Trifunctional bispecific antibody–induced tumor cell lysis of squamous cell carcinomas of the upper aerodigestive tract

Gronau, Silke; Schmitt, Michael; Thess, Bernard; Reinhardt, Peter; Wiesneth, Markus; Schmitt, Anita; Riechelmann, Herbert

doi:10.1002/hed.20170

Cited by 14 publications

(9 citation statements)

References 18 publications

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“…Animal models and in vitro experiments have suggested that the effect of catumaxomab is based on the simultaneous and direct activation of various components of the cellular immune system in the immediate tumor environment. [12][13][14][15][16][17][18] However, catumaxomab's exact mode of action is still unclear and it is unknown whether catumaxomab given intraperitoneally elicits a specific local or systemic immune response against its target antigen EpCAM.…”

Section: Introductionmentioning

confidence: 99%

The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting

Atanackovic¹,

Reinhard²,

Meyer³

et al. 2013

vaccines

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IntroductionGastric cancer is the fourth most common cancer and the second leading cause of cancer-related death worldwide with 5-year survival rates of less than 20%.1 When diagnosed at an early stage, surgery can be performed with a curative intent, however, 20-50% of patients will eventually relapse. [2][3][4][5][6][7] It has long been proposed that adjuvant chemotherapy might improve the perspective of patients with operable gastric cancer and a number of phase III trials have been conducted, however, definitive evidence of the efficacy of adjuvant chemotherapy is still missing. 8Randomized trials have demonstrated that in patients with operable gastric or lower esophageal adenocarcinomas, the application of perioperative chemotherapy leads to a decrease in tumor size and stage and improves survival. However, chemotherapy causes significant toxicity and, accordingly, in the pivotal MAGIC study only ~40% of patients were capable of completing postoperative chemotherapy consisting of epirubicin/cisplatin/fluorouracil. Therefore, the integration of adjuvant/perioperative approaches which are effective, more specific and less toxic seems desirable for improving the multimodal therapy of gastric cancer.It has repeatedly been shown that an infiltration of the tumor tissue by lymphocytes, 9 in particular by memory T cells, 10,11 has a beneficial effect on the survival of patients with esophageal adenocarcinoma or gastric cancer after potentially curative surgery. Unfortunately, immunotherapeutic approaches actively Keywords: catumaxomab, gastric cancer, tumor immunology, adjuvant immunotherapy, T cells, EpCAMBackground: Patients with gastric cancer benefit from perioperative chemotherapy, however, treatment is toxic and many patients will relapse. The trifunctional antibody catumaxomab targets epcaM on tumor cells, cD3 on T cells, and the Fcγ-receptor of antigen-presenting cells. While in europe catumaxomab is approved for treating malignant ascites, it has not been investigated in the perioperative setting and its exact immunological mode of action is unclear.Methods: In our study, gastric cancer patients received neoadjuvant platinum-based chemotherapy, one intraoperative application of catumaxomab, and 4 postoperative doses of intraperitoneal catumaxomab. Immunomonitoring was performed in 6 patients before surgery, after completion of catumaxomab treatment, and one month later.Results: Intraperitoneal application of catumaxomab caused an increased expression of activation markers on the patients' T cells. This was accompanied by a transient decrease in numbers of cXcR3 + effector T cells with a T-helper (Th)-1 phenotype in the peripheral blood. all patients evidenced pre-existing epcaM-specific cD4 + and/or cD8 + T cells. While these cells transiently disappeared from the blood stream after intraperitoneal application of catumaxomab, we detected increased numbers of peripheral epcaM-specific cells and a modified epcaM-specific T-cell repertoire 4 weeks after completion of treatment. Finally, catumaxomab also am...

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Section: Introductionmentioning

confidence: 99%

The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting

Atanackovic¹,

Reinhard²,

Meyer³

et al. 2013

vaccines

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“…Recently cancer immunotherapies have definitively opened new avenues for the treatment of patients with different malignant diseases (2)(3)(4). In contrast to chemo-radiotherapy, T cell based cancer immunotherapies interfere specifically with malignant cells targeting tumor-associated antigens (TAAs) like cancer/germ-line antigens, i.e., the receptor for hyaluronic acid mediated motility (RHAMM) (5,6), and the in tumor ectopically expressed antigens, i.e., carboanhydrase IX (G250/CAIX) (7).…”

Section: Introductionmentioning

confidence: 99%

The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses

Schmitt

Barth²,

Beyer³

et al. 2009

Int J Oncol

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Abstract. Despite advances in surgery, radio-and chemotherapy, therapeutic approaches for patients with head and neck squamous carcinoma (HNSCC) need to be improved. Immunotherapies eliciting tumor specific immune responses might constitute novel treatment options. We therefore investigated the expression and immunogenicity of two tumor-associated antigens (TAA) the receptor for hyaluronic acid mediated motility (RHAMM) and carboanhydrase IX (G250/CAIX) in HNSCC patients. Twenty-two HNSCC samples were examined for the expression of RHAMM and G250 by Western blotting and immunohistochemistry, 14/22 samples were tested for HLA-A2 expression by flow cytometry. For 8/22 samples single tumor-cell suspensions were generated, and mixed lymphocyte peptide cultures (MLPC) were performed to evaluate the frequencies of cytotoxic T cells specifically recognizing RHAMM and G250 using Tetramer staining/multi-color flow cytometry and enzyme linked immunosorbent spot (ELISPOT) assays. RHAMM and G250 were expressed in 73 and 80% of the HNSCC samples at the protein level. A co-expression of both TAAs could be detected in 60% of the patients. In 4/8 HLA-A2 + patients, 0.06-0.13% of CD8 + effector T cells recognized Tetramers for RHAMM or G250 and secreted IFNÁ and granzyme B in ELISPOT assays. RHAMM and G250 are expressed at high frequency and high protein level in HNSCCs and are recognized by cytotoxic CD8 + effector T cells. Therefore both TAAs constitute interesting targets for T cell based immunotherapies for HNSCC.

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“…Further supportive results for the combination of chemotherapeutics and trifunctional antibodies have been obtained in other preclinical models. In two ex vivo studies using the chicken embryo chorioallantoic membrane assay, the combination of catumaxomab and cisplatin enhanced the antitumour activity of immune effector cells from squamous cell carcinoma patients against autologous tumour cells [38,39]. Notably, the effect of each individual drug alone was lower.…”

Section: Discussionmentioning

confidence: 99%

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

et al. 2011

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Background Trifunctional antibodies, such as catumaxomab (anti-EpCAManti-CD3) and ertumaxomab (anti-HER-2/neuanti-CD3), transiently link immune effector cells to tumour cells, which results in cellular cytotoxicity towards the tumour cells. A functional immune system is therefore essential for effective anti-tumour activity. However, the commonly observed haematotoxicity of chemotherapeutics and radiation therapy may be associated with some degree of immunosuppression. Combining chemotherapy and trifunctional antibodies in cancer treatment requires understanding of the impact of chemotherapeutics on immune cell function and, thus, on the activity of trifunctional antibodies. Methods The effect of chemotherapeutic treatment on trifunctional antibody-mediated anti-tumour activity was assessed in vitro. Blood samples were collected from 12 head and neck squamous cell carcinoma patients after chemotherapy (5-fl uorouracil, cisplatin) and radiotherapy, and from one healthy control donor. The immune cell status was analysed and mononuclear cells (MNC) were isolated. The potency of catumaxomab and ertumaxomab was assessed in a cytotoxicity assay using MNC isolated from each patient sample in co-culture with a tumour target cell line. The release of infl ammatory cytokines was also monitored in the cell culture supernatant. Results Most patients included in this study had decreased immune cell counts during the course of chemotherapy. Nonetheless, an effective and concentration-dependent anti-tumour activity mediated by trifunctional antibodies was demonstrated using these patient immune effector cells. The immune response activity of the patient immune cells was not impaired one week after cisplatin administration or even three days after the last 5-fl uorouracil treatment. Conclusion This study shows for the fi rst time that immune effector cells from cancer patients undergoing standard chemotherapy and radiotherapy can be activated by trifunctional antibodies for effi cient killing of tumour cells.

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Trifunctional bispecific antibody–induced tumor cell lysis of squamous cell carcinomas of the upper aerodigestive tract

Abstract: In an autologous human ex vivo system, the tbAB-induced tumor cell lysis was comparable to that by cisplatin.

Cited by 14 publications

References 18 publications

The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting

The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting

The tumor antigens RHAMM and G250/CAIX are expressed in head and neck squamous cell carcinomas and elicit specific CD8+ T cell responses

Trifunctional antibodies induce efficient antitumour activity with immune cells from head and neck squamous cell carcinoma patients after radio-chemotherapy treatment

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