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Fully Synthetic Carbohydrate-Based Vaccines in Biochemically Relapsed Prostate Cancer: Clinical Trial Results With -N-Acetylgalactosamine-O-Serine/Threonine Conjugate Vaccine

Susan F. Slovin, Govindaswami Ragupathi, Cristina Musselli, Krystyna Olkiewicz, David Verbel, Scott D. Kuduk, Jacob B. Schwarz, Dalibor Sames, Samuel Danishefsky, Philip O. Livingston, Howard I. Scher

From the Division of Genitourinary Oncology and Laboratory of Solid Tumor Immunology, Laboratory of Vaccinology, Division of Clinical Immunology, Department of Medicine, Department of Biostatistics, and the Laboratory of Bio-Organic Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Susan F. Slovin, MD, PhD, Genitourinary Solid Tumor Service, 1275 York Ave, New York, NY 10021; e-mail: slovins{at}mskcc.org.

Purpose: We report the synthesis of a mucin-related O-linked glycopeptide, -N-acetylgalactosamine-O-serine/threonine (Tn), which is highly simplistic in its structure and can induce a relevant humoral response when given in a trimer or clustered (c) formation. We tested for an antitumor effect, in the form of a change in the posttreatment versus pretreatment prostate-specific antigen (PSA) slopes, that might serve as a surrogate for effectiveness of vaccines in delaying the time to radiographic progression.

Methods: We compared the antibody response to immunization with two conjugates, Tn(c)-keyhole limpet hemocyanin (KLH) and Tn(c)-palmitic acid (PAM) with the saponin immunologic adjuvant QS21, in a phase I clinical trial in patients with biochemically relapsed prostate cancer. Patients received Tn(c)-KLH vaccine containing either 3, 7, or 15 µg of Tn(c) per vaccination. Ten patients received 100 µg of Tn(c)-PAM. QS21 was included in all vaccines. Five vaccinations were administered subcutaneously during 26 weeks with an additional booster vaccine at week 50.

Results: Tn(c), when given with the carrier molecule KLH and QS21, stimulated the production of high-titer immunoglobulin M (IgM) and IgG antibodies. Inferior antibody responses were seen with T(c)-PAM. There was no evidence of enhanced immunogenicity with increasing doses of vaccine. An antitumor effect in the form of a decline in posttreatment versus pretreatment PSA slopes was also observed.

Conclusion: A safe synthetic conjugate vaccine in a trimer formation was developed that can break immunologic tolerance by inducing specific humoral responses. It seemed to affect the biochemical progression of the disease as determined by a change in PSA log slope.

Supported by the Association for the Cure of Cancer of the Prostate (CaP CURE) and the PepsiCo Foundation.

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