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

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

doi:10.1200/jco.2003.04.112

Cited by 160 publications

(118 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Smorodin¹,

Kurtenkov²,

Sergeyev³

et al. 2008

WJG

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AIM:To study the influence of tumor removal on the serum level of IgG antibodies to tumor-associated Thomsen-Friedenreich (TF), Tn carbohydrate epitopes and xenogeneic αGal, and to elucidate on the change of the level during the follow-up as well as its association with the stage and morphology of the tumor and the values of blood parameters in gastrointestinal cancer. METHODS: Sixty patients with gastric cancer and 34 patients with colorectal cancer in stages Ⅰ-Ⅳ without distant metastases were subjected to followup. The level of antibodies in serum was determined by the enzyme-linked immunosorbent assay (ELISA) using synthetic polyacrylamide (PAA) glycoconjugates. Biochemical and haematological analyses were performed using automated equipment. RESULTS: In gastrointestinal cancer, the TF antibody level was found to have elevated significantly after the removal of G3 tumors as compared with the preoperative level (u = 278.5, P < 0.05). After surgery, the TF and Tn antibody level was elevated in the majority of gastric cancer patients (sign test, 20 vs 8, P < 0.05, and 21 vs 8, P < 0.05, respectively). In gastrointestinal cancer, the elevated postoperative level of TF, Tn and αGal antibodies was noted in most patients with G3 tumors (sign test, 22 vs 5, P < 0.01; 19 vs 6, P < 0.05; 24 vs 8, P < 0.01, respectively), but the elevation was not significant in patients with G1 + G2 resected tumors. The postoperative follow-up showed that the percentage of patients with G3 resected tumors of the digestive tract, who had a mean level of anti-TF IgG above the cutoff value (1.53), was significantly higher than that of patients with G1 + G2 resected tumors (χ 2 = 3.89, all patients; χ 2 = 5.34, patients without regional lymph node metastases; P < 0. No positive delayed-type hypersensitivity reaction in skin test challenges with TF-PAA in any of the fifteen patients, including those with a high level of anti-TF IgG, was observed. CONCLUSION: The surgical operation raises the level of anti-carbohydrate IgG in most patients, especially in those with the G3 tumor of the gastrointestinal tract. The follow-up demonstrates that after surgery the low preoperative level of TF antibodies may be considerably increased in patients with the carcinoma in its early stage but remains low in its terminal stages. The stageand morphology-dependent immunosuppression affects the TF-antibody response and may be one of the reasons for unresponsiveness to the immunization with TF-antigens.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Smorodin¹,

Kurtenkov²,

Sergeyev³

et al. 2008

WJG

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“…Vaccines utilizing these Tn, sTn or TF antigens synthesized as trimers or clusters (c) and then conjugated to KLH induced comparable antibody titers by ELISA but far higher and more consistent reactivity against tumor cells. 37,41,42 The improvement in cell surface reactivity resulting from these changes in antigen configuration are summarized in Table 3. Several additional features of these antibody responses should be noted.…”

Section: Modification Of the Tumor Antigen Is Sometimes Requiredmentioning

confidence: 99%

Cancer Vaccines Targeting Carbohydrate Antigens

Livingston¹,

Ragupathi²

2006

Human Vaccines

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“…For example, mice immunizations with a trimeric cluster of Tn-antigens conjugated to KLH (Tn(c)-KLH) in the presence of the adjuvant QS-21 elicited modest titers of IgG antibodies 28 . In a clinical trial of relapsed prostate cancer patients, the vaccine gave low median IgG and IgM antibody titers 29 . In another study, it was found that only KLH conjugates of glycopeptides composed of multiple repeat units that are highly glycosylated with Tn antigens elicited IgG antibodies 30 .…”

Section: Online)mentioning

confidence: 99%

Robust immune responses elicited by a fully synthetic three-component vaccine

et al. 2007

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The over-expression of saccharides such as Globo-H, Lewis Y and Tn antigen is a common feature of oncogenic transformed cells. Endeavors to exploit this aberrant glycosylation for cancer vaccine development has been complicated by difficulties of eliciting high titers of IgG antibodies against classical conjugates of tumor-associated carbohydrates to carrier proteins. We have designed, chemical synthesized and immunologically evaluated a number of fully synthetic vaccine candidates to establish strategies to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides. We have found that a three-component vaccine composed of a TLR2 agonist, a promiscuous peptide T-helper epitope and a tumor-associated glycopeptide, can elicit in mice exceptionally high titers of IgG antibodies that can recognize cancer cells expressing the tumor-associated carbohydrate. The superior properties of the vaccine candidate are attributed to the local production of cytokines, upregulation of co-stimulatory proteins, enhanced uptake by macrophages and dendritic cells and avoidance of epitope suppression.A broad and expanding body of preclinical and clinical studies [1][2][3][4] demonstrates that naturally acquired, passively administered or actively induced antibodies against carbohydrate-associated tumor antigens are able to eliminate circulating tumor cells and micro-metastases in cancer patients. Tumor-associated saccharides are, however, of low antigenicity, because they are self-antigens and consequently tolerated by the immune system. In addition, foreign carrier proteins such as keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) and the linker that attach the saccharides to the carrier protein can elicit strong B-cell responses, which may lead to the suppression of antibody responses against the carbohydrate epitope 5,6 . It is clear that the successful development of carbohydrate-based cancer vaccines requires novel strategies for the more efficient presentation of tumor-associated carbohydrate epitopes to the immune system, resulting in a more efficient class switch to IgG antibodies 7-17 .We reasoned that a three-component vaccine composed of a tumor-associated carbohydrate B-epitope, a promiscuous peptide T-helper (Th) epitope and a Toll-like receptor (TLR) ligand will circumvent immune suppression caused by a carrier protein or the linker region of a classical conjugate vaccine. Such a vaccine candidate contains, however, all mediators required for eliciting a strong IgG immune response. In the first instance, vaccine candidates 1 and 2 were designed, which contain as a B-epitope a tumor-associated glycopeptide derived from MUC1 1,18 and the well-documented murine MHC class II restricted Th (Fig. 1). Furthermore, compound 1 contains as an built-in adjuvant the lipopeptide Pam 2 CysSK 4 , which is a potent activator of TLR2/6, whereas compound 2 contains Pam 3 CysSK 4 , which induces cellular activation through TLR1/2 20 .Compound 1 was prepared by a solid-phase peptide synthesis ...

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

Abstract: 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.

Cited by 160 publications

References 16 publications

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

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

Cancer Vaccines Targeting Carbohydrate Antigens

Robust immune responses elicited by a fully synthetic three-component vaccine

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