Keyhole limpet hemocyanin conjugate vaccines against cancer: The Memorial Sloan Kettering experience

Abstract

Passively administered and actively induced antibodies have been associated with the eradication of circulating tumor cells and micrometastases in mice and humans. We have identified a series of cell surface carbohydrate and peptide antigens on melanomas, sarcomas, and cancer of the breast, prostate. ovary, and lung tissues. We found that breaking tolerance toward these tumor antigens was best achieved using vaccines containing antigens chemically conjugated to keyhole limpet hemocyanin (KLH) plus a potent immunological adjuvant (QS-21). To date, by using this approach to vaccination. antibodies have been induced in patients against glycolipid antigens GM2, GD2, GD3, FucosylGM1, Globo H, and Lewis Y, and glycoprotein (mucin) antigens Tn, sialyl Tn. TF, and MUC1. More recently, in a comparative study we investigated the T cell response induced by MUCI-KLH conjugates. Although a MUC1-specific T cell response was not consistently detected in any patient, the role of KLH in orienting the cytokine environment was crucial. We were able to confirm that KLH in these conjugate vaccines induces a Th1 T cell response as demonstrated by the high anti-KLH INF-gamma secretion and the IgGI and IgG3 subclasses of this high titer IgG antibodies induced. Clinical trials using KLH conjugated glycolipid and glycoprotein vaccines, are currently ongoing. These range from phase I/II single antigens trials with glycosilated MUC1, polysialic acid, synthetic Fucosyl GMI and GD2, to phase II trials with a polyvalent vaccine containing six or seven antigens. Randomized phase II trials with polyvalent vaccines are planned for initiation in 2001-2002 in patients with ovarian, breast, and prostate cancer.

Vaccines based on the cell surface carbohydrates of pathogenic bacteria

“…It has been shown possible to make effective glycoconjugate immunogens from low molecular weight oligosaccharides such as those present on the lipo-oligosaccharides of pathogens such as a Neisseria meningitidis (Mieszala et al 2003). The same glycoconjugate technology has been used to prepare immunotherapeutics to slow the redevelopment of cancer following chemotherapy, prepared from the glycan chains of glycolipids overexpressed by tumour cells (Musselli et al 2001). Further discussion of cancer immunotherapeutics is outside the remit of this review.…”

Heat shock fusion protein induces both specific and nonspecific anti‐tumor immunity

“…Vaccinia viruses that express both MUC1 VNTR and IL-2 were shown to induce MUC1-specific antibodies and CTL in some of the patients with advanced inoperable breast cancer [7]. MUC1 coupled with keyhole limpet hemocyanin (KLH) + QS-21 (a potent adjuvant) was demonstrated to induce MUC-1-specific antibody but only a minimal T cell response in clinical trials [8][9][10]. A MUC1-mannan fusion protein was found to induce a high frequency of anti-tumor CTL responses in mice.…”

Sulfhydryl-Based Tumor Antigen-Carrier Protein Conjugates Stimulate Superior Antitumor Immunity against B Cell Lymphomas

“…Meanwhile, a number of other investigators have sought to use maleimide chemistry to enhance the immunogenicity of tumor Ag-carrier protein conjugate vaccines. Livingston and colleagues have extensively characterized the immune response to a variety of lipid, carbohydrate, and peptide tumor Ags linked to KLH, in general finding an advantage of maleimide over glutaraldehyde conjugation for the induction of humoral responses (50,51). However, enhanced T cell responses against short MUC1 tumor Ag-derived peptides are not detectable in mice or humans after immunization with maleimide-conjugated MUC1-KLH (50,52).…”