOC patients from the Netherlands Cancer Registry treated with neoadjuvant chemotherapy (NACT) ± followed by interval debulking surgery (IDS). Patient KELIM values were calculated in patients with ≥ 3 CA-125 measurements during NACT. KELIM was standardized with a pre-specified cut-off and scored as unfavorable/favorable (<1.0/≥1.0). KELIM's prognostic value regarding radiological response, completeness of IDS, progression-free survival (PFS), and overall survival (OS) was assessed using univariate/multivariate analyses. RESULTS: The data from 1,582 patients treated with heterogeneous chemotherapy regimens and sequences were assessable. KELIM was prognostic for radiological response and the likelihood of complete IDS after NACT (odds ratio=2.59; 95% confidence interval [CI]=2.04-3.29). Moreover, KELIM was independently associated with PFS (hazard ratio [HR]=0.76; 95% CI=0.66-0.87), and OS (HR=0.79; 95% CI=0.69-0.91). Combining KELIM with the completeness of the IDS resulted in 3 prognostic groups (satisfactory, intermediate, and poor) with significant OS differences, namely a good, intermediate, and poor survival respectively. CONCLUSION: The value of KELIM, as a pragmatic indicator of response to chemotherapy, was maintained in a large real-life population-based cohort, highlighting its applicability in routine conditions.

Nomograms for predicting overall survival and cancer-specific survival of endometrioid ovarian carcinoma: A retrospective cohort study from the SEER database.

OBJECTIVE: Endometrioid ovarian cancer (EnOC) accounts for approximately 10%-15% of epithelial ovarian cancer cases. There are no effective tools for predicting the prognosis of EnOC in clinical work. The aim of this study was to construct and validate a nomogram to predict overall survival and cancer-specific survival (CSS) in patients with EnOC. METHODS: Data regarding patients diagnosed with primary EnOC between 2004 and 2019 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. LASSO Cox regression and Cox regression analyses were performed to screen for prognostic factors, which were used to construct nomograms. In addition, we performed subgroup analyses of the prognostic value of chemotherapy and lymph node surgery. RESULTS: In total, 3957 patients with primary EnOC were included in the analysis: 2770 in a training cohort and 1187 in a validation cohort. Age, stage, grade, lymph node surgery, and race were significantly and independently correlated with overall survival and CSS. Nomograms were constructed to predict 3- and 5-year overall survival and CSS. Nomograms have good predictive ability and clinical practicability. Subgroup analysis showed that lymph node surgery improved the prognosis of patients with EnOC (P < 0.05) except for patients with grade III-IV and Stage I disease (overall survival P = 0.272, CSS P = 0.624). Chemotherapy did not improve survival time in most patients (P > 0.05) except for patients with grade I-II and Stage II-IV disease (overall survival P = 0.008, CSS P = 0.046). CONCLUSION: We constructed predictive nomograms and a risk classification system to evaluate overall survival and CSS in EnOC patients. For most patients with EnOC, chemotherapy did not improve the prognosis. In contrast to chemotherapy, lymph node surgery improved prognosis in most patients with EnOC.

Racial and socioeconomic disparities in survival among women with advanced-stage ovarian cancer who received systemic therapy.

PURPOSE: The purpose of this study was to assess the association between race/ethnicity and all-cause mortality among women with advanced-stage ovarian cancer who received systemic therapy. METHODS: We analyzed data from the National Cancer Database on women diagnosed with advanced-stage ovarian cancer from 2004 to 2015 who received systemic therapy. Race/ethnicity was categorized as Non-Hispanic (NH) White, NH-Black, Hispanic, NH-Asian/Pacific Islander, and Other. Income and education were combined to form a composite measure of socioeconomic status (SES) and categorized into low-, mid-, and high-SES. Multivariable Cox proportional hazards models were used to assess whether race/ethnicity was associated with the risk of death after adjusting for sociodemographic, clinical, and treatment factors. Additionally, subgroup analyses were conducted by SES, age, and surgery receipt. RESULTS: The study population comprised 53,367 women (52.4% ages ≥ 65 years, 82% NH-White, 8.7% NH-Black, 5.7% Hispanic, and 2.7% NH-Asian/Pacific Islander) in the analysis. After adjusting for covariates, the NH-Black race was associated with a higher risk of death versus NH-White race (aHR: 1.12; 95% CI: 1.07,1.18), while Hispanic ethnicity was associated with a lower risk of death compared to NH-White women (aHR: 0.87; 95% CI: 0.80, 0.95). Furthermore, NH-Black women versus NH-White women had an increased risk of mortality among those with low-SES characteristics (aHR:1.12; 95% CI:1.03-1.22) and mid-SES groups (aHR: 1.13; 95% CI:1.05-1.21). CONCLUSIONS: Among women with advanced-stage ovarian cancer who received systemic therapy, NH-Black women experienced poorer survival compared to NH-White women. Future studies should be directed to identify drivers of ovarian cancer disparities, particularly racial differences in treatment response and surveillance.

Perspectives of Healthcare Professionals on the Management and Treatment of Advanced Ovarian Cancer in the UK: Results From the KNOW-OC Survey.

AIMS: New treatment options for advanced ovarian cancer have the potential to significantly change the treatment pathway in the UK. Understanding the structures and responsibilities of multidisciplinary teams/tumour boards (MDT) and regional variations will enable services to adapt more effectively to these changes. MATERIALS AND METHODS: The KNOW-OC survey was conducted in 2020 to understand the views of a selected group of 66 healthcare professionals (HCPs) involved in advanced ovarian cancer care in UK hospitals. RESULTS: The results showed that MDT involvement in the management of advanced ovarian cancer varied depending on pathway stage and line of relapse, with 98.5% of HCPs responding that the MDT was involved in decisions at initial presentation, but only 40.9% for patients with multiple relapses. The MDT was mostly responsible for determining whether the patients would undergo primary or interval cytoreductive surgery according to 75.8% of respondents, and most HCPs (80.3%) stated that tumour dissemination patterns were the most important factor influencing this decision. The most commonly assessed biomarkers at the time of the survey were CA125, gBRCA and tBRCA. Homologous recombination deficiency was viewed as the second most important factor for determining prognosis, but few centres had access to testing at the time of survey completion. The use of active surveillance was expected to decrease in favour of first-line targeted therapies. Nearly all (98.5%) HCPs agreed there is a role for secondary cytoreductive surgery for the treatment of recurrence (for carefully selected patients). CONCLUSIONS: The results highlighted UK-specific geographical variation in the views of HCPs on MDT involvement and specific practices, such as molecular biomarker testing, and the overall treatment approach. Together, these findings improve the understanding of reported clinical practice across the UK for ovarian cancer and provide insight into decision-making associated with updates to recommendations for best practice (e.g. European Society for Medical Oncology/European Society of Gynaecological Oncology consensus statements) and the introduction of new treatment options.

Transforming ovarian cancer care by targeting minimal residual disease.

Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a multidisciplinary approach aimed at gaining novel therapeutic insights by focusing on the poorly understood minimal residual disease phase of ovarian cancer that leads to eventual incurable recurrences.

Prognostic value of CA125 kinetics, half-life, and nadir in the treatment of epithelial ovarian cancer: a systematic review and meta-analysis.

OBJECTIVE: To investigate the prognostic value of cancer antigen 125 (CA125) related variables on progression free survival and overall survival in primary and recurrent ovarian cancers. METHOD: A comprehensive review of the Medline, Embase, and Cochrane Library databases was conducted to identify relevant literature on survival outcomes according to the ELIMination Rate Constant K (KELIM), Gynecologic Cancer InterGroup (GCIG) CA125 response criteria, CA125 half-life, and CA125 nadir levels during first line or later line chemotherapy. The search included articles published before February 2023. Cut-off values determining the favorable/unfavorable score of each study were extracted, and pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were analyzed using a random effects model to identify the relationship between survival outcomes of the favorable/unfavorable groups, which was determined by an individual model using CA125 kinetics. RESULTS: A total of 27 studies with 14 444 patients with epithelial ovarian cancer were included in this meta-analysis. In primary ovarian cancer, a favorable KELIM score, determined by individual modeled cut-off values, was associated with a significant progression free survival (HR 0.53, 95% CI 0.45 to 0.62) and overall survival (HR 0.51, 95% CI 0.43 to 0.62) benefit in the primary setting. The favorable KELIM scored group also correlated with a better progression free survival (HR 0.54, 95% CI 0.47 to 0.62) in relapsed disease. We failed to demonstrate a better prognostic value of the GCIG response criteria and the CA125 half-life for progression free survival and overall survival. CONCLUSION: Novel chemotherapy response scores, such as KELIM, may be more clinically relevant than other prognostic models using CA125 kinetics, being directly associated with a more favorable survival in both the primary and relapsed setting in patients with epithelial ovarian cancer. STUDY REGISTRATION: The systemic review and meta-analysis were registered in PROSPERO (CRD42023385512).

Association of guideline-concordant care with survival, health care utilization, and costs among older women with advanced epithelial ovarian cancer.

OBJECTIVES: To examine guideline-concordant care (GCC) for ovarian cancer, identify its predictors, and evaluate the associations between GCC and survival, health care expenditures, and utilization. STUDY DESIGN: A retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare data. METHODS: Women aged 66 to 90 years who received a diagnosis of stage II or higher epithelial ovarian cancer during 2011-2015 were included (N = 3237). The National Comprehensive Cancer Network clinical practice guidelines were used to identify GCC. Logistic regression was conducted to identify predictors of GCC, a Cox proportional hazards model was used to examine mortality, and generalized linear models were used to examine mean monthly Medicare expenditures and health care utilization. RESULTS: Approximately 57% of women received GCC and 11.6% of women did not receive any cancer-specific treatment. Women who were relatively older (adjusted odds ratio [AOR], 0.272; 95% CI, 0.210-0.351), had Census tract income of $50,000 or less (AOR, 0.709; 95% CI, 0.551-0.913), had a psychiatric condition (AOR, 0.655; 95% CI, 0.464-0.923), and had adenocarcinoma histology (AOR, 0.564; 95% CI, 0.441-0.721) were significantly less likely to receive GCC. Race/ethnicity was not found to be a significant predictor of GCC. Women who received surgery only or chemotherapy only had a significant higher hazard of all-cause mortality and ovarian cancer-specific mortality compared with those who received GCC (surgery only: adjusted HR [AHR], 2.307; chemotherapy only: AHR, 1.802). Receiving chemotherapy only was associated with 45% (P < .0001) higher mean monthly expenditures compared with those who received GCC. CONCLUSIONS: Non-GCC was associated with worsened survival, higher health care utilization, and increased expenditures. It is important to highlight that women who received GCC were associated with better survival likely due to favorable prognostic clinical factors.

Extracellular vesicles as a potential delivery platform for CRISPR-Cas based therapy in epithelial ovarian cancer.

Ovarian Cancer (OC) is the most common gynecological malignancy and the eighth most diagnosed cancer in females worldwide. Presently, it ranks as the fifth leading cause of cancer-related mortality among patients globally. Major factors contributing to the lethality of OC worldwide include delayed diagnosis, chemotherapy resistance, high metastatic rates, and the heterogeneity of subtypes. Despite continuous efforts to develop novel targeted therapies and chemotherapeutic agents, challenges persist in the form of OC resistance and recurrence. In the last decade, CRISPR-Cas-based genome editing has emerged as a powerful tool for modifying genetic and epigenetic mechanisms, holding potential for treating numerous diseases. However, a significant challenge for therapeutic applications of CRISPR-Cas technology is the absence of an optimal vehicle for delivering CRISPR molecular machinery into targeted cells or tissues. Recently, extracellular vesicles (EVs) have gained traction as potential delivery vehicles for various therapeutic agents. These heterogeneous, membrane-derived vesicles are released by nearly all cells into extracellular spaces. They carry a molecular cargo of proteins and nucleic acids within their intraluminal space, encased by a cholesterol-rich phospholipid bilayer membrane. EVs actively engage in cell-to-cell communication by delivering cargo to both neighboring and distant cells. Their inherent ability to shield molecular cargo from degradation and cross biological barriers positions them ideally for delivering CRISPR-Cas ribonucleoproteins (RNP) to target cells. Furthermore, they exhibit higher biocompatibility, lower immunogenicity, and reduced toxicity compared to classical delivery platforms such as adeno-associated virus, lentiviruses, and synthetic nanoparticles. This review explores the potential of employing different CRISPR-Cas systems to target specific genes in OC, while also discussing various methods for engineering EVs to load CRISPR components and enhance their targeting capabilities.

Improving the cytotoxic response of tumor-infiltrating lymphocytes towards advanced stage ovarian cancer with an oncolytic adenovirus expressing a human vIL-2 cytokine.

While the presence of tumor-infiltrating lymphocytes (TILs) associates with improved survival prognosis in ovarian cancer (OvCa) patients, TIL therapy benefit is limited. Here, we evaluated an oncolytic adenovirus coding for a human variant IL-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, as an immunotherapeutic strategy to enhance TIL responsiveness towards advanced stage OvCa tumors. Fragments of resected human OvCa tumors were processed into single-cell suspensions, and autologous TILs were expanded from said samples. OvCa tumor specimens were co-cultured with TILs plus vIL-2 virus, and cell killing was assessed in real time through cell impedance measurement. Combination therapy was further evaluated in vivo through a patient-derived xenograft (PDX) ovarian cancer murine model. The combination of vIL-2 virus plus TILs had best cancer cell killing ex vivo compared to TILs monotherapy. These results were supported by an in vivo experiment, where the best OvCa tumor control was obtained when vIL-2 virus was added to TIL therapy. Furthermore, the proposed therapy induced a highly cytotoxic phenotype demonstrated by increased granzyme B intensity in NK cells, CD4+ T, and CD8+ T cells in treated tumors. Our results demonstrate that Ad5/3-E2F-d24-vIL2 therapy consistently improved TILs therapy cytotoxicity in treated human OvCa tumors.

Low-grade serous ovarian cancer: expert consensus report on the state of the science.

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade serous carcinoma diagnosis and treatment, a panel of experts convened for a workshop in October 2022 to develop a consensus document addressing pathology, translational research, epidemiology and risk, clinical management, and ongoing research. In addition, the patient perspective was discussed. The recommendations developed by this expert panel-presented in this consensus document-will guide practitioners in all settings regarding the clinical management of women with low-grade serous carcinoma and discuss future opportunities to improve research and patient care.

Dual targeting ovarian cancer by Muc16 CAR T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1.

Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers.

Evaluation of follow-up strategies for women with epithelial ovarian cancer following completion of primary treatment.

BACKGROUND: This is an update of a previous Cochrane Review, last updated in 2014. Ovarian cancer is the eighth most common cancer and seventh most common cause of death due to cancer in women worldwide. Traditionally, most women who have been treated for cancer undergo long-term follow-up in secondary care. However, it has been suggested that the use of routine review may not be effective in improving survival, or health-related quality of life (HRQOL), or relieving anxiety. In addition, traditional follow-up may not be cost-effective. OBJECTIVES: To compare the potential effects of different strategies of follow-up in women with epithelial ovarian cancer, following completion of primary treatment. SEARCH METHODS: For this update, we searched the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL 2022, Issue 11, MEDLINE, and Embase from August 2013 to November 2022. We also searched review articles and contacted experts in the field. SELECTION CRITERIA: All randomised controlled trials (RCTs) that evaluated follow-up strategies for women with epithelial ovarian cancer following completion of primary treatment. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. Two review authors independently selected potentially relevant trials, extracted data, and assessed risk of bias. They compared results, and resolved disagreements by discussion. We assessed the certainty of evidence, using the GRADE approach, for the outcomes of interest: overall survival (OS), health-related quality of life (HRQOL), psychological effects, and cost analysis. MAIN RESULTS: For this update, we included one new RCT, including 112 women with ovarian, fallopian tube, or peritoneal cancer, who had completed primary treatment by surgery, with or without chemotherapy. This study reported the effect of individualised, i.e. individually tailored, nurse-led follow-up versus conventional medical follow-up on HRQOL, psychological outcomes, and cost-analysis. Individualised follow-up improved HRQOL in one of the two scales, with a decrease in mean difference (MD) in the QLQ-C30 discomfort scale following 12 months of individualised treatment compared to 12 months of conventional treatment (MD -5.76 points, 95% confidence interval (CI) -10.92 to -0.60; 1 study, 112 participants; low-certainty evidence; minimal important difference 4 to 10 points). There may be little or no difference in the other HRQOL scale (QLQ-Ov28, MD -0.97 points, 95% CI -2.57 to 0.63; 1 study, 112 participants: low-certainty evidence); psychological outcome, measured with the hospital anxiety and depression scale (HADS; MD 0.10 point, 95% CI -0.81 to 1.02; 1 study, 112 participants: low-certainty evidence), or cost analysis (MD -GBP 695.00, 95% CI -1467.23 to 77.23; 1 study, 112 participants: moderate-certainty evidence). Our previous review included one RCT, with 529 women in a confirmed remission, with normal CA125 concentration and no radiological evidence of disease, after surgery and first-line chemotherapy for ovarian cancer. This study evaluated immediate treatment of ovarian cancer relapse following a rise of serum CA125 levels versus delaying treatment until symptoms developed for OS, and HRQOL. There was little or no difference in OS between the immediate and delayed arms after a median follow-up of 56.9 months (unadjusted hazard ratio (HR) 0.98, 95% CI 0.80 to 1.20; 1 study, 529 participants; moderate-certainty evidence). Time from randomisation to first deterioration in global health score or death was shorter in the immediate treatment group than in the delayed treatment group (HR 0.71, 95% CI 0.58 to 0.88). AUTHORS' CONCLUSIONS: Limited evidence from one trial suggests that routine surveillance with CA125 in asymptomatic women and treatment at CA125-defined relapse does not seem to offer survival advantage when compared to treatment at symptomatic relapse. However, this study pre-dates the use of PARPi maintenance treatment and the increased use of secondary cytoreductive surgery, so the results may be limited in their applicability to current practice. Limited evidence from one trial suggests that individualised nurse-led follow-up may improve HRQOL in women with ovarian cancer following completion of primary treatment. Large RCTs are needed to compare different types of follow-up, looking at survival, HRQOL, psychological effects, and cost as outcomes.