(381a) Tumor Idiotype-Based Virus-Like Particle Vaccines for B-Cell Lymphoma

Vaccines derived from lymphoma tumor idiotypes are promising therapeutics for treating B cell lymphoma since idiotypic antigens are unique to each individual tumor and are capable of inducing protective immunity when coupled to immune-enhancers. Several idiotype vaccine concepts have been effective in mouse B-cell lymphoma models. These include full-length idiotype antibodies chemically cross-linked to Keyhole Limpet Hemocyanin (KLH) as well as scFv fragments expressed as fusion proteins containing immunogens such as Tetanus Toxoid Fragment C (TTFrC) and cytokines including Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), IL2 and IL4. The idiotype-KLH vaccine was evaluated in two Phase III clinical trials. Subset analysis of the Genitope trial results indicates that a fraction of patients developed humoral responses and these patients experienced significant delays in disease recurrence. Unfortunately, the clinical trial failed, because the fraction of patients responding to the vaccine was small. Cell-free protein synthesis (CFPS) can provide patient-specific vaccines much more quickly than the technologies used for the clinical trials. This will allow vaccination before the patients' immune systems have been compromised by the disease and/or chemotherapies. Yet, we may still need a vaccine that elicits more rapid and potent protective responses. We are assembling virus-like particles (VLPs) with surface displayed idiotype scFv antigens along with different combinations of cytokines to create more efficacious lymphoma vaccines. VLPs are attractive as vaccines since they traffic into draining lymph nodes and offer a repetitive antigenic structure that more efficiently activates the immune system. We use CFPS to produce VLPs, tumor idiotype scFvs, and several cytokines; all containing non-natural amino acids (nnAAs) at specific sites. The nnAAs provide alkyne and azide side chains for direct attachment of the idiotype antigens and cytokines to the VLP surface using ?click chemistry?. The production and functional evaluation of tumor idiotype-based VLP vaccines will be discussed.