Cancer Immunology, Immunotherapy

, Volume 54, Issue 7, pp 694–702

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

  • Susan F. Slovin
  • Govind Ragupathi
  • Cristina Musselli
  • Celina Fernandez
  • Meghan Diani
  • David Verbel
  • Samuel Danishefsky
  • Philip Livingston
  • Howard I. Scher
Original Article

DOI: 10.1007/s00262-004-0598-5

Cite this article as:
Slovin, S.F., Ragupathi, G., Musselli, C. et al. Cancer Immunol Immunother (2005) 54: 694. doi:10.1007/s00262-004-0598-5

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 μg of synthetic TF in a clustered formation (c) which was conjugated to KLH and given with 100 μg 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 μg, 1/320 at 30 μg, 1/1,280 at 3 μg and 1/1,280 at 1 μg 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 μg 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 μg). 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 μg as a relevant antigenic target in a multivalent phase II vaccine trial in patients in the high-risk minimal disease state.

Keywords

Vaccine TF Cluster Prostate cancer KLH PSA 

Abbreviations

TF

Thomsen-Friedenreich

TF(c)

TF in a clustered formation

sTF

Sialyted TF

PSA

Prostate-specific antigen

KLH

Keyhole limpet hemocyanin

HSA

Human serum albumin

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Susan F. Slovin
    • 1
  • Govind Ragupathi
    • 2
  • Cristina Musselli
    • 2
  • Celina Fernandez
    • 1
  • Meghan Diani
    • 1
  • David Verbel
    • 3
  • Samuel Danishefsky
    • 4
  • Philip Livingston
    • 2
  • Howard I. Scher
    • 1
  1. 1.Genitourinary Oncology ServiceMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Laboratory of VaccinologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3. Department of Biostatistics and EpidemiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Laboratory of Bio-Organic ChemistryMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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