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Syed YY. Catumaxomab: First Approval. Drugs 2025:10.1007/s40265-025-02187-9. [PMID: 40304879 DOI: 10.1007/s40265-025-02187-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 05/02/2025]
Abstract
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or no longer feasible, catumaxomab was marketed by Fresenius Biotech GmbH (later Neovii Biotech GmbH) before being withdrawn on 2 June 2017 for commercial reasons.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.
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Affiliation(s)
- Yahiya Y Syed
- Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand.
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2
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Liao JB, Jejurikar NS, Hitchcock-Bernhardt KM, Gwin WR, Reichow JL, Dang Y, Childs JS, Coveler AL, Swensen RE, Goff BA, Disis ML, Salazar LG. Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer. Gynecol Oncol 2024; 191:74-79. [PMID: 39362046 PMCID: PMC11637896 DOI: 10.1016/j.ygyno.2024.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024]
Abstract
BACKGROUND Denileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. PATIENTS AND METHODS A phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 μg/kg, 15 μg/kg, and 25 μg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. RESULTS The maximum tolerated dose was 15 μg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1-2. One patient treated at the 25 μg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-β, sIL2Ra in ascites or peripheral blood. CONCLUSIONS Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov # NCT00357448.
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Affiliation(s)
- John B Liao
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America.
| | - Nikita S Jejurikar
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Katie M Hitchcock-Bernhardt
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - William R Gwin
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Jessica L Reichow
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Yushe Dang
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Jennifer S Childs
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Andrew L Coveler
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Ron E Swensen
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America; Valley Medical Center, 400 South 43(rd) Street, Renton, WA 98055, United States of America
| | - Barbara A Goff
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America
| | - Mary L Disis
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
| | - Lupe G Salazar
- UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America
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Massariol Pimenta T, Carlos de Souza J, da Silva Martins B, Silva Butzene SM, Simões Padilha JM, Ganho Marçal M, Dos Santos Elias G, Rangel LBA. Emerging strategies to overcome ovarian cancer: advances in immunotherapy. Front Pharmacol 2024; 15:1490896. [PMID: 39564107 PMCID: PMC11573523 DOI: 10.3389/fphar.2024.1490896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/21/2024] [Indexed: 11/21/2024] Open
Abstract
Ovarian cancer is the second most common malignant neoplasm of gynecological origin and the leading cause of death from cancer in the female reproductive system worldwide. This scenario is largely due to late diagnoses, often in advanced stages, and the development of chemoresistance by cancer cells. These challenges highlight the need for alternative treatments, with immunotherapy being a promising option. Cancer immunotherapy involves triggering an anti-tumor immune response and developing immunological memory to eliminate malignant cells, prevent recurrence, and inhibit metastasis. Some ongoing research investigate potentially immunological advancements in the field of cancer vaccines, immune checkpoint blockade, CAR-T cell, and other strategies.
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Affiliation(s)
- Tatiana Massariol Pimenta
- Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Josiany Carlos de Souza
- Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Bárbara da Silva Martins
- Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Solenny Maria Silva Butzene
- Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - José Matheus Simões Padilha
- Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Milleny Ganho Marçal
- Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Guilherme Dos Santos Elias
- Biochemistry Program, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Leticia Batista Azevedo Rangel
- Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
- Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
- Biochemistry Program, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
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Zhao Q, Zong H, Zhu P, Su C, Tang W, Chen Z, Jin S. Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs. Exp Hematol Oncol 2024; 13:6. [PMID: 38254219 PMCID: PMC10802076 DOI: 10.1186/s40164-024-00474-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/06/2024] [Indexed: 01/24/2024] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.
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Affiliation(s)
- Qi Zhao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hong Zong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chang Su
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Wenxue Tang
- The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jing‑ba Road, Zhengzhou, 450014, China.
| | - Zhenzhen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Shuiling Jin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Wilczyński JR, Wilczyński M, Paradowska E. "DEPHENCE" system-a novel regimen of therapy that is urgently needed in the high-grade serous ovarian cancer-a focus on anti-cancer stem cell and anti-tumor microenvironment targeted therapies. Front Oncol 2023; 13:1201497. [PMID: 37448521 PMCID: PMC10338102 DOI: 10.3389/fonc.2023.1201497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Ovarian cancer, especially high-grade serous type, is the most lethal gynecological malignancy. The lack of screening programs and the scarcity of symptomatology result in the late diagnosis in about 75% of affected women. Despite very demanding and aggressive surgical treatment, multiple-line chemotherapy regimens and both approved and clinically tested targeted therapies, the overall survival of patients is still unsatisfactory and disappointing. Research studies have recently brought some more understanding of the molecular diversity of the ovarian cancer, its unique intraperitoneal biology, the role of cancer stem cells, and the complexity of tumor microenvironment. There is a growing body of evidence that individualization of the treatment adjusted to the molecular and biochemical signature of the tumor as well as to the medical status of the patient should replace or supplement the foregoing therapy. In this review, we have proposed the principles of the novel regimen of the therapy that we called the "DEPHENCE" system, and we have extensively discussed the results of the studies focused on the ovarian cancer stem cells, other components of cancer metastatic niche, and, finally, clinical trials targeting these two environments. Through this, we have tried to present the evolving landscape of treatment options and put flesh on the experimental approach to attack the high-grade serous ovarian cancer multidirectionally, corresponding to the "DEPHENCE" system postulates.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecological Surgery and Gynecological Oncology, Medical University of Lodz, Lodz, Poland
| | - Miłosz Wilczyński
- Department of Gynecological, Endoscopic and Oncological Surgery, Polish Mother's Health Center-Research Institute, Lodz, Poland
- Department of Surgical and Endoscopic Gynecology, Medical University of Lodz, Lodz, Poland
| | - Edyta Paradowska
- Laboratory of Virology, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, Poland
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An J, Hu X, Liu F. Current understanding of cancer stem cells: Immune evasion and targeted immunotherapy in gastrointestinal malignancies. Front Oncol 2023; 13:1114621. [PMID: 36910604 PMCID: PMC9996315 DOI: 10.3389/fonc.2023.1114621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
As a relatively rare population of cancer cells existing in the tumor microenvironment, cancer stem cells (CSCs) possess properties of immune privilege to evade the attack of immune system, regulated by the microenvironment of CSCs, the so-called CSCs niche. The bidirectional interaction of CSCs with tumor microenvironment (TME) components favors an immunosuppressive shelter for CSCs' survival and maintenance. Gastrointestinal cancer stem cells (GCSCs) are broadly regarded to be intimately involved in tumor initiation, progression, metastasis and recurrence, with elevated tumor resistance to conventional therapies, which pose a major hindrance to the clinical efficacy for treated patients with gastrointestinal malignancies. Thus, a multitude of efforts have been made to combat and eradicate GCSCs within the tumor mass. Among diverse methods of targeting CSCs in gastrointestinal malignancies, immunotherapy represents a promising strategy. And the better understanding of GCSCs immunomodulation and immunoresistance mechanisms is beneficial to guide and design novel GCSCs-specific immunotherapies with enhanced immune response and clinical efficacy. In this review, we have gathered available and updated information to present an overview of the immunoevasion features harbored by cancer stem cells, and we focus on the description of immune escape strategies utilized by CSCs and microenvironmental regulations underlying CSCs immuno-suppression in the context of gastrointestinal malignancies. Importantly, this review offers deep insights into recent advances of CSC-targeting immunotherapeutic approaches in gastrointestinal cancers.
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Affiliation(s)
- Junyi An
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohua Hu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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7
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Wei GX, Du Y, Zhou YW, Li LJ, Qiu M. Peritoneal carcinomatosis with intraperitoneal immunotherapy: current treatment options and perspectives. Expert Rev Gastroenterol Hepatol 2022; 16:851-861. [PMID: 36107723 DOI: 10.1080/17474124.2022.2125866] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Peritoneal carcinomatosis (PC) is an advanced malignancy that is not sensitive to systemic conventional chemotherapy. Treatment options for PC are usually palliative rather than curative. Cytoreductive surgery and hyperthermic intraperitoneal (IP) chemotherapy are associated with limited efficacy in patients with PC. However, the peritoneum can produce effective immunity by inducing T-lymphocyte recruitment and proliferation, and the unique immune environment of the peritoneum provides the rationale for IP immunotherapy in PC. AREAS COVERED The authors retrieved relevant documents of IP immunotherapy for PC from PubMed and Medline. This review elaborates on the knowledge of the peritoneal immune microenvironment and IP immunotherapy for PC covering immune stimulators, radioimmunotherapy, catumaxomab, cancer vaccines, chimeric antigen receptor (CAR)-T cells, and immune checkpoint inhibitors. EXPERT OPINION The prognosis of PC is poor. However, the peritoneal cavity is a unique immune compartment with abundant immune cells which can produce effective immunity. IP immunotherapy may be a promising strategy in patients with PC.
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Affiliation(s)
- Gui-Xia Wei
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yang Du
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yu-Wen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Lin-Juan Li
- Thoracic Oncology Ward, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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8
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NK and cells with NK-like activities in cancer immunotherapy-clinical perspectives. Med Oncol 2022; 39:131. [PMID: 35716327 DOI: 10.1007/s12032-022-01735-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/13/2022] [Indexed: 01/10/2023]
Abstract
Natural killer (NK) cells are lymphoid cells of innate immunity that take important roles in immune surveillance. NK cells are considered as a bridge between innate and adaptive immunity, and their infiltration into tumor area is related positively with prolonged patient survival. They are defined as CD16+ CD56+ CD3- cells in clinic. NK cells promote cytolytic effects on target cells and induce their apoptosis. Loss of NK cell cytotoxic activity and reduction in the number of activating receptors are the current issues for application of such cells in cellular immunotherapy, which resulted in the diminished long-term effects. The focus of this review is to discuss about the activity of NK cells and cells with NK-like activity including natural killer T (NKT), cytokine-induced killer (CIK) and lymphokine-activated killer (LAK) cells in immunotherapy of human solid cancers.
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Neural stem cells secreting bispecific T cell engager to induce selective antiglioma activity. Proc Natl Acad Sci U S A 2021; 118:2015800118. [PMID: 33627401 DOI: 10.1073/pnas.2015800118] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor in adults. No treatment provides durable relief for the vast majority of GBM patients. In this study, we've tested a bispecific antibody comprised of single-chain variable fragments (scFvs) against T cell CD3ε and GBM cell interleukin 13 receptor alpha 2 (IL13Rα2). We demonstrate that this bispecific T cell engager (BiTE) (BiTELLON) engages peripheral and tumor-infiltrating lymphocytes harvested from patients' tumors and, in so doing, exerts anti-GBM activity ex vivo. The interaction of BiTELLON with T cells and IL13Rα2-expressing GBM cells stimulates T cell proliferation and the production of proinflammatory cytokines interferon γ (IFNγ) and tumor necrosis factor α (TNFα). We have modified neural stem cells (NSCs) to produce and secrete the BiTELLON (NSCLLON). When injected intracranially in mice with a brain tumor, NSCLLON show tropism for tumor, secrete BiTELLON, and remain viable for over 7 d. When injected directly into the tumor, NSCLLON provide a significant survival benefit to mice bearing various IL13Rα2+ GBMs. Our results support further investigation and development of this therapeutic for clinical translation.
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Takahashi K, Kurashina K, Saito S, Kanamaru R, Ohzawa H, Yamaguchi H, Miyato H, Hosoya Y, Lefor AK, Sata N, Kitayama J. Flow cytometry-based analysis of tumor-leukocyte ratios in peritoneal fluid from patients with advanced gastric cancer. CYTOMETRY PART B-CLINICAL CYTOMETRY 2020; 100:666-675. [PMID: 33277773 PMCID: PMC9290827 DOI: 10.1002/cyto.b.21978] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/29/2020] [Accepted: 11/19/2020] [Indexed: 01/08/2023]
Abstract
Background 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. Methods 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. Results 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%. Conclusion 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.
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Affiliation(s)
- Kazuya Takahashi
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Kentaro Kurashina
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Shin Saito
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Rihito Kanamaru
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyuki Ohzawa
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan
| | - Hironori Yamaguchi
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan
| | - Hideyo Miyato
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yoshinori Hosoya
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Alan Kawarai Lefor
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Joji Kitayama
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
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11
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Sitagliptin Modulates the Response of Ovarian Cancer Cells to Chemotherapeutic Agents. Int J Mol Sci 2020; 21:ijms21238976. [PMID: 33256016 PMCID: PMC7731375 DOI: 10.3390/ijms21238976] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 01/01/2023] Open
Abstract
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.
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12
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Chivu-Economescu M, Necula LG, Matei L, Dragu DL, Neagu AI, Alexiu I, Bleotu C, Diaconu CC. Gastrointestinal cancer stem cells as targets for innovative immunotherapy. World J Gastroenterol 2020; 26:1580-1593. [PMID: 32327907 PMCID: PMC7167409 DOI: 10.3748/wjg.v26.i14.1580] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/22/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells (GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies, recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system. Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio- or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.
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MESH Headings
- 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
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Laura Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Irina Alexiu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen Cristina Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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13
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Ceelen W, Braet H, van Ramshorst G, Willaert W, Remaut K. Intraperitoneal chemotherapy for peritoneal metastases: an expert opinion. Expert Opin Drug Deliv 2020; 17:511-522. [PMID: 32142389 DOI: 10.1080/17425247.2020.1736551] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 02/26/2020] [Indexed: 12/13/2022]
Abstract
Introduction: The rationale for intraperitoneal (IP) drug delivery for patients with peritoneal metastases (PM) is based on the pharmacokinetic advantage resulting from the peritoneal-plasma barrier, and on the potential to adequately treat small, poorly vascularized PM. Despite a history of more than three decades, many aspects of IP drug delivery remain poorly studied.Areas covered: We outline the anatomy and physiology of the peritoneal cavity, including the pharmacokinetics of IP drug delivery. We discuss transport mechanisms governing tissue penetration of IP chemotherapy, and how these are affected by the biomechanical properties of the tumor stroma. We provide an overview of the current clinical evidence on IP chemotherapy in ovarian, colorectal, and gastric cancer. We discuss the current limitations of IP drug delivery and propose several potential areas of progress.Expert opinion: The potential of IP drug delivery is hampered by off-label use of drugs developed for systemic therapy. The efficacy of IP chemotherapy for PM depends on cancer type, disease extent, and mode of drug delivery. Results from ongoing randomized trials will allow to better delineate the potential of IP chemotherapy. Promising approaches include IP aerosol therapy, prolonged delivery platforms such as gels or biomaterials, and the use of nanomedicine.
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Affiliation(s)
- Wim Ceelen
- Department of GI Surgery, Ghent University Hospital, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Belgium
| | - Helena Braet
- Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Ghent University, Ghent, Belgium
| | | | - Wouter Willaert
- Department of GI Surgery, Ghent University Hospital, Ghent, Belgium
| | - Katrien Remaut
- Cancer Research Institute Ghent (CRIG), Belgium
- Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Ghent University, Ghent, Belgium
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14
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Ceelen W, Ramsay RG, Narasimhan V, Heriot AG, De Wever O. Targeting the Tumor Microenvironment in Colorectal Peritoneal Metastases. Trends Cancer 2020; 6:236-246. [PMID: 32101726 DOI: 10.1016/j.trecan.2019.12.008] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 02/01/2023]
Abstract
Peritoneal metastasis (PM) occurs in approximately one in four colorectal cancer (CRC) patients. The pathophysiology of colorectal PM remains poorly characterized. Also, the efficacy of current treatment modalities, including surgery and intraperitoneal (IP) delivery of chemotherapy, is limited. Increasingly, therefore, efforts are being developed to unravel the PM cascade and at understanding the PM-associated tumor microenvironment (TME) and peritoneal ecosystem as potential therapeutic targets. Here, we review recent insights in the structure and components of the TME in colorectal PM, and discuss how these may translate into novel therapeutic approaches aimed at re-engineering the metastasis-promoting activity of the stroma.
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Affiliation(s)
- Wim Ceelen
- Department of Human Structure and Repair, Ghent University, B-9000 Ghent, Belgium; Department of GI Surgery, Ghent University Hospital, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
| | - Robert G Ramsay
- Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Vignesh Narasimhan
- Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; Department of Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Alexander G Heriot
- Department of Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Olivier De Wever
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium; Laboratory for Experimental Cancer Research, Ghent University, Ghent, Belgium
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15
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Abstract
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.
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16
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Chiu ML, Goulet DR, Teplyakov A, Gilliland GL. Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel) 2019; 8:antib8040055. [PMID: 31816964 PMCID: PMC6963682 DOI: 10.3390/antib8040055] [Citation(s) in RCA: 298] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/25/2019] [Accepted: 11/28/2019] [Indexed: 12/11/2022] Open
Abstract
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.
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Affiliation(s)
- Mark L. Chiu
- Drug Product Development Science, Janssen Research & Development, LLC, Malvern, PA 19355, USA
- Correspondence:
| | - Dennis R. Goulet
- Department of Medicinal Chemistry, University of Washington, P.O. Box 357610, Seattle, WA 98195-7610, USA;
| | - Alexey Teplyakov
- Biologics Research, Janssen Research & Development, LLC, Spring House, PA 19477, USA; (A.T.); (G.L.G.)
| | - Gary L. Gilliland
- Biologics Research, Janssen Research & Development, LLC, Spring House, PA 19477, USA; (A.T.); (G.L.G.)
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17
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Cutaneous Metastases in Ovarian Cancer. Cancers (Basel) 2019; 11:cancers11091292. [PMID: 31480743 PMCID: PMC6788186 DOI: 10.3390/cancers11091292] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 08/20/2019] [Accepted: 08/28/2019] [Indexed: 12/12/2022] Open
Abstract
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.
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18
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Nersesian S, Glazebrook H, Toulany J, Grantham SR, Boudreau JE. Naturally Killing the Silent Killer: NK Cell-Based Immunotherapy for Ovarian Cancer. Front Immunol 2019; 10:1782. [PMID: 31456796 PMCID: PMC6699519 DOI: 10.3389/fimmu.2019.01782] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 07/15/2019] [Indexed: 12/31/2022] Open
Abstract
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.
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Affiliation(s)
- Sarah Nersesian
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Department of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Haley Glazebrook
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Jay Toulany
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Department of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Stephanie R Grantham
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Jeanette E Boudreau
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.,Department of Pathology, Dalhousie University, Halifax, NS, Canada
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19
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2017 Update on Ovarian Cancer Peritoneal Carcinomatosis Multimodal-Treatment Considerations. Gastroenterol Res Pract 2018; 2018:5284814. [PMID: 29849590 PMCID: PMC5907426 DOI: 10.1155/2018/5284814] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 11/02/2017] [Indexed: 12/13/2022] Open
Abstract
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.
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20
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Functional activity of natural killer cells in biological fluids in patients with colorectal and ovarian cancers. Cent Eur J Immunol 2018; 43:26-32. [PMID: 29736145 PMCID: PMC5927170 DOI: 10.5114/ceji.2018.74870] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 12/05/2017] [Indexed: 11/25/2022] Open
Abstract
Aim of the study To compare the functional activity of natural killer cells depending on the presence of a malignant process and its dissemination. Material and methods 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. Results 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.
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21
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Sedykh SE, Prinz VV, Buneva VN, Nevinsky GA. Bispecific antibodies: design, therapy, perspectives. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:195-208. [PMID: 29403265 PMCID: PMC5784585 DOI: 10.2147/dddt.s151282] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Antibodies (Abs) containing two different antigen-binding sites in one molecule are called bispecific. Bispecific Abs (BsAbs) were first described in the 1960s, the first monoclonal BsAbs were generated in the 1980s by hybridoma technology, and the first article describing the therapeutic use of BsAbs was published in 1992, but the number of papers devoted to BsAbs has increased significantly in the last 10 years. Particular interest in BsAbs is due to their therapeutic use. In the last decade, two BsAbs - catumaxomab in 2009 and blinatumomab in 2014, were approved for therapeutic use. Papers published in recent years have been devoted to various methods of BsAb generation by genetic engineering and chemical conjugation, and describe preclinical and clinical trials of these drugs in a variety of diseases. This review considers diverse BsAb-production methods, describes features of therapeutic BsAbs approved for medical use, and summarizes the prospects of practical application of promising new BsAbs.
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Affiliation(s)
- Sergey E Sedykh
- Laboratory of Repair Enzymes, Siberian Branch of Russian Academy of Sciences Institute of Chemical Biology and Fundamental Medicine, Novosibirsk State University, Novosibirsk, Russia
| | - Victor V Prinz
- Laboratory of Repair Enzymes, Siberian Branch of Russian Academy of Sciences Institute of Chemical Biology and Fundamental Medicine, Novosibirsk State University, Novosibirsk, Russia
| | - Valentina N Buneva
- Laboratory of Repair Enzymes, Siberian Branch of Russian Academy of Sciences Institute of Chemical Biology and Fundamental Medicine, Novosibirsk State University, Novosibirsk, Russia
| | - Georgy A Nevinsky
- Laboratory of Repair Enzymes, Siberian Branch of Russian Academy of Sciences Institute of Chemical Biology and Fundamental Medicine, Novosibirsk State University, Novosibirsk, Russia
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22
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Cortez AJ, Tudrej P, Kujawa KA, Lisowska KM. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol 2018; 81:17-38. [PMID: 29249039 PMCID: PMC5754410 DOI: 10.1007/s00280-017-3501-8] [Citation(s) in RCA: 398] [Impact Index Per Article: 56.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 12/11/2017] [Indexed: 02/06/2023]
Abstract
Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment.
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Affiliation(s)
- Alexander J Cortez
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland
| | - Patrycja Tudrej
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland
| | - Katarzyna A Kujawa
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland
| | - Katarzyna M Lisowska
- Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch, Wybrzeże Armii Krajowej 15, Gliwice, 44-100, Poland.
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23
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Yu S, Li A, Liu Q, Yuan X, Xu H, Jiao D, Pestell RG, Han X, Wu K. Recent advances of bispecific antibodies in solid tumors. J Hematol Oncol 2017; 10:155. [PMID: 28931402 PMCID: PMC5607507 DOI: 10.1186/s13045-017-0522-z] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 09/01/2017] [Indexed: 01/04/2023] Open
Abstract
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.
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Affiliation(s)
- Shengnan Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Anping Li
- Department of Interventional Radiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qian Liu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Xun Yuan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Hanxiao Xu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Dechao Jiao
- Department of Interventional Radiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Richard G Pestell
- Pennsylvania Center for Cancer and Regenerative Medicine, Wynnewood, PA, 19096, USA
| | - Xinwei Han
- Department of Interventional Radiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
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24
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Kim S, Kim B, Song YS. Ascites modulates cancer cell behavior, contributing to tumor heterogeneity in ovarian cancer. Cancer Sci 2016; 107:1173-1178. [PMID: 27297561 PMCID: PMC5021036 DOI: 10.1111/cas.12987] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
Malignant ascites constitute a unique tumor microenvironment providing a physical structure for the accumulation of cellular and acellular components. Ascites is initiated and maintained by physical and biological factors resulting from underlying disease and forms an ecosystem that contributes to disease progression. It has been demonstrated that the cellular contents and the molecular signatures of ascites change continuously during the course of a disease. Over the past decade, increasing attention has been given to the characterization of components of ascites and their role in the progression of ovarian cancer, the most malignant gynecologic cancer in women. This review will discuss the role of ascites in disease progression, in terms of modulating cancer cell behavior and contributing to tumor heterogeneity.
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Affiliation(s)
- Soochi Kim
- Interdisciplinary Program in Cancer Biology, College of Medicine, Seoul National University, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Boyun Kim
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Nano System Institute, Seoul National University, Seoul, Korea
| | - Yong Sang Song
- Interdisciplinary Program in Cancer Biology, College of Medicine, Seoul National University, Seoul, Korea.
- Cancer Research Institute, Seoul National University, Seoul, Korea.
- Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea.
- Department of Obstetrics and Gynecology, Seoul National University, Seoul, Korea.
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