Anti-idiotypic antibodies (Ab2) as immunizing agents for cancer patients are safe, highly specific, and may break immunological tolerance of the patients to antigen expressed by their own growing tumors. Monoclonal rat Ab2 BR3E4 directed against anti-colorectal carcinoma (CRC) antibody C)17-1A (Ab1) has induced in rabbits and mice antigen-specific humoral and cellular immunity, respectively. In the two independent Phase I trials proposed here, the monoclonal Ab2, either as intact IgG or as F(ab')2 coupled with keyhole limpet hemocyanin, will be precipitated with aluminum hydroxide (alum) and administered to 48 patients total with histologically documented, surgically untreatable CRC which express the C017-1A antigen. The goal of this trial is to evaluate the immunogenicity and toxicity of the two vaccines. Alum-precipitated Ab2 (intact IgG or F(ab')2-KLH) will be administered subcutaneously in 3 different doses (1, 2, or 4 mg) to 8 patients each on days 0, 7, 14, and 35. Patients evaluable for immune responses on day 70 will have completed a minimum adequate trial. Patients' anti-CRC antibody response and skin test reactivity to the C017-1A tumor antigen are the gold standards for induction of humoral and cellular immunity, respectively. the dose that induces the highest response rates for the two parameters will be determined in both trials. Humoral and cellular immune responses of those patients who developed anti-CRC antibodies and/or antigen-specific skin test reactivities will be characterized in detail: antibodies will be evaluated for lytic activities against antigen positive tumor cells, expression of idiotopes shared with the Ab1, and epitope specificities. Peripheral blood mononuclear cells will be tested for their in vitro proliferative responses to stimulation with Ab2, antigen or autologous tumor cells, and cytolytic activities against these cells. Considerations for further clinical application of the Ab2 will require, at lest, a 75% response rate for induction of anti- CRC antibody and/or antigen specific skin test reactivity. In the event that both vaccines achieve this goal, additional parameters of immune responses, such as induction of cytotoxic T lymphocytes, will be compared for the two treatment arms. Toxicity of the vaccines will be assessed using the National Cancer Institute's criteria. Although these are Phase I trials with emphasis on patients' immune responses, patients with measurable disease will be monitored and the responses of their tumors assessed. When indicated, future Phase II/III trials will evaluate beneficial vaccine effects in adjuvant settings.
