Zhongping Cheng

Purpose:Recurrent ovarian cancer (rOC) remains an unmet need. This first-in-human phase I trial evaluated GC203, an autologous tumor-infiltrating lymphocyte (TIL) product genetically modified via piggyBac transposon to overcome the immunosuppressive tumor microenvironment. Patients and Methods:A cohort of 18 patients with rOC who were heavily pretreated (median, 3.5 prior lines of therapy) underwent lymphodepletion with cyclophosphamide and hydroxychloroquine, followed by GC203 infusion. The primary endpoints were safety and tolerability. Secondary endpoints, assessed in the full analysis set using RECIST 1.1 guidelines, encompassed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses included the Morisita overlap index (MOI) to quantify T-cell receptor repertoire similarity between infused TILs and circulating T cells. Results:The GC203 regimen demonstrated a favorable safety profile. Treatment-related adverse events were primarily hematologic, with grade ≥ 3 lymphopenia and neutropenia each occurring in 57% of patients. All proved to be transient with a median resolution of 7 days. The regimen achieved an unconfirmed ORR of 33.3% (6/18 patients) alongside a disease control rate of 83.3%. Survival analyses revealed a median PFS of 7.2 months [95% confidence interval (CI), 1–13.4] and a median OS of 17.1 months (95% CI, 9.5–24.7). A key exploratory analysis identified the MOI as a significant predictor of treatment response, achieving an area under the curve of 0.79. Conclusions:The GC203 regimen, combining piggyBac membrane-bound IL7 autologous TILs with anti–PD-1 antibody, demonstrates favorable safety and promising efficacy in heavily pretreated patients with rOC, which supports its further development in this high-need population.

Supplementary materials and methods, Figure S1-S7, supplementary figure legends, and Table S1-S4.

Following the publication of the above article, a concerned author drew to the authors' attention that the western blot data showing the TGF β1‑experiments in Fig. 4C and D on p. 3129 for the HO‑8910 and A2780 cell lines were strikingly similar, suggesting that the data in this figure had been assembled incorrectly. In addition, various of the western blots featured in this figure, and also in Fig. 2B on p. 3127, were remarkably similar to data which were subsequently submitted for publication in articles written by different authors at different research institutes to a number of different journals, at least one of which has since been retracted on account of data sharing issues with other papers. The authors have been contacted by the Editorial Office to offer an explanation for the apparent anomalies in the presentation of the western blot data in this paper, and we are awaiting their response. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Oncology Reports 33: 3124‑3130, 2015; DOI: 10.3892/or.2015.3902]

Purpose: Recurrent ovarian cancer (rOC) remains an unmet need. This first-in-human phase I trial evaluated GC203, an autologous tumor-infiltrating lymphocyte (TIL) product genetically modified via piggyBac transposon to overcome the immunosuppressive tumor microenvironment. Patients and Methods: A cohort of 18 patients with rOC who were heavily pretreated (median, 3.5 prior lines of therapy) underwent lymphodepletion with cyclophosphamide and hydroxychloroquine, followed by GC203 infusion. The primary endpoints were safety and tolerability. Secondary endpoints, assessed in the full analysis set using RECIST 1.1 guidelines, encompassed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses included the Morisita overlap index (MOI) to quantify T-cell receptor repertoire similarity between infused TILs and circulating T cells. Results: The GC203 regimen demonstrated a favorable safety profile. Treatment-related adverse events were primarily hematologic, with grade ≥ 3 lymphopenia and neutropenia each occurring in 57% of patients. All proved to be transient with a median resolution of 7 days. The regimen achieved an unconfirmed ORR of 33.3% (6/18 patients) alongside a disease control rate of 83.3%. Survival analyses revealed a median PFS of 7.2 months [95% confidence interval (CI), 1–13.4] and a median OS of 17.1 months (95% CI, 9.5–24.7). A key exploratory analysis identified the MOI as a significant predictor of treatment response, achieving an area under the curve of 0.79. Conclusions: The GC203 regimen, combining piggyBac membrane-bound IL7 autologous TILs with anti–PD-1 antibody, demonstrates favorable safety and promising efficacy in heavily pretreated patients with rOC, which supports its further development in this high-need population.

Alternative splicing is an evolutionarily conserved and essential cellular process that is catalyzed by a multi-complex spliceosome. Dysregulation of this process has been implicated in various tumors over the recent years. SF3a1 is a critical subunit of U2 small nuclear ribonucleoprotein (snRNP) in the spliceosome, which has been found to be aberrant in several human diseases. Recent reports suggest that SF3a1 might be a novel therapeutic target. However, a comprehensive description of SF3a1 is lacking. In this review, we present the findings of SF3a1 from protein structure, biological function to strong associations with human diseases including cancer. Studies have reported that SF3a1 dysregulation and associated alternative splicing events mediate tumorigenesis and other immune-related disorders. However, further functional and mechanistic studies are needed to fully understand the regulatory network of SF3a1 in human diseases. In conclusion, SF3a1 could serve as a promising prognostic biomarker and therapeutic target for specific cancer types, including prostate cancer, colorectal cancer and hepatocellular carcinoma.

Cell death plays a pivotal role in a multitude of biological processes, including embryonic development, organ maintenance, aging, immune response, and autoimmunity. These processes are underpinned by distinct molecular mechanisms and have significant implications for biological systems. Currently, research on regulatory cell death (RCD) is primarily focused on apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and autophagy. These pathways have been shown to play a crucial role in regulating the tumor microenvironment (TME) and influencing the clinical outcome of cancer immunotherapy. RCD exerts a dual regulatory effect on TME, releasing intracellular components and regulating the distribution of immune cells. These cells are involved in fine-tuning the antitumor immune response in the TME. The treatment of gynecological tumors frequently presents a challenge due to the lack of immunotherapeutic responsiveness. This review will focus on apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and autophagy. It will explore how the molecular messengers released during these processes are involved in regulating their complex interactions with tumor tissues as well as with the immune response. It will also analyze the immunological consequences of regulated cell death and its potential impact on the future development of gynecological oncology therapy. By investigating the mechanisms of cell death, we can gain insight into their role in the development of gynecological tumors and potentially identify new therapeutic strategies to enhance the efficacy of existing treatments and advance cancer care.

Peritoneal dissemination frequently develops in patients with ovarian cancer (OC) and is associated with recurrence and metastasis. However, the cellular components and mechanisms supporting OC peritoneal metastasis are poorly understood. To elucidate these, we utilized RNA sequencing to investigate the cellular composition and function. Insights from transcriptome analyses suggested that OC cells from malignant ascites persisted in a quiescent state of low metabolic activity and after metastases to the peritoneum, arrested OC cells were reactivated and induced back to the cell cycle, suggesting that the peritoneum served as a favor tumor microenvironment. To elucidate the mechanisms, we then developed long-range migration and competitive inhibition assays and showed that peritoneal adipose-derived stem cells-derived extracellular vesicles (ADSCs-EVs) mediated preferential migration of OC cells toward peritoneal ADSCs but not other representative cells from the peritoneal cavity. In line with phenotypic changes, transcriptomic analysis revealed that patient peritoneal ADSCs-EVs stimulated the expression of numerous genes associated with OC cell proliferation and migration; among them, the epidermal growth factor receptor (EGFR) and nuclear factor kappa B (NF-κB) signaling pathways were highly enriched. We also found that peritoneal ADSCs produced and secreted key EGFR signaling molecules, including EGF and EGFR, into ADSCs-EVs. Upon fusion with OC cells, ADSCs-EVs up-regulated the EGFR-NF-κB axis and promoted OC cell proliferation and migration. Interference with either ADSCs-EVs production or EGFR signaling abolished the proliferation and migration effect. The results show that ADSCs modulate OC cell proliferation and migration at multiple layers, constituting a key mechanism in OC progression.