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

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.

Postoperative change of anti-Thomsen-Friedenreich and Tn IgG level: The follow-up study of gastrointestinal cancer patients

“…Synthetic TF and Tn glycoconjugates deserve to be studied from a viewpoint of development of anticancer vaccines [12,13] . Synthetic PAA-glycoconjugates may be promising preparations because they have been described well and can be modified by epitope density or supplemented with the amplifier of immune response and synthesized in necessary quantities.…”

“…The dynamic changes of the level of TFand Tn-antibodies in the serum of patients with cancer and its association with survival have been insufficiently studied. Investigations have mainly focused on clinical trials of antigen-specific immunotherapy [12,13] . The authors have undertaken a long-term follow-up of cancer patients to determine changes in the postoperative level of TFand Tn antibodies, as well as to elucidate the association of this level with the progression of cancer, and survival.…”

CD176 antiserum treatment leads to a therapeutic response in a murine model of leukemia

“…Anticancer vaccines targeting tumor-associated carbohydrates, such as CD176, provide an attractive approach for the prevention and treatment of cancer. Several studies suggested that the vaccination with a CD176 antigen could effectively improve breast cancer patient survival (5,14,15). In patients immunized with CD176 antigen, aside from the activation of CD176-specific antibody responses, a CD176-specific DTH reflecting the activation of specific T cells was also observed (5).…”

“…These studies demonstrated that the CD176 (TF) vaccine was effective and safe for the patients. In the patients immunized with CD176 antigen, CD176-specific delayed type hypersensitivity (DTH; 4,5) and high-titer CD176 IgM and IgG antibodies (15) were observed, indicating that both responses of cellular and humoral immunity are involved in this immunotherapeutic approach.…”

“…Immunotherapy using a CD176 vaccine has been studied on patients with advanced breast carcinoma (4,5), ovarian carcinoma (14) and prostate carcinoma (15). These studies demonstrated that the CD176 (TF) vaccine was effective and safe for the patients.…”