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Use of Immunotherapy in Gynaecological and Breast Cancer
Published in Shazia Rashid, Ankur Saxena, Sabia Rashid, Latest Advances in Diagnosis and Treatment of Women-Associated Cancers, 2022
Showket Hussain, Sandeep Sisodiya, Vishakha Kasherwal, Sonam Tulsyan, Asiya Khan
Bispecific antibodies have two arms: one binds with tumour-associated antigen and another with the activator receptor on effector cells, which activates the cytolytic activity for killing the tumour cell [32–33]. In 2009, the first bsAb, named catumaxomab (trifunctional antibody), was approved and targets epithelial cell adhesion molecules in tumours. Blinatumomab was the second approved bsAb and got an official license in 2014 [34]. These antibody-based therapeutics have recently got attention in treating TNBC patients who are highly metastatic and have poor prognosis [35].
Immunotherapy of peritoneal carcinomatosis
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Michael A. Ströhlein, Markus M. Heiss
The trifunctional antibody catumaxomab showed clinically meaningful activity after i.p. administration in patients with malignant ascites due to EpCAM expressing epithelial cancers. To date, catumaxomab is the only drug for specific and targeted treatment of malignant ascites in patients with peritoneal carcinomatosis. This observation is outstanding, as it is accompanied by complete destruction of tumor cells by a unique mode of action. Moreover, it is the only approved drug for ascites treatment.
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
59 Heiss MM, Murawa P, Koralewski P, Kutarska E et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int. J. Cancer. 2010;127:2209-2221.
Intraperitoneal chemotherapy for peritoneal metastases: an expert opinion
Published in Expert Opinion on Drug Delivery, 2020
Wim Ceelen, Helena Braet, Gabrielle van Ramshorst, Wouter Willaert, Katrien Remaut
A major drawback of IPDD is the fact that none of the currently used drugs were developed or approved for intraperitoneal instillation. Therefore, clinical practice is limited to off-label use. The most commonly used chemotherapy drugs for IP use are the platinum compounds (cisplatin, carboplatin, oxaliplatin), mitomycin C, and paclitaxel. Intraperitoneal immune therapy has as yet found only a very limited clinical application. The trifunctional antibody Catumaxomab contains binding sites for EpCAM and CD3+T cells, while the Fc domain binds to type I, IIa, and III Fcγ receptors on DCs, NKs, and macrophages. The molecule was approved by the European Medicines Agency for palliation of ascites in EpCAM positive epithelial cancers. Analysis of clinical ascites samples showed that treatment with IP Catumaxomab enhances the expression of the activation molecules CD69 and CD38 in T cells, NK cells, and macrophages, while accumulation of CD8+T cells into the peritoneal cavity was enhanced [63]. Also, IP Catumaxomab was shown to promote recruitment of inflammatory TH1 cells (capable of degranulating and secreting IFN-γ) and to stimulate expression of TRAIL by NK cells, and costimulatory molecules by monocytes [64]. However, due to its high immunogenicity rate and narrow indications, commercial sale of Catumaxomab was discontinued in 2017. A comparable approach was reported by Froysnes et al., who successfully treated colorectal PM patients with IP MOC31PE immunotoxin, consisting of an antibody recognizing EpCAM conjugated to the potent Pseudomonas exotoxin A [65].
Bispecific antibodies for the treatment of breast cancer
Published in Expert Opinion on Biological Therapy, 2022
Patrick M. Dillon, Jogender Tushir-Singh, Lawrence G. Lum
As mentioned above, there are several bispecific agents at various stages of development in breast cancer. The first agent that was aggressively developed in breast cancer was Ertumaxomab, which targeted a unique HER2 epitope (different from trastuzumab) on tumor cells. Ertumaxomab was CD3 co-targeting and acted via Fc fragment resulting in macrophage activation and antibody dependent cellular cytotoxicity (ADCC). It was thus effectively a trifunctional antibody believed to temporarily attract immune effector cells to tumor cells [32,33]. Ertumaxomab was manufactured by a quadroma cell-line fusion of rat (anti-CD3) and mouse hybridoma cell line (anti-HER2). The heavy chain contains murine IgG2a and rat IgG2b subclasses and there is binding selectivity to Fcγ type I/III. The rationale for activity of this BsAb agent is that both T cells and accessory cells might complex together with a HER2+ cancer cell. The T cells would be activated by the CD3 binding and would release cytokines and perforin. At the same time, the T cells would be prevented from anergy by the release of costimulatory cytokines and cell surface receptors on accessory monocytes/macrophages. Finally, phagocytosis of tumor cells by macrophages and dendritic cells should result in uptake, processing and presentation of any additional antigens beyond HER2. Preclinical studies with ertumaxomab showed that it could kill HER2+ cell lines in vitro. In a translational study, ertumaxomab eliminated HER2+ tumor cells from leukapheresis products of patients with breast cancer[34]. Two phase I studies were then performed [33,35].
A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors
Published in OncoImmunology, 2018
Maxim Kebenko, Marie-Elisabeth Goebeler, Martin Wolf, Annette Hasenburg, Ruth Seggewiss-Bernhardt, Barbara Ritter, Beate Rautenberg, Djordje Atanackovic, Andrea Kratzer, James B. Rottman, Matthias Friedrich, Eva Vieser, Stefanie Elm, Ingrid Patzak, Dorothea Wessiepe, Sabine Stienen, Walter Fiedler
The AEs associated with solitomab treatment likely represent a direct targeting effect, since EpCAM is expressed on normal liver bile ducts and GI tract epithelia.5 Similar AEs, including liver toxicities and diarrhea, have been reported in a phase 1 study of the trifunctional antibody catumaxomab, which targets EpCAM, CD3, and Fcγ receptors. However, catumaxomab appears to mediate a target-independent interaction between Fcγ and Kupffer cells in the liver.21 The exact mechanism leading to changes in liver parameters after the start of solitomab infusion or after dose escalation remains unclear. A current hypothesis proposes that solitomab administration may lead to local lysis of EpCAM-positive cells in the liver, accompanied by transient and localized release of proinflammatory cytokines by involved cytotoxic T cells. Locally released cytokines may affect target-negative hepatocytes, resulting in bile acid transport impairment and accumulation of bile acids. The ensuing transient increase in liver enzymes and bilirubin in serum may reflect a reversible and self-limiting damage to hepatocytes and bile duct epithelial cells. Despite continued dosing with solitomab in most patients, increases in liver parameters did not indicate chronic or severe drug-induced liver injury. Step-wise intrapatient dose escalation and concomitant dexamethasone partly mitigated the initial elevation in liver parameters. However, the potential for liver injury must be carefully balanced against anticipated benefit with solitomab, which, in most patients, was limited by the occurrence of sometimes severe diarrhea with longer infusions at higher doses.