Fully synthetic carbohydrate-based vaccines in biochemically relapsed prostate cancer: clinical trial results with alpha-N-acetylgalactosamine-O-serine/threonine conjugate vaccine.
OBJECTIVE
We report the synthesis of a mucin-related O-linked glycopeptide, alpha-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 microg of Tn(c) per vaccination. Ten patients received 100 microg 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.


CONCLUSIONS
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.
Slovin
Susan F
SF
Genitourinary Solid Tumor Service, 1275 York Ave, New York, NY 10021, USA. slovins@mskcc.org
Ragupathi
Govindaswami
G
Musselli
Cristina
C
Olkiewicz
Krystyna
K
Verbel
David
D
Kuduk
Scott D
SD
Schwarz
Jacob B
JB
Sames
Dalibor
D
Danishefsky
Samuel
S
Livingston
Philip O
PO
Scher
Howard I
HI
D000368:Aged; D000369:Aged, 80 and over; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D019496:Cancer Vaccines / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D002240:Carbohydrate Sequence; D003165:Complement System Proteins / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D006433:Hemocyanins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009077:Mucins / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D019308:Palmitic Acid / Q000737:chemistry / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D014611:Vaccination; D018074:Vaccines, Conjugate / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*
D015295:Antigens, Tumor-Associated, Carbohydrate; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009077:Mucins; C040286:Tn antigen; D018074:Vaccines, Conjugate; D019308:Palmitic Acid; D003165:Complement System Proteins; D006433:Hemocyanins; D017430:Prostate-Specific Antigen; C032808:keyhole-limpet hemocyanin