Idiotypic cascades in cancer patients treated with monoclonal antibody CO17-1A.

Abstract

We have previously shown that gastrointestinal cancer patients treated with monoclonal antibody C017-1A (Abl) developed anti-idiotypic antibodies (Ab2) to the Abl. We now demonstrate that patients produce anti-anti-idiotypic antibodies (Ab3) to their autologous Ab2. Ab3 were demonstrated in culture supernatants of peripheral blood mononuclear cells from five Abl-treated patients after stimulation of the cells with heterologous Ab2 that functionally mimicked the tumor antigen (Ag) defined by Abl and immunologically cross reacted with the patients' Ab2. Ab3 shared idiotopes with AbM and were Abl-like in their binding specificities to tumor cells, Ag, and Ab2. Such antibodies were also elicited by stimulating cells with Ag. However, they were not produced by stimulating posttreatment mononuclear cells with control proteins or by stimulating pretreatment cells with either Ag or Ab2. Our results demonstrate idiotypic cascades in cancer patients treated with monoclonal antibody. Ag-specific Ab3 responses may underlie delayed clinical responses often observed in cancer patients treated with monoclonal antibodies of various specificities.We have previously demonstrated that gastrointestinal cancer patients treated with anti-colorectal carcinoma (CRC) monoclonal antibody (mAb) C017-1A, referred to hereafter as Abl, raised anti-idiotypic antibodies (Ab2) to the administered Abl. The Ab2 functionally mimicked in vitro the tumor antigen (Ag) defined by AbM (1-3). We had originally postulated that Ab2 induced in the patients anti-anti-idiotypic antibodies (Ab3) with Abl-like binding specificities for tumor cells (1). We had further postulated that Ab3 responses may underlie delayed clinical responses observed in some of the Abl-treated patients (1, 4). In the initial studies, Ab3 could not be demonstrated in patients' sera, presumably because they were bound to circulating Ab2 or to the patients' tumor cells. Therefore, in the present study, peripheral blood mononuclear cells (PBMCs) of Abl-treated patients were stimulated in culture with the Ag defined by AbM or with heterologous Ab2 that functionally mimics the Ag (5) and immunologically cross reacts with the patients' Ab2. The secreted human antibodies were characterized. Our results demonstrate idiotypic cascades in cancer patients treated with Abl. MATERIALS AND METHODSPatients. The clinical history and treatment plan of the five patients included in the present study have been described in detail (6). Briefly, five patients with advanced adenocarcinoma of the pancreas were treated with a single infusion of 400 mg of AbM mixed with autologous leukocytes. Two untreated patients (patients 7 and 8) with metastatic CRC also were included.Tumor Cells. Human CRC cells SW 1116 (7) and melanoma cells were used as target cells in mixed hemadsorption assay.Antibodies. Anti-CRC mAb C017-1A (IgG2a), referred to as Abl, has been described (7). As controls, anti-CRC mAb C029 (IgG1), anti-breast carcinoma mAb BR-140 (IgG2a), and anti-lung carcinoma mAb LU-16B13 (IgG2a) were u...

Molecular cloning of cDNA for the carcinoma-associated antigen GA733-2.

“…2), led to an evaluation of their immunotherapeutic potential in cancer patients. Idiotypic cascades have been demonstrated in cancer patients treated with mAb C017-1A, providing support to the hypothesis that antigen-specific anti-anti-idiotypic antibody (Ab3) responses may explain some of the observed delayed clinical responses (3).…”

Molecular Characterization of the Anti-Idiotypic Immune Response of a Relapse-Free Neuroblastoma Patient following Antibody Therapy: A Possible Vaccine against Tumors of Neuroectodermal Origin?

“…Interestingly, in contrast to some of the above studies (22,23,(41)(42)(43)(44)(45), Cheung et al (46) found that high HAMA levels prevented Ab3 formation in neuroblastoma patients treated with anti-GD2 mAbs. Compiling results from previous studies they found the following: 1) patients with more intensive chemotherapy pretreatment before immunotherapy had lower and usually only transient HAMA/Ab2-levels than others (20); 2) Ab3 production, starting ϳ6 -14 mo after mAb-therapy and persisting over years, was positively correlated with improved outcome, i.e., prolonged event-free survival, and was more pronounced in patients with lower and only transient HAMA/Ab2-levels (46); and 3) high HAMA concentrations were counterproductive for survival, as they limited efficacy of further treatment cycles.…”

“…Numerous clinical trials using Ab2␤ as an antitumor vaccine were performed or are currently underway, investigating Ab3 development and clinical remissions (35)(36)(37)(38)(39)(40)(41). Interestingly, in contrast to some of the above studies (22,23,(41)(42)(43)(44)(45), Cheung et al (46) found that high HAMA levels prevented Ab3 formation in neuroblastoma patients treated with anti-GD2 mAbs.…”

Idiotypic Cascades after Injection of the Monoclonal Antibody OC125: A Study in a Mouse Model. Induction of Antibodies against OC125 and CA 125 after Immunization with an Anti-CA 125 (MAb OC125) Monoclonal Antibody by Activation of the Idiotypic Network

“…The induction of anti-idiotype Ab2 is correlated with a delayed clinical response in these patients (6,8,11,22).…”

“…Anti-idiotypic antibodies were found in tumour patients after treatment with monoclonal antibodies of different specificities (8,9,18,20,21). The induction of anti-idiotype Ab2 is correlated with a delayed clinical response in these patients (6,8,11,22).…”