• Denileukin diftitox
• Intraperitoneal immunotherapy
• Ovarian cancer
• Regulatory T cells

• Humans
• Female
• Ovarian Neoplasms/immunology
• Ovarian Neoplasms/drug therapy
• Diphtheria Toxin/administration & dosage
• Diphtheria Toxin/therapeutic use
• Middle Aged
• Recombinant Fusion Proteins/administration & dosage
• Recombinant Fusion Proteins/therapeutic use
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/drug effects
• Interleukin-2/administration & dosage
• Interleukin-2/therapeutic use
• Aged
• Neoplasm Recurrence, Local/immunology
• Neoplasm Recurrence, Local/drug therapy
• Adult
• Immunotherapy/methods
• Maximum Tolerated Dose
• Cytokines/blood
• Cytokines/immunology

• K23 CA100691 NCI NIH HHS
• M01 RR000037 NCRR NIH HHS

• CAR-T cell therapy
• antibody therapy
• cancer vaccines
• immunotherapy
• ovarian cancer

• Colorectal cancer stem cells
• Immune Cells
• Immunotherapy
• Targeting cancer stem cells
• Tumor immune microenvironment

• 82273478 National Natural Science Foundation of China
• 82000164 National Natural Science Foundation of China

• chemo-resistance
• clinical trial
• experimental therapy
• high-grade serous ovarian cancer
• metastatic niche
• ovarian cancer stem cells
• tumor microenvironment

• anti-tumor therapy
• cancer stem cells
• gastrointestinal malignancies
• immune evasion
• immunotherapy

• Peritoneal carcinomatosis
• immune microenvironment
• immunotherapy
• intraperitoneal treatment
• peritoneal metastasis

• Cytokine-induced killer (CIK)
• Dendritic cell (DC)
• Immunotherapy
• Natural killer (NK)
• Natural killer T (NKT)
• Tumor microenvironment (TME)

• GBM
• bispecific T cell engagers
• delivery
• immunotherapy
• neural stem cells

The frequency of tumor cell dissemination in the peritoneal cavity is critically related to the progression of peritoneal metastases (PM). Recently, flow cytometry (FCM) has been successfully used to detect tumor cells in malignant effusions.

A total of 143 single cell suspensions derived from ascites or peritoneal lavages from patients with advanced gastric cancer (GC) were stained with monoclonal antibodies to CD45 and to CD326 as well as 4,6‐diamidino‐2‐phenylindole (DAPI) and FVS780. Using FCM, tumor‐leukocyte ratio (TLR) were calculated from CD45(−)CD326(+) tumor cell counts/ CD45(+)CD326(+) leukocyte counts in DAPI (+) FVS780(−) gated area. In 54 patients, the ratios of CD11b(+), CD4(+) and CD8(+) cells in CD45(+) leukocytes were evaluated in parallel.

TLR of 69 patients with PM were significantly higher than those of 74 without PM (p < .001) and log(TLR) showed strong correlation with peritoneal cancer index scores in 51 PM (+) patients (r = 0.439). TLR in PM (+) patients also correlated with the ratio of CD11b (+) myeloid cells (r = 0.547), and correlated inversely with those of CD4(+) (r = −0.490) and CD8(+) T cells (r = −0.648). In PM (−) patients who underwent gastrectomy, TLR never exceeded 0.1% in patients with primary GC without serosal involvement (<T4). However, TLR in patients with T4 GC were significantly higher (p < .05) and peritoneal recurrence occurred in 6/8 patients whose TLR exceeded 0.1%.

TLR in peritoneal fluid reflects tumor burden and the immune environment in peritoneal cavity. Multicolor FCM may provide additional information which can be used for the treatment of the patients with PM.

• CD326
• cytology
• flow cytometry
• intraperitoneal tumor cells
• peritoneal metastasis

The strong association between diabetes mellitus type 2 and cancer is observed. The incidence of both diseases is increasing globally due to the interaction between them. Recent studies suggest that there is also an association between cancer incidence and anti-diabetic medications. An inhibitor of dipeptidyl-peptidase 4 (DPP-4), sitagliptin, is used in diabetes treatment. We examined the influence of sitagliptin alone or in combination with a cytostatic drug (paclitaxel) on the development of epithelial ovarian cancer cells and the process of metastasis. We examined migration, invasiveness, apoptosis, and metalloproteinases (MMPs) and their inhibitors’ (TIMPs) production in two human ovarian cancer cell lines. Sitagliptin induced apoptosis by caspase 3/7 activation in paclitaxel-treated SKOV-3 and OVCAR-3 cells. Sitagliptin maintained paclitaxel influence on ERK and Akt signaling pathways. Sitagliptin additionally reduced migration and invasiveness of SKOV-3 cells. There were distinct differences of metalloproteinases production in sitagliptin-stimulated ovarian cancer cells in both cell lines, despite their identical histological classification. Only the SKOV-3 cell line expressed MMPs and TIMPs. SKOV-3 cells co-treated with sitagliptin and paclitaxel decreased concentrations of MMP-1, MMP-2, MMP-7, MMP-10, TIMP-1, TIMP-2. The obtained data showed that sitagliptin used with paclitaxel may be considered as a possibility of pharmacological modulation of intracellular transmission pathways to improve the response to chemotherapy.

• apoptosis
• diabetes
• metalloproteinases
• metastasis
• ovarian cancer
• sitagliptin

• CAR-T
• Cancer stem cells
• Dendritic cells vaccines
• Gastrointestinal cancer
• Immune checkpoints inhibitors
• Immunotherapy

• Antigens, Neoplasm/immunology
• Antigens, Neoplasm/metabolism
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/immunology
• Biomarkers, Tumor/metabolism
• Cancer Vaccines/administration & dosage
• Combined Modality Therapy/methods
• Dendritic Cells/immunology
• Drug Resistance, Neoplasm/immunology
• Gastrointestinal Neoplasms/immunology
• Gastrointestinal Neoplasms/pathology
• Gastrointestinal Neoplasms/therapy
• Humans
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Immunity, Innate/drug effects
• Immunity, Innate/immunology
• Immunotherapy/methods
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/immunology
• Killer Cells, Natural/transplantation
• Neoplasm Recurrence, Local/immunology
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/prevention & control
• Neoplastic Stem Cells/immunology
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Receptors, Chimeric Antigen/immunology
• T-Lymphocytes/drug effects
• T-Lymphocytes/immunology
• T-Lymphocytes/transplantation
• Tumor Escape/drug effects
• Tumor Escape/immunology

• Peritoneal
• chemotherapy
• intraperitoneal
• mesothelial
• metastasis

• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/pharmacokinetics
• Drug Delivery Systems
• Humans
• Injections, Intraperitoneal
• Peritoneal Neoplasms/drug therapy
• Peritoneal Neoplasms/secondary
• Peritoneum/metabolism
• Tissue Distribution

• colorectal cancer
• peritoneal metastasis
• tumor microenvironment

Passive antibody therapies have a long history of use. In the 19th century, antibodies from xenographic sources of polyclonal antibodies were used to treat infections (diphtheria). They were used often as protection from infectious agents and toxins. Complications related to their use involved development of immune complexes and severe allergic reactions. As a result, human source plasma for polyclonal antibodies became the preferential source for antibodies. They are used to treat infection, remove toxins, prevent hemolytic disease of the newborn, modify inflammatory reactions, and control autoimmune diseases. Continued improvements in processing decreased the transfusion/infusion transmission of infections. In the late 20th century (∼1986), monoclonal antibodies were developed. The first monoclonal antibodies were of xenographic source and were wrought with problems of immunogenicity. These forms of antibodies did not gain favor until chimerization took pace in the mid-1990s and in 1998 two monoclonal antibodies were approved one to treat respiratory syncytial virus and the other for breast cancers. Further development of humanized and then fully human monoclonal antibodies has led to an evolution of therapies with these agents. Monoclonal antibodies are being researched or approved to treat a multitude of diseases to include oncologic, inflammatory, autoimmune, cardiovascular, respiratory, neurologic, allergic, benign hematologic, infections, orthopedic, coagulopathy, metabolic and to decrease morbidity of disease (diminution of pain), modify disease progression, and potentially anatomic development. In this chapter, we will review the history of use of these passive antibody therapies, their mechanism of action, pharmacologic-therapeutic classification, particular medical indication, adverse reactions, and potential future use of these medications.

• antibodies
• bispecific t-cell engager
• chimeric
• humanized
• monoclonal
• polyclonal
• trimeric

Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics). Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host of therapeutic indications. In this review, our basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties. The platforms examined include the development of antibodies, antibody fragments, bispecific antibody, and antibody fusion products, whose efficacy and manufacturability can be improved via humanization, affinity modulation, and stability enhancement. We also review the design and selection of binding arms, and avidity modulation. Different strategies of preparing bispecific and multispecific molecules for an array of therapeutic applications are included.

• antibody engineering
• therapeutic biologics

Skin metastases in ovarian cancer are uncommon, but their incidence may be increasing due to improved survival rates. Skin metastases can be divided into umbilical metastases, which are known as Sister Joseph nodules (SJNs) and are associated with peritoneal metastasis, and non-SJN skin metastases, which usually develop within surgical scars and in the vicinity of superficial lymphadenopathy. As most skin metastases develop after specific conditions, recognition of preceding metastatic diseases and prior treatments is necessary for early diagnosis of skin lesions. The prognosis of skin metastases in ovarian cancer varies widely since they are heterogeneous in the site of lesion and the time of appearance. Patients with SJNs at initial diagnosis and patients with surgical scar recurrences without concomitant metastases may have prolonged survival with a combination of surgery and chemotherapy. In patients who developed skin recurrences as a late manifestation, symptoms should be treated with external beam radiotherapy and immune response modifiers. Immune checkpoint blockade can enhance anti-tumor immunity and induce durable clinical responses in multiple tumor types, including advanced chemoresistant ovarian cancer. With the use of radiation therapy, which enhances the systemic anti-tumor immune response, immune checkpoint blockade may be a promising therapeutic strategy for distant metastasis, including skin metastasis.

• immune checkpoint blockade
• ovarian cancer
• radiation therapy
• skin metastasis

Ovarian cancer (OC) is diagnosed in ~22,000 women in the US each year and kills 14,000 of them. Often, patients are not diagnosed until the later stages of disease, when treatment options are limited, highlighting the urgent need for new and improved therapies for precise cancer control. An individual's immune function and interaction with tumor cells can be prognostic of the response to cancer treatment. Current emerging therapies for OC include immunotherapies, which use antibodies or drive T cell-mediated cancer recognition and elimination. In OC, these have been limited by adverse side effects and tumor characteristics including inter- and intra-tumoral heterogeneity, lack of targetable antigens, loss of tumor human leukocyte antigen expression, high levels of immunosuppressive factors, and insufficient immune cell trafficking. Natural killer (NK) cells may be ideal as primary or collateral effectors to these nascent immunotherapies. NK cells exhibit multiple functions that combat immune escape and tumor relapse: they kill targets and elicit inflammation through antigen-independent pathways and detect loss of HLA as a signal for activation. NK cells are efficient mediators of tumor immune surveillance and control, suppressed by the tumor microenvironment and rescued by immune checkpoint blockade. NK cells are regulated by a variety of activating and inhibitory receptors and already known to be central effectors across an array of existing therapies. In this article, we highlight interactions between NK cells and OC and their potential to change the immunosuppressive tumor microenvironment and participate in durable immune control of OC.

• high grade serous ovarian cancer
• immunotherapy
• natural killer cell
• oncoimmunology
• ovarian cancer immunology
• tumor microenvironment

Ovarian cancer peritoneal carcinomatosis requires a multimodal-treatment approach. Current treatment considerations are analyzed in this update and include the management of recurrent malignant ascites and the understanding of its pathophysiology, the role of peritoneal washing cytology in detecting peritoneal metastases, capsular invasion and ovarian cancer histologic type, interpretation of pretreatment Ca-125 levels at different time points of ovarian cancer therapeutic management, characteristics of 10-year survivors of high-grade ovarian cancer, and the role of lymphadenectomy in ovarian cancer peritoneal carcinomatosis. This update also includes current considerations on the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in ovarian cancer peritoneal carcinomatosis as well as relevant ongoing phase III randomized controlled trial protocols.

To compare the functional activity of natural killer cells depending on the presence of a malignant process and its dissemination.

The study included 20 patients with Stage IIIB, C (FIGO, 2009) ovarian cancer, 10 patients with benign ovarian tumours (BOT), and 20 patients with colorectal cancer (T2-4N0-2M0). The control group consisted of 9 healthy donors. To evaluate the number and functional activity of NK cells, multicolour flow cytometry was performed.

In cancer patients, the relative number of activated NK cells secreting granzyme B (GB) (CD56+CD107a+GB+PF–) was significantly decreased, and the proportion of degranulated NK cells (CD56+CD107a+GB–PF–) was significantly increased, compared to those observed in healthy donors. The total number of NK cells in peripheral blood was low in ovarian cancer patients (p < 0.05). The proportion of activated peripheral blood NK cells containing cytolytic granules GB and perforin (PF) in colorectal cancer patients increased with tumour growth. However, lymph node metastasis did not affect the content and activation of NK cells. Comparative analysis of NK-cell populations in patients with benign and malignant ovarian tumours revealed that the level of CD56+ cells was significantly higher in ascites than in peripheral blood. However, CD56+CD107a+ activated cells and CD56+CD107a+GB+PF+ cells were found more frequently in ascites of BOT patients than in ovarian cancer patients. The degranulated population of NK cells (CD56+CD107a+GB–PF–) was mainly observed in the peripheral blood of ovarian cancer patients.

• Colorectal cancer
• ascites
• functional activity
• natural killer cells
• ovarian cancer
• peripheral blood

• bispecific antibodies
• monoclonal antibodies
• therapeutic antibodies

• Biological drugs
• Clinical trials
• Ovarian cancer
• Targeted therapy

• Angiogenesis Inhibitors/therapeutic use
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/therapeutic use
• Clinical Trials as Topic
• Cost-Benefit Analysis
• Cytoreduction Surgical Procedures
• ErbB Receptors/antagonists & inhibitors
• Female
• Folic Acid Antagonists/therapeutic use
• Humans
• Hyperthermia, Induced
• Immunotherapy
• Infusions, Parenteral
• Neoplasm Recurrence, Local/drug therapy
• Neoplasm Recurrence, Local/therapy
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/surgery
• Ovarian Neoplasms/therapy
• Palliative Care
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
• Precision Medicine/economics
• Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors

• Narodowe Centrum Nauki

Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated. According to the structure of Fc domain, BsAb can be classified into two types: IgG-like format and Fc-free format. Among these formats, bispecific T cell engagers (BiTEs) and triomabs are commonly investigated. BsAb has achieved an exciting breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. In this review, we focus on the preclinical experiments and clinical studies of epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor (HER) family, carcinoembryonic antigen (CEA), and prostate-specific membrane antigen (PSMA) related BsAbs in solid tumors, as well as discuss the challenges and corresponding approaches in clinical application.

• BsAb
• CEA
• EpCAM
• HER family
• PSMA
• Radioimmunotherapy
• Solid tumor

• Ascites
• ovarian cancer
• tumor heterogeneity

• Animals
• Ascites/metabolism
• Ascites/pathology
• Biomarkers, Tumor
• Cell Communication
• Disease Progression
• Female
• Humans
• Molecular Targeted Therapy
• Ovarian Neoplasms/diagnosis
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Ovarian Neoplasms/therapy
• Precision Medicine
• Prognosis
• Tumor Microenvironment

• R01 CA116984 NCI NIH HHS