Title: Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas
Design: In what was the first Phase I study to use a dual-gene vector in a clinical trial, investigators evaluated the toxicity, as well as clinical, serological and immunological responses to the ALVAC-CEA B7.1 vaccine in 39 patients with recurrent adenocarcinomas expressing CEA. The ALVAC-CEA B7.1 vaccine is a canarypox vector engineered to encode for CEA and B7.1, a T-cell co-stimulatory molecule. The majority of patients had metastatic colorectal cancer, the remaining having a variety of other cancers, all of them metastatic as well, and all but one having measurable disease. All patients were HLA-typed to identify those who were HLA-A2-positive, but HLA-A2 negative patients were not excluded from the study. Patients received the vaccine intradermally and subcutaneously every two weeks for four injections. Those who had evidence of either an objective response or in whom disease stabilized at the end of eight weeks were invited to remain on study and receive boost injections every four weeks. Those who progressed were removed from the study.
Results: The most frequent toxicity was local erythema and swelling at the vaccination site, accompanied by myalgias and flu-like symptoms but these reactions diminished with further vaccination. A total of 30 patients had received four vaccinations and were evaluable for clinical response, out of which eight patients, seven of whom had colorectal cancer, had stable disease on re-evaluation. All eight patients received one to seven boost injections and disease continued to remain stable, but there were no partial or complete objective responses. Serum CEA levels increased between baseline and weeks 4 and 8, but in six patients, CEA levels declined while they received vaccine treatments and this decline in CEA levels lasted as long as 12 weeks. Nineteen of 26 patients who were HLA-A2-positive also received four vaccinations, and T-cell assay data on 15 of these patients indicated that 12 out of the 15 had at least a 2-fold increase in T-cell precursors specific to CEA peptide. Indeed, three patients had at least a four-fold increase in post-vaccination precursor frequency, and two others had significantly greater increases than the rest of the group.
Commentary: No objective clinical responses were seen in this Phase I study, and most patients had rises in serum CEA values. Nevertheless, disease stabilized following four vaccinations in 20% of all participants, and in 27% of all evaluable patients, and serum CEA levels declined in six patients. Moreover, disease remained stable in all patients whose serum CEA initially declined after four vaccinations. Thus, the study demonstrated that patients can develop anti-CEA peptide-specific T-cell responses on receiving the ALVAC-CEA B7.1 vaccine. The limited clinical response was likely a reflection of the patient population enrolled in the study, all of whom had metastatic disease and who were largely heavily pre-treated. The authors thus suggest that findings from this study support further testing of vaccine strategies, including the use of the ALVAC-CEA B7.1 vaccine, in the adjuvant setting in patients with minimal disease, among whom an even more robust immune response might be elicited.
Citation:Margaret von Mehren, Philip Arlen, Kwong Y. Tsang, et al. Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas. Clinical Cancer Research. 2000;6:2219-2228
