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Nature Communications Jul 2023All antibodies approved for cancer therapy are monoclonal IgGs but the biology of IgE, supported by comparative preclinical data, offers the potential for enhanced...
All antibodies approved for cancer therapy are monoclonal IgGs but the biology of IgE, supported by comparative preclinical data, offers the potential for enhanced effector cell potency. Here we report a Phase I dose escalation trial (NCT02546921) with the primary objective of exploring the safety and tolerability of MOv18 IgE, a chimeric first-in-class IgE antibody, in patients with tumours expressing the relevant antigen, folate receptor-alpha. The trial incorporated skin prick and basophil activation tests (BAT) to select patients at lowest risk of allergic toxicity. Secondary objectives were exploration of anti-tumour activity, recommended Phase II dose, and pharmacokinetics. Dose escalation ranged from 70 μg-12 mg. The most common toxicity of MOv18 IgE is transient urticaria. A single patient experienced anaphylaxis, likely explained by detection of circulating basophils at baseline that could be activated by MOv18 IgE. The BAT assay was used to avoid enrolling further patients with reactive basophils. The safety profile is tolerable and maximum tolerated dose has not been reached, with evidence of anti-tumour activity observed in a patient with ovarian cancer. These results demonstrate the potential of IgE therapy for cancer.
Topics: Female; Humans; Immunoglobulin E; Antibodies, Monoclonal; Ovarian Neoplasms; Basophils; Folic Acid
PubMed: 37491373
DOI: 10.1038/s41467-023-39679-9 -
Biomedicine & Pharmacotherapy =... Oct 2023Premature ovarian insufficiency (POI) is clinically irreversible and seriously damages female fertility. We previously demonstrated that menstrual blood stromal cells...
Exosomes derived from menstrual blood stromal cells ameliorated premature ovarian insufficiency and granulosa cell apoptosis by regulating SMAD3/AKT/MDM2/P53 pathway via delivery of thrombospondin-1.
Premature ovarian insufficiency (POI) is clinically irreversible and seriously damages female fertility. We previously demonstrated that menstrual blood stromal cells (MenSCs)-derived exosomes (EXOs) effectively improved ovarian functions in the POI rat model. In this study, we investigated whether TSP1 is the key component in EXOs to ameliorate ovarian functions and further explored the molecular mechanism of EXOs in improving granulosa cell (GCs) activities. Our results demonstrated that knockdown TSP1 significantly debilitated the therapeutic effect of EXOs on estrous cyclicity, ovarian morphology, follicle numbers and pregnancy outcomes in 4-vinylcyclohexene diepoxide (VCD) induced POI rat model. In addition, EXOs treatment significantly promoted the activities and inhibited the apoptosis of VCD induced granulosa cells in vitro. Moreover, EXOs stimulation markedly activated the phosphorylation of SMAD3(Ser425) and AKT(Ser473), up-regulated the expressions of BCL2 and MDM2 as well as down-regulated the expressions of CASPASE3, CASPASE8, P53 and BAX. All these effects were supressed by SIS3, a inhibitor of TGF1/SMAD3. Our study revealed the key role of TSP1 in EXOs in improving POI pathology, restoring ovarian functions and GCs activities, andprovided a promising basis for EXOs in the treatment of ovarian dysfunction.
Topics: Animals; Female; Humans; Pregnancy; Rats; Apoptosis; Exosomes; Granulosa Cells; Menstruation; Primary Ovarian Insufficiency; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-mdm2; Smad3 Protein; Stromal Cells; Thrombospondins; Tumor Suppressor Protein p53
PubMed: 37573658
DOI: 10.1016/j.biopha.2023.115319 -
Journal of Extracellular Vesicles Jul 2023Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and...
Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and cancer cell-derived extracellular vesicles (EV). The mechanisms of how chemoresistance is sustained by EV remained elusive. One potentially contributing factor is A Disintegrin and Metalloprotease 17 (ADAM17)-itself being able to promote chemoresistance and inducing tumour cell proliferation and survival via the Epidermal Growth Factor Receptor (EGFR) pathway by shedding several of its ligands including Amphiregulin (AREG). We now demonstrate that upon chemotherapeutic treatment, proteolytically active ADAM17 is released in association with EV from OvCa cells. In terms of function, we show that patient-derived EV induce AREG shedding and restore chemoresistance in ADAM17-deficient cells. Confirming that ADAM17-containing EV transmit chemoresistance in OvCa, we propose that ADAM17 levels (also on EV) might serve as an indicator for tumour progression and the chemosensitivity status of a given patient.
Topics: Humans; Female; ADAM Proteins; ErbB Receptors; Extracellular Vesicles; Ovarian Neoplasms; Antineoplastic Agents; ADAM17 Protein
PubMed: 37408115
DOI: 10.1002/jev2.12338 -
Cancer Immunology, Immunotherapy : CII Nov 2023Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single...
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.
Topics: Humans; Mice; Female; Animals; Carcinoma, Ovarian Epithelial; Receptors, Chimeric Antigen; Ovarian Neoplasms; Antigens, Neoplasm; T-Lymphocytes; WT1 Proteins
PubMed: 37635172
DOI: 10.1007/s00262-023-03529-w -
Frontiers in Medicine 2023Ovarian leiomyomas (OLs) are rare and account for only 0.5 to 1% of benign ovarian tumors. This study investigated the ultrasonographic manifestations of OL and the...
OBJECTIVES
Ovarian leiomyomas (OLs) are rare and account for only 0.5 to 1% of benign ovarian tumors. This study investigated the ultrasonographic manifestations of OL and the potential reasons for misdiagnosis.
METHODS
Between July 2018 and July 2023, 7 patients diagnosed with OL by surgical pathology and immunohistochemistry were enrolled in this retrospective analysis. Ultrasound (US) examinations were performed before surgery. Clinical characteristics, pathological findings, ultrasonographic manifestations, and treatment were reviewed.
RESULTS
The mean age of the 7 patients was 39.0 ± 11.57 years, with a disease course of 0.1 to 24 months. All ovarian leiomyomas were unilateral. Four cases occurred in the right ovary, and three cases occurred in the left ovary. All lesions presented as hypoechogenic, well-circumscribed, round or oval in shape, and regular in morphology. No significant blood flow signal was detected peripheral to or inside the mass in 3 cases (42.8%), and a minimal flow signal was detected peripheral to or inside the mass in 4 cases (58.2%). A total of 7 ultrasonographic images of OL were misdiagnosed: 1 patient was misdiagnosed with subserosal uterine leiomyoma, and 6 patients were misdiagnosed with a tumor in the ovarian thecoma-fibroma group.
CONCLUSION
The imaging manifestation of OL lacks specificity; thus, preoperatively distinguishing OL from other ovarian tumors and subserosal uterine leiomyomas is difficult. Immunohistochemistry may be helpful for the definitive diagnosis of OL. The possibility of ovarian leiomyoma should be considered in patients with uterine leiomyomas coexisting with an adnexal ovarian solid mass.
PubMed: 38213912
DOI: 10.3389/fmed.2023.1289522 -
Frontiers in Immunology 2023Despite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a... (Observational Study)
Observational Study
INTRODUCTION
Despite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a strong need for better identifying local immune dynamics and immune-suppressive pathways limiting T-cell mediated anti-tumor immunity.
METHODS
In this observational study we analyzed by immunohistochemistry, gene expression profiling and flow cytometry the antigenic landscape and immune composition of 48 EOC specimens, with a focus on tumor-infiltrating lymphocytes (TILs).
RESULTS
Activated T cells showing features of partial exhaustion with a CD137CD39PD-1TIM-3CD45RACD62LCD95 surface profile were exclusively present in EOC specimens but not in corresponding peripheral blood or ascitic fluid, indicating that the tumor microenvironment might sustain this peculiar phenotype. Interestingly, while neoplastic cells expressed several tumor-associated antigens possibly able to stimulate tumor-specific TILs, macrophages provided both co-stimulatory and inhibitory signals and were more abundant in TILs-enriched specimens harboring the CD137CD39PD-1TIM-3CD45RACD62LCD95 signature.
CONCLUSION
These data demonstrate that EOC is enriched in CD137CD39PD-1TIM-3CD45RACD62LCD95 T lymphocytes, a phenotype possibly modulated by antigen recognition on neoplastic cells and by a combination of inhibitory and co-stimulatory signals largely provided by infiltrating myeloid cells. Furthermore, we have identified immunosuppressive pathways potentially hampering local immunity which might be targeted by immunotherapeutic approaches.
Topics: Humans; Female; T-Lymphocytes; Hepatitis A Virus Cellular Receptor 2; Programmed Cell Death 1 Receptor; Carcinoma, Ovarian Epithelial; Leukocyte Common Antigens; Ovarian Neoplasms; Myeloid Cells; Tumor Microenvironment
PubMed: 37868997
DOI: 10.3389/fimmu.2023.1212444 -
Nature Communications Apr 2024Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR)...
Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8 T cells. In orthotopic, syngeneic EOC models in female mice, inhibiting branched N-glycans using 2-Deoxy-D-glucose sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion.
Topics: Humans; Female; Animals; Mice; BRCA1 Protein; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; Glycosylation; BRCA2 Protein; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; B7-H1 Antigen
PubMed: 38565883
DOI: 10.1038/s41467-024-47069-y -
Science Advances Nov 2023Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused...
Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti-Siglec-7 mAb (DB7.2) enhanced survival in OC-challenged mice. In addition, the combination of DB7.2 and anti-PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.
Topics: Female; Humans; Mice; Animals; Biological Products; Killer Cells, Natural; Ovarian Neoplasms; Antigens, CD; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 37910620
DOI: 10.1126/sciadv.adh4379 -
American Journal of Obstetrics and... Apr 2024This study aimed to provide procedure-specific estimates of the risk of symptomatic venous thromboembolism and major bleeding in the absence of thromboprophylaxis,... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to provide procedure-specific estimates of the risk of symptomatic venous thromboembolism and major bleeding in the absence of thromboprophylaxis, following gynecologic cancer surgery.
DATA SOURCES
We conducted comprehensive searches on Embase, MEDLINE, Web of Science, and Google Scholar for observational studies. We also reviewed reference lists of eligible studies and review articles. We performed separate searches for randomized trials addressing effects of thromboprophylaxis and conducted a web-based survey on thromboprophylaxis practice.
STUDY ELIGIBILITY CRITERIA
Observational studies enrolling ≥50 adult patients undergoing gynecologic cancer surgery procedures reporting absolute incidence for at least 1 of the following were included: symptomatic pulmonary embolism, symptomatic deep vein thrombosis, symptomatic venous thromboembolism, bleeding requiring reintervention (including reexploration and angioembolization), bleeding leading to transfusion, or postoperative hemoglobin <70 g/L.
METHODS
Two reviewers independently assessed eligibility, performed data extraction, and evaluated risk of bias of eligible articles. We adjusted the reported estimates for thromboprophylaxis and length of follow-up and used the median value from studies to determine cumulative incidence at 4 weeks postsurgery stratified by patient venous thromboembolism risk factors. The GRADE approach was applied to rate evidence certainty.
RESULTS
We included 188 studies (398,167 patients) reporting on 37 gynecologic cancer surgery procedures. The evidence certainty was generally low to very low. Median symptomatic venous thromboembolism risk (in the absence of prophylaxis) was <1% in 13 of 37 (35%) procedures, 1% to 2% in 11 of 37 (30%), and >2.0% in 13 of 37 (35%). The risks of venous thromboembolism varied from 0.1% in low venous thromboembolism risk patients undergoing cervical conization to 33.5% in high venous thromboembolism risk patients undergoing pelvic exenteration. Estimates of bleeding requiring reintervention varied from <0.1% to 1.3%. Median risks of bleeding requiring reintervention were <1% in 22 of 29 (76%) and 1% to 2% in 7 of 29 (24%) procedures.
CONCLUSION
Venous thromboembolism reduction with thromboprophylaxis likely outweighs the increase in bleeding requiring reintervention in many gynecologic cancer procedures (eg, open surgery for ovarian cancer and pelvic exenteration). In some procedures (eg, laparoscopic total hysterectomy without lymphadenectomy), thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding venous thromboembolism and bleeding.
Topics: Adult; Humans; Female; Anticoagulants; Venous Thromboembolism; Postoperative Complications; Hemorrhage; Thrombosis; Neoplasms
PubMed: 37827272
DOI: 10.1016/j.ajog.2023.10.006 -
Cancers Aug 2023Ovarian tissue cryopreservation and transplantation are the only available fertility techniques for prepubertal girls with cancer. Though autotransplantation carries a... (Review)
Review
BACKGROUND
Ovarian tissue cryopreservation and transplantation are the only available fertility techniques for prepubertal girls with cancer. Though autotransplantation carries a risk of reintroducing malignant cells, it can be avoided by identifying minimal infiltrative disease (MID) within ovarian tissue.
METHODS
A broad search for peer-reviewed articles in the PubMed database was conducted in accordance with PRISMA guidelines up to March 2023. Search terms included 'minimal residual disease', 'cryopreservation', 'ovarian', 'cancer' and synonyms.
RESULTS
Out of 542 identified records, 17 were included. Ovarian tissues of at least 115 girls were evaluated and categorized as: hematological malignancies ( = 56; 48.7%), solid tumors ( = 42; 36.5%) and tumors of the central nervous system ( = 17; 14.8%). In ovarian tissue of 25 patients (21.7%), MID was detected using RT-qPCR, FISH or multicolor flow cytometry: 16 of them (64%) being ALL ( rearrangements with/without , , , fusion transcripts), 3 (12%) Ewing sarcoma ( fusion transcript, rearrangements), 3 (12%) CML ( fusion transcript, ) and 3 (12%) AML (leukemia-associated immunophenotypes, fusion transcript) patients.
CONCLUSION
While the majority of malignancies were found to have a low risk of containing malignant cells in ovarian tissue, further studies are needed to ensure safe implementation of future fertility restoration in clinical practice.
PubMed: 37686475
DOI: 10.3390/cancers15174199