Activating anti-idiotypic human anti-mouse antibodies for immunotherapy of ovarian carcinoma

Abstract

Human anti‐mouse antibodies (HAMA) are observed frequently after immunoscintigraphy with monoclonal antibodies (MoAb) directed against CA‐125.1 As the authors have shown previously,2–5 HAMA can cause false‐positive CA‐125 values in routine CA‐125 immunoradiometric assay (IRMA) tumor‐marker assays (in one case, up to 900 days after immunoscintigraphy). In 32 patients, the authors found a HAMA frequency of 34% (11/32: 3/7 after the first administration, 6/13 after the second, and 2/2 after the third). Ten patients developed extremely high CA‐125 levels after undergoing the CIS IRMA assay (up to 80,000 U/ml) in parallel to a significant HAMA increase. The use of different assays, or HAMA removal before in vitro testing, can solve this problem. After a new CA‐125 assay containing antibodies that recognize different epitopes on the CA‐125 antigen (Biomira Tru‐Quant OV) was applied, only mildly increased assay results or normal levels were measured. Most of HAMA‐positive patients demonstrated a predominantly anti‐idiotypic response, determined with two different HAMA assays. Seven patients with anti‐idiotypic HAMA responses after OC‐125 immunoscintigraphy remained free of tumor or had stable disease (2–42 or more months), contrary to their poor prognoses that had been made based on the underlying stages of their tumors. All of these patients are currently doing well (Karnofsky Index > 70%) and show no significant tumor progression. In light of their extremely poor prognoses (5‐year survival rates of 3–5% in recurrent International Federation of Gynecology and Obstetrics III/IV stages), without further chemotherapy, these courses are extremely unusual. Preliminary in vitro experiments lead to the postulatation that anti‐idiotypic HAMA may trigger an antitumor effect either by suppressing the growth of CA‐125‐expressing cancer cells directly, or by activating the patient's immune response via induction of Ab3. Similar results are observed after immunoscintigraphy with a technetium‐99m‐labeled anti‐CA‐125 monoclonal antibody (B43.13), which the authors now also use for immunotherapy of ovarian cancer patients by repeated injections, hoping that induction of anti‐idiotypic HAMA will be beneficial for prolonged survival of patients with ovarian carcinoma. Cancer 1994; 73:1121–5.

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?

“…The potential role of a "vaccination-like" effect in long-term neuroblastoma survivors suggested by Cheung et al and other research teams (4, 10, 19 -21) indicated that patients with an immune response benefited from passive immunotherapy. Similar results were confirmed for the adult patient population (22)(23)(24).…”

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

“…The appearance of such reactions has been correlated with improved disease prognosis after antibody therapies in other settings. [16][17][18] Four years after therapy, analysis of this long-term survivor's circulating antibodies revealed a strong anti-idiotypic HAMA response to MAT and no response against the IgG constant domains. In itself, this marks this patient as unusual in that HAMA responses were observed only in a minority of patients who were treated: ATL patients are immunosuppressed to new antigens, and typically do not make HAMAs.…”

The use of monoclonal antibodies for the treatment of epithelial ovarian cancer (review)

“…One of the first RIS studies with 99m Tc-B43.13 showed an unexpected prolonged survival in 26 ovarian cancer patients receiving RIS compared to a control group (69,80). The improved clinical outcome was suggested to be due to the induction of the idiotypic cascade by this Mab (Ab1) (65). Further investigation of the immune response showed activation of both a humoral and a cellular CA 125 specific responses.…”

“…To date, 15 different antibodies have been used directed against 5 different tumor-associated antigens and one antiangiogenesis antigen (VEGF). Of the 44 clinical trials, 23 trials studied immunotherapy with unconjugated Mab (27,, five trials studied vaccination with Mabs (58-62), while 16 trials studied RIT (63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78). Two of the RIT trials used a combination of cytotoxic chemotherapy and RIT (64,71).…”