Thomsen-Friedenreich (TF) antigen as a target for prostate cancer vaccine: clinical trial results with TF cluster (c)-KLH plus QS21 conjugate vaccine in patients with biochemically relapsed prostate cancer.
Academic Article
Overview
abstract
The differential overexpression of self-antigens on tumor cells is a prime feature of malignant transformation. Thomsen-Friedenreich (TF), a core disaccharide of O-glycosylated complex glycoproteins, is one of many "self" antigens expressed on malignantly transformed cells that has served as a target for immune recognition and attack. Previously, we conducted clinical trials with a series of synthetic glycolipid, peptide and carbohydrate antigens conjugated to the immunological carrier keyhole limpet hemocyanin (KLH) mixed with the immunological saponin adjuvant, QS21. These trials resulted in the generation of high-titer IgM and IgG antibody responses specific for the individual antigens, and, in several cases, the capacity of those antibodies to mediate complement lysis. Four groups of five patients who had evidence of a biochemical relapse defined as rising prostate-specific antigens (PSAs) following primary therapy for prostate cancer with either prostatectomy or radiation were treated with escalating doses of 1, 3, 10 and 30 microg of synthetic TF in a clustered formation (c) which was conjugated to KLH and given with 100 microg of QS21. Patients received a total of five subcutaneous vaccines over 6 months and were monitored expectantly with scans every 3-4 months. Serum samples were obtained at weeks 1, 2, 3, 7, 9, 13, 19, 26, 50 and every 3 months. Antibody titers were monitored by ELISA and antibody binding to the cell surface of prostate cell lines was performed by flow cytometry. Complement-dependent cytotoxicity was performed on selected patients. Twenty evaluable patients were accrued to the study, of whom only one did not receive all six vaccinations. All patients developed maximum IgM and IgG antibody titers by week 9. The median IgM antibody titer by week 7 was 1/1,280 at 10 microg, 1/320 at 30 microg, 1/1,280 at 3 microg and 1/1,280 at 1 microg dose groups. The IgM titers from all groups remained greater than 1/320 by week 32 and beyond through week 50. We report here the results of a dose-escalating trial of a TF(c)-KLH conjugate vaccine in patients in the clinical state of a rising PSA in the absence of radiographic disease. For the first time, a synthetically made TF trimer or cluster (c) was made with three TF disaccharides attached to three sequential threonines on a peptide backbone. TF(c) doses of 1, 3, 10 and 30 microg were conjugated to KLH and administered with QS21. All doses induced high-titer IgM and IgG antibodies against TF. Unlike our findings in previous dose-escalating phase I trials, there did not appear to be increased antibody production with increasing doses of vaccine; higher titers of IgM and IgG antibodies developed at the lowest dose level (1 microg). An anti-tumor effect in the form of a change in post-treatment versus pretreatment logPSA slopes was also observed. The results justify the inclusion of TF(c) at a dose of 1 microg as a relevant antigenic target in a multivalent phase II vaccine trial in patients in the high-risk minimal disease state.
