For gastric cancer patients, peritoneal metastasis poses a life-threatening risk due to the high incidence of treatment failure and disease recurrence. Conducting additional research aimed at identifying more efficacious strategies is imperative for enhancing treatment outcomes. This study examined the efficacy and safety of systemic chemotherapy plus a PD-1 inhibitor combination with intravenous or intraperitoneal bevacizumab for gastric cancer with peritoneal metastasis.

We conducted the open label, two-arm pilot study involved receiving albumin-bound paclitaxel (260 mg/m2, d1) plus S-1 (80 mg/m2, d1-14) combined with sintilimab (200 mg, d1) and bevacizumab (7.5 mg/m2, d1) (Arm A) intraperitoneally for moderate or large ascites or intravenously (Arm B) for non- or small ascites. The clinical trial was registered at the Chinese Clinical Trial Registry (ChiCTR2100048947 DATE: 2021-07-19).

Ten gastric cancer patients with peritoneal metastasis were enrolled in two arms (four in Arm A and six in Arm B) from August 19th, 2021 to June 1st, 2022. Until the end of the follow-up date, the mPFS for Arm A was 5.70 m (95% CI: 1.29-10.11), while Arm B had a mPFS of 9.07 m (95% CI: 3.79-14.35). The mOS for Arm A and Arm B was 8.43 (95% CI: 6.70-10.17) and 11.23 months (95% CI: 2.90-19.56). At least one common Grade 3/4 AE occurred in 25% of Arm A participants and 16.7% of Arm B patients.

Albumin-bound paclitaxel plus S-1 with a PD-1 inhibitor and intraperitoneal or intravenous bevacizumab was well tolerated in gastric cancer patients with peritoneal metastasis.

For survival studies, pooling hazard ratios (HRs) across multiple clinical trials through meta-analysis is commonly performed to achieve widely accepted and robust conclusions. However, clinical trials sometimes do not report HRs.

We developed a new, simple approach to estimate HRs by reconstructing life tables from Kaplan-Meier (KM) curves, particularly for small clinical trials. First, we extracted the time points and survival rates from the published KM curves. Then, we reconstructed the life table by reverse derivation of its parameters, using time points and survival rates extracted from the KM curves. Finally, we replotted the KM curves using the Kaplan-Meier method and estimated the HRs via the Cox regression method by SPSS software, using the survival data from the reconstructed life table.

The estimated HRs of 3 examples were 0.510 (95% CI 0.272-0.958, P = 0.036), 2.472 (95% CI 1.548-3.949, P < 0.001), and 0.591 (95% CI 0.291-1.199, P = 0.145), compared with the original HRs of 0.51 (95% CI 0.27-0.96, P = 0.04), 2.33 (95% CI 1.45-3.73, P < 0.001), and 0.62 (95% CI 0.31-1.26, P = 0.18), respectively.

This simple approach allows for the estimate of HRs from published KM curves in small survival studies without reported HRs, facilitating their inclusion in meta-analyses. This increases the overall sample size and enhances the reliability of synthesized clinical evidence.

Catumaxomab (Korjuny®) is a first-in-class bispecific trifunctional rat-mouse hybrid monoclonal antibody currently under development with Lindis Biotech for malignant ascites, and bladder, gastric and ovarian cancers. It binds epithelial cell adhesion molecule (EpCAM) on tumour cells and CD3 on T cells, while its Fc domain engages Fcγ receptor-positive accessory cells, bringing immune and tumour cells into close proximity to enhance tumour cell killing through multiple immunological mechanisms. Initially approved in the EU on 20 April 2009 for malignant ascites in adults with EpCAM+ carcinomas when standard therapy was unavailable or no longer feasible, catumaxomab was marketed by Fresenius Biotech GmbH (later Neovii Biotech GmbH) before being withdrawn on 2 June 2017 for commercial reasons. Lindis Biotech later acquired the rights and pursued reapproval. On 11 February 2025, catumaxomab was approved in the EU for the intraperitoneal treatment of malignant ascites in adults with EpCAM+ carcinomas who are not eligible for further systemic anticancer therapy. This article summarizes the milestones in the development of catumaxomab leading to this new approval.

Malignant ascites (MA) develops when malignant disease of the peritoneum causes excess fluid to accumulate in the abdominal cavity. It portends a poor prognosis and is associated with debilitating symptoms. While several palliative therapies exist, none have proven curative or free from side effects and complications. This review article describes experimental therapies on the horizon and the contemporary management of MA.

A literature review was performed using MEDLINE/PubMed, in which studies of emerging or experimental therapies under investigation for the management of MA were reviewed. Current therapies were also reviewed to provide important context. Data, including study design, sample size, primary and secondary outcomes, and side effects were recorded and described. Studies were then categorized into distinct sections and subsections, with tables corresponding to each section.

Five current therapies, including paracentesis, diuretics, peritoneovenous shunting, permanent catheters, and intraperitoneal chemotherapy, are described. Their limitations in effectively managing MA are highlighted. The "Experimental therapies" section is subsectioned into several categories, with the major studies corresponding to each section thoroughly described regarding methods, results, and validity. A final section describes treatments for mucinous ascites, which has distinct characteristics.

While each of the experimental therapies described offers unique benefits and has demonstrated some promise in managing MA, they all have limitations that have thus far prevented any one of them from being routinely used in practice. MA remains a challenging condition to treat, warranting further research into novel therapies.

The advent of immune checkpoint inhibitors (ICIs) has deeply reshaped the therapeutic algorithm of triple-negative breast cancer (TNBC). However, there is considerable scope for better engagement of the immune system in other BC subtypes. ICIs have paved the way for investigations into emerging immunotherapeutic strategies, such as immune cell engagers (ICEs) that work by promoting efficient tumor cell killing through the redirection of immune system against cancer cells. Most ICEs are bispecific antibodies that simultaneously recognize and bind to both cancer and immune cells generating an artificial synapse. Major side effects are cytokine release syndrome, hepatotoxicity, and neurotoxicity related to inappropriate immune system activation. Here, we provide a comprehensive overview of this compounds, the available preclinical and clinical evidence supporting their investigation and development in BC also highlighting the challenges that have prevented their widespread use in oncology. Finally, major strategies are explored to broaden their use in BC.

In the past decade, T-cell-based immunotherapies have grown to become some of the most promising treatments for cancer. Following the success of immune checkpoint inhibitors, other T-cell-based therapies emerged including CAR-T cells and bispecific T-cell engagers (BiTEs). BiTEs have the unique ability to crosslink T cells and tumor cells independently of major histocompatibility complex (MHC) restriction. They do not rely on TCR specificity or the CD4+/CD8+ costimulatory molecules, overcoming tumor MHC downregulation and low-affinity TCR binding. However, like many other immunotherapies, BiTEs have shown limited success beyond the treatment of hematological malignancies. BiTEs for the treatment of solid tumors still face challenges. Studies in gastrointestinal tumors have revealed Fc toxicity, short half-lives, and immunotoxicity, leading to Fc-silenced half-life extended BiTEs with humanized single-chain variable fragments. Studies in prostate tumors, lung tumors, and malignant gliomas have identified promising targets in PSMA, DLL3, and EGFRvIII, respectively, but also highlighted the problems of on-target off-tumor and BiTE-specific toxicities and inaccessible or immunosuppressive tumor microenvironments. Ongoing research to overcome these limitations remains an interesting field to follow, as BiTEs have the potential to be a powerful tool, especially when used in combination with other immunotherapies.

Ovarian cancer remains the most lethal gynecological malignancy. Despite the approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target the pivotal hallmarks of cancer. This review is giving an updated overview of innovative and upcoming therapies for the treatment of ovarian cancer that focuses specific on the hallmarks of cancer. The hallmarks of cancer constitute a broad concept to reenact complexity of malignancies and furthermore identify possible targets for new treatment strategies. For this purpose, we analyzed approvals and current clinical phase III studies (registered at ClinicalTrials.gov (National Library of Medicine, National Institutes of Health; U.S. Department of Health and Human Services, 2024)) for new drugs on the basis of their mechanisms of action and identified new target approaches. A broad spectrum of new promising drugs is currently under investigation in clinical phase III studies targeting mainly the hallmarks "self-sufficiency in growth signals," "genomic instability," and "angiogenesis." The benefit of immune checkpoint inhibitors in ovarian cancer has been demonstrated for the first time. Besides, targeting the tumor microenvironment is of growing interest. Replicative immortality, energy metabolism, tumor promoting inflammation, and the microbiome of ovarian cancer are still barely targeted by drugs. Nevertheless, precision medicine, which focuses on specific disease characteristics, is becoming increasingly important in cancer treatment.

After decades of gradual progress from conceptualization to early clinical trials (1960-2000), the therapeutic potential of bispecific antibodies (bisp Abs) is now being fully realized. Insights gained from both successful and unsuccessful trials are helping to identify which mechanisms of action, antibody formats, and targets prove most effective, and which may benefit from further refinement. While T-cell engagers remain the most commonly used class of bisp Abs, current efforts aim to increase their effectiveness by co-engaging costimulatory molecules, reducing escape mechanisms, and countering immunosuppression. Strategies to minimize cytokine release syndrome (CRS) are also actively under development. In addition, novel antibody formats that are selectively activated within tumors are an exciting area of research, as is the precise targeting of specific T-cell subsets. Beyond T cells, the recruitment of macrophages and dendritic cells is attracting increasing interest, with researchers exploring various macrophage receptors to promote phagocytosis or to carry out specialized functions, such as the immunologically silent clearance of amyloid-beta plaques in the brain. While bisp Abs targeting B cells are relatively limited, they are primarily aimed at inhibiting B-cell activity in autoimmune diseases. Another evolving application involves the forced interaction between proteins. Beyond the successful development of Hemlibra for hemophilia, bispecific antibodies that mimic cytokine activity are being explored. Additionally, the recruitment of cell surface ubiquitin ligases and other enzymes represents a novel and promising therapeutic strategy. In regard to antibody formats, some applications such as the combination of T-cell engagers with costimulatory molecules are driving the development of trispecific antibodies, at least in preclinical settings. However, the increasing structural complexity of multispecific antibodies often leads to more challenging development paths, and the number of multispecific antibodies in clinical trials remains low. The clinical success of certain applications and well-established production methods position this therapeutic class to expand its benefits into other therapeutic areas.

Malignant ascites (MA), a common and serious complication of various cancers in the abdominal cavity, originates from the extensive infiltration, metastasis, and growth of cancer cells in or on the abdominal cavity, leading to abnormal accumulation of fluid in the abdominal cavity and the formation of MA. MA seriously reduces the quality of life of cancer patients, shortens their survival period, and generally has a poor prognosis. Modern medicine has developed various strategies for the treatment of MA, including targeted supportive treatment, diuretic treatment, abdominal paracentesis, surgical intervention, and intraperitoneal administration therapy. Among them, chemotherapy, as one of the important treatment methods, includes both systemic chemotherapy and intraperitoneal chemotherapy, especially pressurized intraperitoneal aerosol chemotherapy (PIPAC), hyperthermic intraperitoneal chemotherapy (HIPEC), and foam-based intraperitoneal chemotherapy (FBIC), providing a new choice for the treatment of MA. In addition, innovative treatment methods such as gas-based intra-abdominal hyperthermia (GIH) combined with dehydration therapy have also shown promising application prospects. This article delves into multiple aspects of MA, including its concept, mechanism of occurrence, clinical manifestations, differential diagnostic methods, and current treatment status and research progress. This comprehensive review aims to provide valuable references for effectively controlling MA, improving cancer patients' quality of life, and prolonging the survival cycle of cancer patients in clinical practice. Malignant ascites (MA) is a common complication of cancer, which originates from the extensive infiltration, metastasis, and growth of cancer cells in the abdominal cavity or peritoneum, leading to abnormal accumulation of peritoneal fluid. It is a common clinical manifestation in the late stage of cancer. Its symptoms are stubborn and recurrent, which can lead to abdominal pain, bloating, poor appetite, fatigue, breathing difficulties, and even multiple organ failure. The median survival time for cancer patients with MA is generally 5 to 6 months. The prognosis is poor, and it is imperative to seek more active and effective treatment plans. This article reviews the research and treatment status of MA, aiming to provide certain value for controlling MA and improving the quality of life of patients.

Substantial progress in understanding T cell signalling, particularly with respect to T cell co-receptors such as the co-stimulatory receptor CD28, has been made in recent years. This knowledge has been instrumental in the development of innovative immunotherapies for patients with cancer, including immune checkpoint blockade antibodies, adoptive cell therapies, tumour-targeted immunostimulatory antibodies, and immunostimulatory small-molecule drugs that regulate T cell activation. Following the failed clinical trial of a CD28 superagonist antibody in 2006, targeted CD28 agonism has re-emerged as a technologically viable and clinically promising strategy for cancer immunotherapy. In this Review, we explore recent insights into the molecular functions and regulation of CD28. We describe how CD28 is central to the success of current cancer immunotherapies and examine how new questions arising from studies of CD28 as a clinical target have enhanced our understanding of its biological role and may guide the development of future therapeutic strategies in oncology.

In recent years, bispecific antibodies (BsAbs) have emerged as a promising therapeutic strategy against tumors. BsAbs can recruit and activate immune cells, block multiple signaling pathways, and deliver therapeutic payloads directly to tumor sites. This review provides a comprehensive overview of the recent advances in the development and clinical application of BsAbs for the treatment of solid tumors. We discuss the different formats, the unique mechanisms of action, and the clinical outcomes of the most advanced BsAbs in solid tumor therapy. Several studies have also analyzed the clinical progress of bispecific antibodies. However, this review distinguishes itself by exploring the challenges associated with bispecific antibodies and proposing potential solutions. As the field progresses, BsAbs hold promise to redefine cancer treatment paradigms and offer new hope to patients with solid tumors.

Pancreatic cancer is a highly aggressive cancer with unfavorable prognosis despite the therapeutic interventions. Intraperitoneal chemotherapy has recently shown potential outcomes in the presence of peritoneal metastases. However, a consensus is still lacking on different methods for intraperitoneal chemotherapy in pancreatic cancer. A variety of drugs and doses via three types of intraperitoneal chemotherapy have been studied. The prognosis and treatment strategies for pancreatic ductal adenocarcinoma (PDAC) will be significantly influenced by peritoneal dissemination and resectability of the macroscopic disease. Normothermic intraperitoneal chemotherapy (NIPEC) has been used for the treatment of peritoneal metastases of pancreatic carcinomas. Intraperitoneal chemotherapy is often combined with systemic therapies or surgical procedures which may lead to favorable combination therapies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a relatively new approach that provides a homogenous and deep penetration of the chemotherapy into the peritoneum by producing aerosols. The present study aims to review the literature for recent evidence on intraperitoneal chemotherapy in pancreatic cancer.

T-cell-engaging bispecific antibody (TCB) therapies have emerged as a promising immunotherapeutic approach, effectively redirecting effector T cells to selectively eliminate tumor cells. The therapeutic potential of TCBs has been well recognized, particularly with the approval of multiple TCBs in recent years for the treatment of hematologic malignancies as well as some solid tumors. However, TCBs encounter multiple challenges in treating solid tumors, such as on-target off-tumor toxicity, cytokine release syndrome (CRS), and T cell dysfunction within the immunosuppressive tumor microenvironment, all of which may impact their therapeutic efficacy. In this review, we summarize clinical data on TCBs for solid tumor treatment, highlight the challenges faced, and discuss potential solutions based on emerging strategies from current clinical and preclinical research. These solutions include TCB structural optimization, target selection, and combination strategies. This comprehensive analysis aims to guide the development of TCBs from design to clinical application, addressing the evolving landscape of cancer immunotherapy.

Off-the-shelf T-cell-redirecting bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 have high activity in multiple myeloma with a manageable toxicity profile. However, not all patients respond to bispecific antibodies and patients can develop bispecific antibody resistance after an initial response. Mechanisms that contribute to bispecific antibody resistance are multifactorial and include tumour-related factors, such as high tumour burden, expression of T-cell inhibitory ligands, and antigen loss. Resistance due to antigen escape can be prevented by simultaneously targeting two tumour-associated antigens with a trispecific antibody or a combination of two bispecific antibodies. There is also increasing evidence that primary resistance to bispecific antibodies is associated with impaired baseline T-cell function. Long-term exposure to bispecific antibodies with chronic T-cell stimulation further aggravates T-cell dysfunction, which could contribute to failure of disease control. Therapeutic interference with T-cell exhaustion by targeting inhibitory or costimulatory pathways could improve bispecific antibody-mediated antitumour activity. The immunosuppressive microenvironment also contributes to bispecific antibody resistance. CD38-targeting antibodies hold promise as combination partners for bispecific antibodies because of their potential to eliminate CD38+ immune suppressor cells. In conclusion, a better understanding of the mechanisms underlying the absence of disease response has provided novel insights to optimise T-cell activity and bispecific antibody efficacy in multiple myeloma.

Immune checkpoints are crucial molecules for the maintenance of antitumor immune responses. The activation or inhibition of these molecules is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals to the various components of the immune system. Over the last 10 years, the inhibition of immune checkpoints, such as cytotoxic T lymphocyte antigen-4, programmed cell death-1, and programmed cell death ligand-1, has taken a leading role in immune therapy. This relatively recent therapy regime is based on the use of checkpoint inhibitors, which enhance the immune response towards various forms of cancer. For a subset of patients with specific forms of cancer, these inhibitors can induce a durable response to therapy; however, the medium response rate to such therapy remains relatively poor. Recent research activities have demonstrated that the disease response to this highly promising therapy resembles the response of many forms of cancer to chemotherapy, where an encouraging initial response is followed by acquired resistance to treatment and progress of the disease. That said, these inhibitors are now used as single agents or in combination with chemotherapies as first or second lines of treatment for about 50 types of cancer. The prevailing opinion regarding immune therapy suggests that for this approach of therapy to deliver on its promise, a number of challenges have to be circumvented. These challenges include understanding the resistance mechanisms to immune checkpoint blockade, the identification of more efficient inhibitors, extending their therapeutic benefits to a wider audience of cancer patients, better management of immune-related adverse side effects, and, more urgently the identification of biomarkers, which would help treating oncologists in the identification of patients who are likely to respond positively to the immune therapies and, last but not least, the prices of therapy which can be afforded by the highest number of patients. Numerous studies have demonstrated that understanding the interaction between these checkpoints and the immune system is essential for the development of efficient checkpoint inhibitors and improved immune therapies. In the present text, we discuss some of these checkpoints, their inhibitors, and some works in which mass spectrometry-based proteomic analyses were applied.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761).

Patients received IP nivolumab (0.5, 1, or 3 mg/kg) using a 3 + 3 dose-escalation design, starting 5 to 7 days after CRS and HIPEC. Four IP Q2W (once every 2 weeks) nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity. Secondary objectives were to assess changes in tolerance of CRS and HIPEC.

A total of 17 patients were enrolled including 10 patients in the dose escalation and 7 patients in the expansion phase. No dose-limiting toxicity was observed at any dose level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications and 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAE), mainly transitory grade 3 to 4 transaminase elevations (6/11) and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3 to 4 adverse events related to IP nivolumab occurred.

This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer. Further investigation at 3 mg/kg is warranted.

The growing clinical success of bispecific antibodies (bsAbs) has led to rapid interest in leveraging dual targeting in order to generate novel modes of therapeutic action beyond mono-targeting approaches. While bsAbs that bind targets on two different cells (trans-targeting) are showing promise in the clinic, the co-targeting of two proteins on the same cell surface through cis-targeting bsAbs (cis-bsAbs) is an emerging strategy to elicit new functionalities. This includes the ability to induce proximity, enhance binding to a target, increase target/cell selectivity, and/or co-modulate function on the cell surface with the goal of altering, reversing, or eradicating abnormal cellular activity that contributes to disease. In this review, we focus on the impact of cis-bsAbs in the clinic, their emerging applications, and untangle the intricacies of improving bsAb discovery and development.

To construct chimeric antigen receptor (CAR)-T cells targeting epithelial cell adhesion molecule (EpCAM) antigen (anti-EpCAM-CAR-T).

A third-generation CAR-T cell construct used a single-chain variable fragment derived from monoclonal antibody against human EpCAM. Peripheral blood mononuclear cells were extracted from volunteers. The proportion of cluster of differentiation 8 positive (CD8+) and CD4 + T cells was measured using flow cytometry. Western blot was used to detect the expression of EpCAM-CAR. The killing efficiency was detected using the MTT assay and transwell assay, and the secretion of killer cytokines tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) was detected using the ELISA. The inhibitory effect of EpCAM-CAR-T on colorectal cancer in vivo was detected using xenografts.

It was found that T cells expanded greatly, and the proportion of CD3+, CD8 + and CD4 + T cells was more than 60%. Furthermore, EpCAM-CAR-T cells had a higher tumour inhibition rate in the EpCAM expression positive group than in the negative group (P < 0.05). The secretion of killer cytokines TNF-α and IFN-γ in the EpCAM expression positive cell group was higher than that in the negative group (P < 0.05). In the experimental group treated with EpCAM-CAR-T cells, the survival rate of nude mice was higher (P < 0.05), and the tumour was smaller than that in the blank and control groups (P < 0.05). The secretion of serum killer cytokines TNF-α and IFN-γ in tumour-bearing nude mice in the experimental group treated with EpCAM-CAR-T cells was higher than that in the blank and control groups (P < 0.05).

This study successfully constructed EpCAM-CAR cells and found that they can target and recognise EpCAM-positive tumour cells, secrete killer cytokines TNF-α and IFN-γ and better inhibit the growth and metastasis of colorectal cancer in vitro and in vivo than unmodified T cells.

Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial (NCT04771676) to investigate the efficacy and safety of oncolytic adenovirus H101 and virotherapy-induced immune response in 25 patients with malignant ascites. Oncolytic virotherapy achieved an increased median time to repeat paracentesis of 45 days (95% confidence interval 16.5-73.5 days), compared with the preset control value of 13 days. Therapy was well-tolerated, with pyrexia, fatigue, nausea, and abdominal pain as the most common toxicities. Longitudinal single-cell profiling identified marked oncolysis, early virus replication, and enhanced CD8+ T cells-macrophages immune checkpoint crosstalk, especially in responsive patients. H101 also triggered a proliferative burst of CXCR6+ and GZMK+CD8+ T cells with promoted tumor-specific cytotoxicity. Further establishment of oncolytic virus-induced T cell expansion signature (OiTE) implicated the potential benefits for H101-responsive patients from subsequent anti-PD(L)1 therapy. Patients with upregulated immune-signaling pathways in tumor cells and a higher proportion of CLEC10A+ dendritic cells and GZMK+CD8+ T cells at baseline showed a superior response to H101 treatment. Our study demonstrates promising clinical responses and tolerability of oncolytic adenovirus in treating malignant ascites and provides insights into the relevant cellular processes following oncolytic virotherapy.

Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30-40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings.

Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.

Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with a poor prognosis and limited treatment options. Recent work identifying high concentrations of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6-Rα) in the peritoneal cavity of patients with PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides a comprehensive overview of the current understanding of the potential role of IL-6 in the development and progression of PC. We discuss mechansims by which the IL-6 pathway may contribute to peritoneal tumor dissemination, mesothelial adhesion and invasion, stromal invasion and proliferation, and immune response modulation. Finally, we review the prospects for targeting the IL-6 pathway in the treatment of PC, focusing on common sites of origin, including ovarian, gastric, pancreatic, colorectal and appendiceal cancer, and mesothelioma.

Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity.

In this phase 1b study, registered at Clinical.

gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients.

i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks.

This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).

Refractory ascites affects the prognosis and quality of life in patients with liver cirrhosis. Peritoneovenous shunt (PVS) is a treatment procedure of palliative interventional radiology for refractory ascites. Although it is reportedly associated with serious complications (e.g., heart failure, thrombotic disease), the clinical course of PVS has not been thoroughly evaluated.

To evaluate the relationship between chronological course and complications after PVS for refractory ascites in liver cirrhosis patients.

This was a retrospective study of 14 patients with refractory ascites associated with decompensated cirrhosis who underwent PVS placement between June 2011 and June 2023. The clinical characteristics, changes in cardiothoracic ratio (CTR), and laboratory data (i.e., brain natriuretic peptide (BNP), D-dimer, platelet) were evaluated. Follow-up CT images in eight patients were also evaluated for ascites and complications.

No serious complication associated with the procedure occurred in any case. Transient increases in BNP and D-dimer levels, decreased platelet counts, and the worsening of CTR were observed in the 2 days after PVS; however, they were improved in 7 days in all cases except one. In the follow-up CT, the amount of ascites decreased in all patients, but one patient with a continuous increase in D-dimer 2 and 7 days after PVS had thrombotic disease (renal and splenic infarction). The mean PVS patency was 345.4 days, and the median survival after PVS placement was 474.4 days.

PVS placement for refractory ascites is a technically feasible palliative therapy. The combined evaluation of chronological changes in BNP, D-dimer, platelet count and CTR, and follow-up CT images may be useful for the early prediction of the efficacy and complications of PVS.

Peritoneal metastases from gastrointestinal malignancies present difficult management decisions, with options consisting primarily of systemic chemotherapy or major surgery with or without hyperthermic intraperitoneal chemotherapy. Current research is investigating expanding therapeutic modalities, and the aim of this review is to provide an overview of the existing and emerging therapies for the peritoneal metastases from gastrointestinal cancers, primarily through the recent literature (2015 and newer). These include the current data with systemic therapy and cytoreduction with hyperthermic intraperitoneal or pressurized intraperitoneal aerosol chemotherapy, as well as novel promising modalities under investigation, including dominating oncolytic viral therapy and adoptive cellular, biologic, and bacteria therapy, or nanotechnology. The novel diverse strategies, although preliminary and preclinical in murine models, individually and collectively contribute to the treatment of peritoneal metastases, offering hope for improved outcomes and quality of life. We foresee that these evolving treatment approaches will facilitate the transfer of knowledge and data among studies and advance discovery of new drugs and optimized treatments for patients with peritoneal metastases.

Bispecific antibody (BsAb)-based cancer immunotherapy has provided new avenues for the treatment of various malignancies. The approval of Blinatumomab has encouraged further investigation into these treatments, and a series of preclinical and clinical trials have been conducted, together with the publication of numerous articles. Here, the knowledge structure of BsAb-based cancer immunotherapy is summarized using bibliometric analysis to provide in-depth insight into current research trends and foci.

The studies included in the bibliometric analysis of BsAbs in cancer immunotherapy were retrieved from the online Web of Science Core Collection (WOSCC) database on April 16th, 2023. Visualization analysis was performed with the help of CtieSpace (version 6.2.2.msi [64-bit]), VOSviewer (version 1.6.19), R (version 4.2.1), and the Bibliometric analysis platform (R-based online data processing tool).

A total of 1750 papers were identified. Analysis of annual publications and total citations indicated that publications have increased steadily over the past few decades. The USA, followed by Germany, had largest number of publications, making significant contributions to the field. The Memorial Sloan Kettering Cancer Center received the highest number of citations (n = 3769). However, its collaboration and cooperation with different institutions require further strengthening. MAbs and Clinical Cancer Research published the most papers, while Blood and Cancer Research were the most commonly co-cited journals. DM Goldenberg from the USA published the most articles with the highest H-index (34), and the most co-cited author (2137 citations) was PA Baeuerle; both these authors have distinguished achievements in this field. Analysis of co-cited references and keywords showed that the hotspots and research focus on the use of BsAbs for solid tumors have increased rapidly while the application of BsAb immunotherapy in hematologic malignancies has expanded significantly. The hot topics in the field included cytokine release syndrome, the efficacy and safety of BsAbs, resistance mechanisms, and the exploration and optimization of combination therapies.

Cancer immunotherapies based on BsAbs are a hot topic in research. Current studies focus on the construction and optimization of BsAb structure, as well as their combination with other treatment modalities to improve their efficacy and overcome resistance. Furthermore, it is expected that the ongoing investigation of BsAb-based immunotherapy for solid tumors will bear fruit with significant clinical application prospects in the near future.

The emergence of malignant ascites (MA) indicates poor prognoses in patients with ovarian, gastrointestinal, breast, and pancreatic cancer. Interleukin-10 (IL-10) is a pleiotropic cytokine with immunoregulatory effects in tumor microenvironment. The level of IL-10 in MA varied across cancer types and patients, influencing cancer progression and outcomes. Originating from various immune and cancer cells, IL-10 contributes to complex signaling pathways in MA. Systemic IL-10 administration, although the evidence of its efficacy on MA is limited, still emerges as a promising therapeutic strategy because it can increase CD8+ T cells cytotoxicity and invigorate exhausted CD8+ tumor infiltration lymphocytes (TILs) directly. IL-10 signaling blockade also demonstrates great potential when combined with other immunotherapies in MA treatment. We reviewed the levels, origins, and functions of IL-10 in malignant ascites and overviewed the current IL-10 signaling targeting therapies, aiming to provide insights for MA treatment.

Multispecific antibodies recognize two or more epitopes located on the same or distinct targets. This added capability through protein design allows these man-made molecules to address unmet medical needs that are no longer possible with single targeting such as with monoclonal antibodies or cytokines alone. However, the approach to the development of these multispecific molecules has been met with numerous road bumps, which suggests that a new workflow for multispecific molecules is required. The investigation of the molecular basis that mediates the successful assembly of the building blocks into non-native quaternary structures will lead to the writing of a playbook for multispecifics. This is a must do if we are to design workflows that we can control and in turn predict success. Here, we reflect on the current state-of-the-art of therapeutic biologics and look at the building blocks, in terms of proteins, and tools that can be used to build the foundations of such a next-generation workflow.

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by dysregulated immune responses. The key mediators of AD pathogenesis are T helper 2 (TH2) cells and TH2 cytokines. Targeting interleukin 4 (IL4), IL13 or IL31 has become a pivotal focus in both research and clinical treatments for AD. However, the need remains pressing for the development of a more effective and safer therapy, as the current approaches often yield low response rates and adverse effects. In response to this challenge, we have engineered a immunoglobulin G-single-chain fragment variable (scFv) format bispecific antibody (Ab) designed to concurrently target IL4R and IL31R. Our innovative design involved sequence optimization of VL-VH and the introduction of disulfide bond (VH44-VL100) within the IL31Rα Ab scFv region to stabilize the scFv structure. Our bispecific Ab efficiently inhibited the IL4/IL13/IL31 signaling pathways in vitro and reduced serum immunoglobulin E and IL31 levels in vivo. Consequently, this intervention led to improved inflammation profiles and notable amelioration of AD symptoms. This research highlighted a novel approach to AD therapy by employing bispecific Ab targeting IL4Rα and IL31Rα with potent efficacy.

The epithelial cell adhesion molecule (EpCAM) is a critical glycoprotein involved in cell cycle progression, proliferation, differentiation, migration, and immune evasion. Its role as a target for bispecific antibodies has shown promise in annihilating cancer cells. EpCAM's potential as a biomarker for tumor-initiating cells, characterized by self-renewal and tumorigenic capabilities, underscores its value in early cancer detection, immunotherapy, and targeted drug delivery. While EpCAM monotherapies have been met with limited success, bispecific antibodies targeting both EpCAM and other proteins have exhibited encouraging results in colorectal cancer (CRC) research. The integration of EpCAM-directed nanotechnology in drug delivery systems has emerged as a pivotal innovation in CRC treatment. Moreover, developing chimeric antigen receptor (CAR) T-cell and CAR natural killer (NK) cell therapies opens promising therapeutic avenues for EpCAM-positive CRC patients. Although preliminary, this review sets the stage for future advances. Additionally, this study advances our understanding of the role of non-coding RNAs in CRC, which may be pivotal in gene regulation and could provide insights into the molecular underpinning. The findings suggest that lncRNA, miRNA, and circRNA could serve as novel therapeutic targets or biomarkers, further enriching the landscape of CRC diagnostics and therapeutics.

In this paper, we discuss a response adaptive randomization method, and why it should be used in clinical trials for rare diseases compared to a randomized controlled trial with equal fixed randomization. The developed method uses a patient's biomarkers to alter the allocation probability to each treatment, in order to emphasize the benefit to the trial population. The method starts with an initial burn-in period of a small number of patients, who with equal probability, are allocated to each treatment. We then use a regression method to predict the best outcome of the next patient, using their biomarkers and the information from the previous patients. This estimated best treatment is assigned to the next patient with high probability. A completed clinical trial for the effect of catumaxomab on the survival of cancer patients is used as an example to demonstrate the use of the method and the differences to a controlled trial with equal allocation. Different regression procedures are investigated and compared to a randomized controlled trial, using efficacy and ethical measures.

The efficacy of CAR-T cells for solid tumors is unsatisfactory. EpCAM is a biomarker of epithelial tumors, but the clinical feasibility of CAR-T therapy targeting EpCAM is lacking. Here, we report pre- and clinical investigations of EpCAM-CAR-T cells for solid tumors. We demonstrated that EpCAM-CAR-T cells costimulated by Dectin-1 exhibited robust antitumor activity without adverse effects in xenograft mouse models and EpCAM-humanized mice. Notably, in clinical trials for epithelial tumors (NCT02915445), 6 (50%) of the 12 enrolled patients experienced self-remitted grade 1/2 toxicities, 1 patient (8.3%) experienced reversible grade 3 leukopenia, and no higher-grade toxicity reported. Efficacy analysis determined two patients as partial response. Three patients showed >23 months of progression-free survival, among whom one patient experienced 2-year progress-free survival with detectable CAR-T cells 200 days after infusion. These data demonstrate the feasibility and tolerability of EpCAM-CAR-T therapy.

Ascites formation is a common complication of cancer with a significant symptomatic burden for patients. Malignant ascites (MA) is defined by the presence of tumor cells within the ascitic fluid. It does not only cause substantial morbidity, but is also associated with impaired survival. Considering the frequent occurrence of MA, it still represents a clinical challenge for physicians with limited therapy options, mainly comprising of the treatment of the primary tumor and effusion drainage. Particularly the lack of pathophysiological insight limits the development of effective, causative therapies. Causes of MA development such as lymphatic vessel obstruction and the effects of tumor secreted vascular endothelial growth factor (VEGF) have been known for decades. Novel research suggests that the intraperitoneal immune system may also induce and maintain MA accumulation. In this review, we assess current knowledge on the pathophysiology of MA and summarize available evidence of treatment approaches. Also, factors contributing to ascites formation without proof of tumor cells in the peritoneal cavity, defined as paramalignant ascites, with potential treatment strategies are discussed. We further focus on novel findings in the pathophysiology of MA that might lead to treatment improvement in the near future and discussed relevant knowledge gaps in this field.

Peritoneal carcinomatosis originating from gastric/gastroesophageal junction cancer (GC-PC) occurs in a defined subset of gastric cancer patients with unique clinical, pathologic, molecular and immunologic characteristics that create significant obstacles to effective treatment with modern therapy. Although systemic chemo- and immuno- therapy have yielded disappointing results in GC-PC, recent advances in the characterization of GC-PC and peritoneal immune biology present new opportunities for targeted therapeutics. In this review article, we discuss the distinct properties of GC-PC and the peritoneal immune environment as they pertain to current and investigative treatment strategies. We discuss pre-clinical studies and clinical trials relevant to the modulation of the peritoneal environment as a therapeutic intervention in GC-PC. Finally, we present a road map for future combinatorial strategies based on the conception of the peritoneal cavity as a bioreactor. Within this isolated compartment, prevailing immunosuppressive conditions can be altered through regional interventions toward an adaptive phenotype that would support the effectiveness of regionally delivered cellular therapy products. It is hoped that novel combination strategies would promote efficacy not only in the sequestered peritoneal environment, but also via migration into the circulation of tumor-reactive lymphocytes to produce durable systemic disease control, thereby improving oncologic outcome and quality of life in patients with GC-PC.

In recent years, the development of bispecific antibodies (bsAbs) has been rapid, with many new structures and target combinations being created. The boom in bsAbs has led to the successive issuance of industry guidance for their development in the US and China. However, there is a high degree of similarity in target selection, which could affect the development of diversity in bsAbs. This review presents a classification of various bsAbs for cancer therapy based on structure and target selection and examines the advantages of bsAbs over monoclonal antibodies (mAbs). Through database research, we have identified the preferences of available bsAbs combinations, suggesting rational target selection options and warning of potential wastage of medical resources. We have also compared the US and Chinese guidelines for bsAbs in order to provide a reference for their development.

The cure rate for metastatic or relapsed osteosarcoma has not substantially improved over the past decades despite the exploitation of multimodal treatment approaches, allowing long-term survival in less than 30% of cases. Patients with osteosarcoma often develop resistance to chemotherapeutic agents, where personalized targeted therapies should offer new hope. T cell immunotherapy as a complementary or alternative treatment modality is advancing rapidly in general, but its potential against osteosarcoma remains largely unexplored. Strategies incorporating immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) modified T cells, and T cell engaging bispecific antibodies (BsAbs) are being explored to tackle relapsed or refractory osteosarcoma. However, osteosarcoma is an inherently heterogeneous tumor, both at the intra- and inter-tumor level, with no identical driver mutations. It has a pro-tumoral microenvironment, where bone cells, stromal cells, neovasculature, suppressive immune cells, and a mineralized extracellular matrix (ECM) combine to derail T cell infiltration and its anti-tumor function. To realize the potential of T cell immunotherapy in osteosarcoma, an integrated approach targeting this complex ecosystem needs smart planning and execution. Herein, we review the current status of T cell immunotherapies for osteosarcoma, summarize the challenges encountered, and explore combination strategies to overcome these hurdles, with the ultimate goal of curing osteosarcoma with less acute and long-term side effects.

T-cell-engaging bispecific antibodies (BsAbs) simultaneously bind to antigens on tumour cells and CD3 subunits on T cells. This simultaneous binding results in the recruitment of T cells to the tumour, followed by T-cell activation and degranulation, and tumour cell elimination. T-cell-engaging BsAbs have shown substantial activity in several haematological malignancies by targeting CD19 in acute lymphoblastic leukaemia, CD20 in B-cell non-Hodgkin lymphoma, and BCMA and GPRC5D in multiple myeloma. Progress with solid tumours has been slower, in part due to the paucity of therapeutic targets with a tumour-specific expression profile, which is needed to limit on-target off-tumour side-effects. Nevertheless, BsAb-mediated recognition of a peptide fragment of gp100 presented by HLA-A2:01 molecules has shown marked activity in patients with unresectable or metastatic uveal melanoma. Cytokine release syndrome is the most frequent toxicity associated with BsAb treatment and is caused by activated T cells secreting proinflammatory cytokines. Understanding of resistance mechanisms has resulted in the development of new T cell-redirecting formats and novel combination strategies, which are expected to further improve depth and duration of response.

Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.

Despite remarkable recent progress in developing anti-cancer agents, outcomes of patients with solid tumors remain unsatisfactory. In general, anti-cancer drugs are systemically administered through peripheral veins and delivered throughout the body. The major problem with systemic chemotherapy is insufficient uptake of intravenous (IV) drugs by targeted tumor tissue. Although dose escalation and treatment intensification have been attempted in order to increase regional concentrations of anti-tumor drugs, these approaches have produced only marginal benefits in terms of patient outcomes, while often damaging healthy organs. To overcome this problem, local administration of anti-cancer agents can yield markedly higher drug concentrations in tumor tissue with less systemic toxicity. This strategy is most commonly used for liver and brain tumors, as well as pleural or peritoneal malignancies. Although the concept is theoretically reasonable, survival benefits are still limited. This review summarizes clinical results and problems and discusses future directions of regional cancer therapy with local administration of chemotherapeutants.

Peritoneal carcinosis is a condition characterized by the spread of cancer cells to the peritoneum, which is the thin membrane that lines the abdominal cavity. It is a serious condition that can result from many different types of cancer, including ovarian, colon, stomach, pancreatic, and appendix cancer. The diagnosis and quantification of lesions in peritoneal carcinosis are critical in the management of patients with the condition, and imaging plays a central role in this process. Radiologists play a vital role in the multidisciplinary management of patients with peritoneal carcinosis. They need to have a thorough understanding of the pathophysiology of the condition, the underlying neoplasms, and the typical imaging findings. In addition, they need to be aware of the differential diagnoses and the advantages and disadvantages of the various imaging methods available. Imaging plays a central role in the diagnosis and quantification of lesions, and radiologists play a critical role in this process. Ultrasound, computed tomography, magnetic resonance, and PET/CT scans are used to diagnose peritoneal carcinosis. Each imaging procedure has advantages and disadvantages, and particular imaging techniques are recommended based on patient conditions. Our aim is to provide knowledge to radiologists regarding appropriate techniques, imaging findings, differential diagnoses, and treatment options. With the advent of AI in oncology, the future of precision medicine appears promising, and the interconnection between structured reporting and AI is likely to improve diagnostic accuracy and treatment outcomes for patients with peritoneal carcinosis.

Monoclonal antibody treatment initially heralded an era of molecularly targeted therapy in oncology and is now widely applied in modulating anti-cancer immunity by targeting programmed cell receptors (PD-1, PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and, more recently, lymphocyte-activation gene 3 (LAG3). Chimeric antigen receptor T-cell therapy (CAR-T) recently proved to be a valid approach to inducing anti-cancer immunity by directly modifying the host's immune cells. However, such cell-based therapy requires extensive resources such as leukapheresis, ex vivo modification and expansion of cytotoxic T-cells and current Good Manufacturing Practice (cGMP) laboratories and presents significant logistical challenges. Bi-/trispecific antibody technology is a novel pharmaceutical approach to facilitate the engagement of effector immune cells to potentially multiple cancer epitopes, e.g., the recently approved blinatumomab. This opens the opportunity to develop 'off-the-shelf' anti-cancer agents that achieve similar and/or complementary anti-cancer effects as those of modified immune cell therapy. The majority of bi-/trispecific antibodies target the tumor-associated antigens (TAA) located on the extracellular surface of cancer cells. The extracellular antigens represent just a small percentage of known TAAs and are often associated with higher toxicities because some of them are expressed on normal cells (off-target toxicity). In contrast, the targeting of intracellular TAAs such as mutant RAS and TP53 may lead to fewer off-target toxicities while still achieving the desired antitumor efficacy (on-target toxicity). Here, we provide a comprehensive review on the emerging field of bi-/tri-specific T-cell engagers and potential therapeutic opportunities.

Increasing proteomic studies focused on epithelial ovarian cancer (EOC) have attempted to identify early disease biomarkers, establish molecular stratification, and discover novel druggable targets. Here we review these recent studies from a clinical perspective. Multiple blood proteins have been used clinically as diagnostic markers. The ROMA test integrates CA125 and HE4, while the OVA1 and OVA2 tests analyze multiple proteins identified by proteomics. Targeted proteomics has been widely used to identify and validate potential diagnostic biomarkers in EOCs, but none has yet been approved for clinical adoption. Discovery proteomic characterization of bulk EOC tissue specimens has uncovered a large number of dysregulated proteins, proposed new stratification schemes, and revealed novel targets of therapeutic potential. A major hurdle facing clinical translation of these stratification schemes based on bulk proteomic profiling is intra-tumor heterogeneity, namely that single tumor specimens may harbor molecular features of multiple subtypes. We reviewed over 2500 interventional clinical trials of ovarian cancers since 1990, and cataloged 22 types of interventions adopted in these trials. Among 1418 clinical trials which have been completed or are not recruiting new patients, about 50% investigated chemotherapies. Thirty-seven clinical trials are at phase 3 or 4, of which 12 focus on PARP, 10 on VEGFR, 9 on conventional anti-cancer agents, and the remaining on sex hormones, MEK1/2, PD-L1, ERBB, and FRα. Although none of the foregoing therapeutic targets were discovered by proteomics, newer targets discovered by proteomics, including HSP90 and cancer/testis antigens, are being tested also in clinical trials. To accelerate the translation of proteomic findings to clinical practice, future studies need to be designed and executed to the stringent standards of practice-changing clinical trials. We anticipate that the rapidly evolving technology of spatial and single-cell proteomics will deconvolute the intra-tumor heterogeneity of EOCs, further facilitating their precise stratification and superior treatment outcomes.

This study aimed to explore the value of M701, targeting epithelial cell adhesion molecule (EpCAM) and CD3, in the immunotherapy of ovarian cancer ascites by the in vitro assay.

The expression of EpCAM in ovarian cancer tissues was analyzed by databases. The EpCAM expression and immune cell infiltration in different foci of ovarian cancer were detected by 8-channel flow cytometry. The toxic effect of M701 on OVCAR3 was tested using the in vitro cytotoxicity assay. The 3D cell culture and drug intervention experiments were performed to evaluate the therapeutic effect of M701 in ovarian cancer specimens. Flow cytometry was used to examine the effect of M701 on the binding of immune cells to tumor cells and the activation capacity of T cells.

The results of the bioinformatic analysis showed that the expression of EpCAM in ovarian cancer tissue was significantly higher than that in normal ovarian tissue. The 8-channel flow cytometry of clinical samples showed that the EpCAM expression and lymphocyte infiltration were significantly heterogeneous among ovarian cancer patients and lesions at different sites. The in vitro experiment results showed that M701 had a significant killing effect on OVCAR3 cells. M701 also obviously killed primary tumor cells derived from some patients with ovarian cancer ascites. M701 could mediate the binding of CD3⁺ T cells to EpCAM⁺ tumor cells and induce T cell activation in a dose-dependent manner.

M701 showed significant inhibitory activity on tumor cells derived from ovarian cancer ascites, which had a promising application in immunotherapy for patients with ovarian cancer ascites.

Peritoneal metastasis, also known as peritoneal carcinomatosis (PC), is a refractory cancer that is typically resistant to conventional therapies. The typical treatment for PC is a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Recently, research in this area has seen significant advances, particularly in immunotherapy as an alternative therapy for PC, which is very encouraging. Catumaxomab is a trifunctional antibody intraperitoneal (IP) immunotherapy authorized in Europe that can be used to diminish malignant ascites by targeting EpCAM. Intraperitoneal (IP) immunotherapy breaks immunological tolerance to treat peritoneal illness. Increasing T-cell responses and vaccination against tumor-associated antigens are two methods of treatment. CAR-T cells, vaccine-based therapeutics, dendritic cells (DCs) in combination with pro-inflammatory cytokines and NKs, adoptive cell transfer, and immune checkpoint inhibitors are promising treatments for PC. Carcinoembryonic antigen-expressing tumors are suppressed by IP administration of CAR-T cells. This reaction was strengthened by anti-PD-L1 or anti-Gr1. When paired with CD137 co-stimulatory signaling, CAR-T cells for folate receptor cancers made it easier for T-cell tumors to find their way to and stay alive in the body.