Ilaria Colombo

CD8+ T cells are involved in natural tumor immune surveillance and are known to play a critical role in mediating responses to PD-1 blockade. High grade serous ovarian cancer (HGSOC) exhibits intrinsic resistance to immune-checkpoint inhibitors (ICI), despite the presence of tumor-infiltrating lymphocytes (TIL) in the tumor immune microenvironment (TIME). Here, we characterized the phenotype and frequency of TILs in the tumor samples of patients with HGSOC and compared our findings to TIL from melanoma (MEL), a tumor highly sensitive to ICI. MEL harboured an increased density of CD8+ TILs compared to HGSOC. However, CD8+ T cells from HGSOC tumor samples expressed higher levels of exhaustion markers such as 2B4 and PD-1 compared with the CD8+ MEL TILs, with the evidence for antigen- specific CD8+ TILs. Our study demonstrates that despite the presence of CD8+ T cells that are phenotypically exhausted, there is limited expansion of CD8+ cells after treatment with anti-PD-1 in patients with HGSOC. These data indicate that CD8+ T cells from ovarian cancer express markers associated with antigen specificity, are on the exhaustion trajectory, yet are unable to contribute to a measurable anti-tumor response after PD-1 blockade.

In recent years, immunotherapy has modified the treatment landscape of advanced and recurrent endometrial cancer (a/rEC), particularly for patients with defective mismatch repair and microsatellite instability-high (dMMR/MSI-H), significantly improving their outcomes. Its success in later treatment lines has led to its investigation and adoption as a first-line therapy, alone or with chemotherapy. However, despite the high and long-lasting efficacy of immune checkpoint inhibitors (ICIs) in dMMR/MSI-H EC, not all patients benefit from this treatment, and reasons underscoring primary resistance in this setting remain poorly understood and are not yet incorporated into clinical decision-making. Additionally, the correlation between ICI response, tumor mutational burden (TMB), and PD-L1 expression, well-documented in other tumors, appears inconsistent in EC. While proficient mismatch repair and microsatellite stable (MMRp/MSS) EC remain an unmet medical need, some patients within this group still respond to ICIs. Although several biomarkers, including TP53, BRCA, and homologous recombination deficiency (HRD), have been investigated, none have proven to be definitively predictive. This review examines the relevant trials with ICIs as a single agent or in combination in EC and explores the available evidence on potential predictive biomarkers.

This investigator-initiated, open-label phase 1/2 clinical trial evaluates maveropepimut-S, a survivin-targeting vaccine, combined with pembrolizumab and low-dose cyclophosphamide in patients with recurrent epithelial ovarian cancer (ClinicalTrials.gov identifier: NCT03029403). The primary endpoints are safety and clinical efficacy measured by overall response rate and disease control rate. Secondary endpoints include recommended phase 2 dose, progression-free survival, overall survival, and survivin-specific immune response. Forty-seven patients are enrolled and forty-four are evaluable. Most treatment-related adverse events are grade 1 or 2, most commonly injection site reactions. The recommended phase 2 dose is 0.25 milliliters. The overall response rate is 23% and the disease control rate is 67%, with greater activity in platinum-sensitive disease. Median progression-free survival is 6.3 months in platinum-sensitive disease and 1.2 months in platinum-resistant disease. Survivin-specific immune responses occur in 62.5% of tested patients and correlate with clinical benefit. The combination demonstrates tolerability and sustained clinical activity.

The endodermal sinus tumor (EST), also known as yolk sac tumor, accounts for 20% of germ cell tumor cases, typically occurring in gonadal locations. However, 1%–5% can present with an extragonadal localization. Primary hepatic EST is an extremely rare entity and poses a diagnostic challenge for the appropriate management of this pathology. We present the case of a 34‐year‐old woman who presented with a single hepatic mass associated with elevated alpha‐fetoprotein (AFP) levels. Initially, hepatocellular carcinoma (HCC) was suspected, leading to a right hepatectomy, which resulted in pathology findings consistent with an EST. Following surgery, the patient underwent four courses of BEP chemotherapy, showing a partial response with residual lesions. The patient received two more courses of EP chemotherapy, with a PET CT showing a complete response. At over 5 years of follow‐up, the patient remains clinically stable, with negative tumor markers, no evidence of disease, and leading a normal life. Primary hepatic EST is an infrequent but important differential diagnosis of HCC, particularly in young women without cirrhosis who present with markedly elevated AFP levels. Early biopsy confirmation and multidisciplinary management are essential, as this chemosensitive tumor may achieve long‐term survival with timely systemic treatment.

Background and Objective Targeted liposomal doxorubicin (TLD-1) is a novel PEGylated liposomal doxorubicin (PLD) with optimized formulation characteristics, developed to improve the benefit-risk profile of PLD. This randomized intrapatient crossover amendment to the phase 1 SAKK 65/16 trial (NCT03387917) compared the pharmacokinetics (PK) of TLD-1 and Caelyx™ and included a pooled analysis of safety and preliminary antitumor activity at the recommended phase 2 dose (RP2D). Methods Patients with advanced breast or platinum-resistant ovarian cancer in the comparative PK part were randomized to receive TLD-1 in cycle 1 and Caelyx™ in cycle 2, or vice versa, followed by TLD-1 thereafter. Both formulations were administered intravenously at 40 mg/m² and PK was assessed using non-compartmental analysis. Safety and antitumor activity were analyzed across 23 patients treated with TLD-1 at the RP2D, including 13 from the comparative PK part and 10 from the published dose-escalation part. Results In 10 evaluable patients from the comparative PK part, TLD-1 showed higher encapsulated doxorubicin exposure (AUC_0–inf: 3222 vs 2139 mg·h/L) and longer median half-life (118 vs 70 h) than Caelyx™. Severe treatment-related events occurred in 43% of patients (10/23) in the full RP2D cohort, most commonly grade 3 palmar-plantar erythrodysesthesia, oral mucositis, and anemia (2 patients each). The investigator-assessed objective response rate was 8.7% (2/23), with partial responses in patients with breast cancer. Conclusions Targeted liposomal doxorubicin demonstrated prolonged systemic circulation and low variability in liposomal drug release, likely due to its formulation characteristics. At 40 mg/m² every 3 weeks, TLD-1 was well tolerated and showed modest preliminary antitumor activity in advanced breast cancer. ClinicalTrials.gov Identifier NCT03387917, registered 2017-11-21.

Gynecological cancer remains one of the leading causes of mortality worldwide. Recent advances in genomic and molecular sequencing have significantly enhanced our understanding of the biological pathways that drive tumor progression and resistance to therapy. Targeted therapies, including monoclonal antibodies (mAbs), have revolutionized cancer treatment by selectively interfering with oncogenic proteins expressed on cancer cells. However, the long-term clinical benefit is often limited due to the emergence of drug resistance, frequently mediated by compensatory signaling pathways or immune escape mechanisms. To overcome these limitations, bispecific antibodies (bsAbs) represent an innovative class of therapeutic agents that have shown promising results across various medical fields. They have been developed to engage two distinct targets simultaneously, such as tumor antigens, immune effectors, or immunomodulatory checkpoints, thereby enhancing anti-tumor activity and reducing the risk of resistance. There are 17 bsAbs approved for clinical use in various countries, with numerous others currently in active development and over 600 bsAbs undergoing clinical trials worldwide. Among these, 11 have received FDA approval for the treatment of hematologic malignancies as well as solid tumors, including uveal melanoma, metastatic non-small cell lung cancer, small cell lung cancer, and biliary tract cancers. Although some studies have explored bsAbs in gynecological cancers, this area remains underdeveloped compared to other oncology fields. Most ongoing studies in this area are still in their early phases (phase I or phase II), and there is a need for optimization in terms of antibody design, efficacy, and safety profiles. Therefore, the purpose of this review is to present a comprehensive summary of the current research on bsAbs in gynecological cancers, with a focus on endometrial, cervical, and ovarian cancers. We will highlight ongoing clinical trials, discuss the mechanisms of action of these agents, and explore their potential benefits in enhancing treatment outcomes.