Abstract
BackgroundB cell malignancies are characterized by clonal expansion of B cells expressing tumor-specific idiotypes on their surface. These idiotypes are ideal target antigens for an individualized immunotherapy. However, previous idiotype vaccines mostly lacked efficiency due to a low immunogenicity of the idiotype. The objective of the present study was the determination of the feasibility, safety and immunogenicity of a novel chemically linked phage idiotype vaccine.MethodsIn the murine B cell lymphoma 1 model, tumor idiotypes were chemically linked to phage particles used as immunological carriers. For comparison, the idiotype was genetically expressed on the major phage coat protein g8 or linked to keyhole limpet hemocynanin. After intradermal immunizations with idiotype vaccines, tolerability and humoral immune responses were assessed.ResultsFeasibility and tolerability of the chemically linked phage idiotype vaccine was demonstrated. Vaccination with B cell lymphoma 1 idiotype expressing phage resulted in a significant survival benefit in the murine B cell lymphoma 1 protection model (60.2 ± 23.8 days vs. 41.8 ± 1.6 days and 39.8 ± 3.8 days after vaccination with wild type phage or phosphate buffered saline, respectively). Superior immunogenicity of the chemically linked phage idiotype vaccine compared to the genetically engineered phage idiotype and keyhole limpet hemocynanin-coupled idiotype vaccine was demonstrated by significantly higher B cell lymphoma 1 idiotype-specific IgG levels after vaccination with chemically linked phage idiotype.ConclusionWe present a novel, simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible therapy and may produce a superior immune response compared to previously employed idiotype vaccination strategies.
Highlights
B cell malignancies are characterized by clonal expansion of B cells expressing tumor-specific idiotypes on their surface
Tumor protection conferred by Id-phage vaccines In order to explore the feasibility of employing bacteriophages in a vaccination strategy in the murine BCL1 lymphoma model, we designed recombinant BCL1-phage vaccines for use as a potential therapeutic agent
Survival of mice vaccinated with BCL1-expressing phage was significantly longer (60.2 ± 23.8 days) compared to mice vaccinated with wild-type bacteriophages serving as a control (41.8 ± 1.6 days) or phosphate-buffered saline (PBS) (39.8 ± 3.8 days) (Figure 2; p < 0.05)
Summary
B cell malignancies are characterized by clonal expansion of B cells expressing tumor-specific idiotypes on their surface. These idiotypes are ideal target antigens for an individualized immunotherapy. For the purpose of provoking immunogenicity, the Id is usually coupled to a strong immunogenic carrier protein, such as keyhole limpet hemocyanin (KLH), and coadministered with immunostimulatory adjuvants, mainly granulocyte-monocyte colony stimulating factor (GM-CSF) [3,4] Despite these procedures, Id-based immunotherapy has so far resulted in mostly disappointing clinical outcomes and clinical phase III studies aimed at obtaining regulatory approval for Id-KLH vaccines failed to reach their primary endpoints [5,6]. We here present a novel chemically linked phage Id vaccine characterized by a higher Id density on the phage surface compared to previously used genetically engineered phage vaccines
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