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

Abstract

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...

A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors

“…Especially the observation of a humoral anti-EpCAM response confirms the potential of the trifunctional antibody to induce a polyclonal anti-tumor response against tumor-associated antigens which are not targeted by the trifunctional antibody itself. Similar immunological activity with increasing humoral and cellular immunity against different tumor-associated antigens was observed with the EpCAM-specific trifunctional antibody catumaxomab applied to gastric cancer patients in the adjuvant setting [19]. These results serve as a further indicator and proof of concept for the “trifunctionality” of ertumaxomab in vivo (with an involvement of antigen presenting cells), leading to immune recognition and priming of a polyclonal humoral immune response against tumor-associated antigens.…”

EpCAM-Selective Elimination of Carcinoma Cells by a Novel MAP-Based Cytolytic Fusion Protein

“…Previously, it was demonstrated that postoperative intraperitoneal application of the anti-CD3/anti-EpCAM bispecific mAb catumaxomab proved to be beneficial in the treatment of patients with gastric cancer (48). It remains to be studied if perhaps anti-EpCAM(scFv)-MAP also shows enhanced efficacy when topically applied in a similar fashion.…”

Regional immunotherapy for liver and peritoneal metastases

“…EpCAM is expressed on several tumors including colon, ovarian, gastric, esophagus, and pancreas . Catumaxomab functions by binding EpCAM on tumor cells, CD3 on T cells, and a receptor on antigen‐presenting cells . This allows it to function without further activation of the immune system.…”