Targeting tumor-associated carbohydrate antigens: a phase I study of a carbohydrate mimetic-peptide vaccine in stage IV breast cancer subjects.

Fariba Jousheghany,Issam Makhoul,Angela Pennisi,Eric R. Siegel,Peter D. Emanuel,Anastas D. Pashov,Behjatolah Monzavi-Karbassi,Xueyan Guo,Laura F. Hutchins,Thomas Kieber-Emmons

doi:10.18632/oncotarget.21959

Abstract

Tumor-associated carbohydrate antigens (TACAs) support cell survival that could be interrupted by anti-TACA antibodies. Among TACAs that mediate cell survival signals are the neolactoseries antigen Lewis Y (LeY) and the ganglioside GD2. To induce sustained immunity against both LeY and GD2, we developed a carbohydrate mimicking peptide (CMP) as a surrogate pan-immunogen that mimics both. This CMP, referred to as P10s, is the N-terminal half of a peptide vaccine named P10s-PADRE, the C-terminal half of which (PADRE) is a Pan-T-cell epitope. A Phase I dose-escalation trial of P10s-PADRE plus adjuvant MONTANIDE™ ISA 51 VG was conducted in subjects with metastatic breast cancer to test 300 and 500 μg/injection in two cohorts of 3 subjects each. Doses of the P10s-PADRE vaccine were administered to research participants subcutaneously on weeks 1, 2, 3, 7 and 19. Antibody responses to P10s, GD2, and LeY were measured by ELISA. The P10s-PADRE vaccine induced antibodies specifically reactive with P10s, LeY and GD2 in all 6 subjects. Serum antibodies displayed Caspase-3-dependent apoptotic functionality against LeY or GD2 expressing breast cancer cell lines. Immunization with the P10s-PADRE vaccine was well-tolerated and induced functional antibodies, and the data suggest potential clinical benefit.

Highlights

Aberrant glycosylation is a common phenotypic change of cancer cells, arising from clustered presentation on a cell surface or through modified synthesis [1]
Monoclonal antibodies directed to some Tumor-associated carbohydrate antigens (TACAs), like those directed to the ganglioside ganglioside disialic 2 (GD2) and the neolactoseries antigen Lewis Y (LeY), are known to inhibit cell signaling that influences cell survival [2,3]
We have developed potential TACA-directed vaccines based on carbohydrate-mimetic peptides (CMPs) that induce anti-tumor-reactive humoral [7,8,9] and cellular [10, 11] responses in mice

Summary

INTRODUCTION

Aberrant glycosylation is a common phenotypic change of cancer cells, arising from clustered presentation on a cell surface or through modified synthesis [1]. We have developed potential TACA-directed vaccines based on carbohydrate-mimetic peptides (CMPs) that induce anti-tumor-reactive humoral [7,8,9] and cellular [10, 11] responses in mice These CMPs are Pan-immunogens, developed to induce antibodies reactive with multiple TACAs when immunizing with a single agent [7,8,9,10, 12]. We have moved one of these CMPs, with the sequence WRYTAPVHLGDG (referred to as P10s) conjugated to the Pan-T-cell epitope PADRE, into an early-phase clinical trial in Stage IV breast cancer subjects This CMP was designed to mimic and induce responses to the ganglioside GD2 [9] and the LeY antigen [12, 13]. Our results provide further insight into the relative importance of inducing humoral responses to TACAs and the potential use of P10s as an immunogen to induce immune responses that could have clinical benefit

RESULTS

DISCUSSION

Study design

Ethics approval and consent to participate

Availability of data and materials

CONFLICTS OF INTEREST