Programmable vaccines: From protein to cell-based vaccines
Over the years the laboratory has developed a new approach to program the adaptive immune response using immunoglobulin genes as the foundation of the technology. The first accomplishment was to modify the variable domain in such a way as to code for heterologous epitopes (i.e., epitopes present in viruses, tumor antigens, parasite antigens and other self or non-self antigens distinct from the immunoglobulin kingdom). The process was termed “antibody antigenization”, suggesting that pieces of antigen are embedded into the structure of an antibody. This is a quintessential modular system for the ad hoc assembly of epitopes of interest for immunization.
Heterologous epitopes of antigenized antibodies were shown to be immunogenic and able to induce antibody responses and activate CD4 T cells after uptake, processing and presentation in the context of the MHC molaecule, by dendritic cells or other antigen-presenting cells. By direct injection of plasmid DNA coding for antigenized antibody genes into secondary lymphoid organs, it was possible to induce high fidelity cytotoxic T cell responses. This step in the development of the technology was termed “somatic transgenic immunization” and is predicated on direct targeting and internalization of plasmid DNA by B-lymphocytes in secondary lymphoid organs. The approach owes its efficiency and uniqueness to the fact that the antigenized antibody gene is under the control of a B-cell specific promoter, a fact that lends itself to specific targeting of B cells.
The last step in the evolution of the system came from the realization that naïve B-lymphocytes uptake plasmid DNA spontaneously. This unexpected property of B-lymphocytes, which we termed “spontaneous lymphocyte transgenesis”, made it possible to design a model immunization strategy whereby B-lymphocytes are spontaneously transfected ex vivo and then reinjected in vivo yielding durable and specific T cell mediated immunity. The uniqueness of this process is that it requires no activation or culture of B lymphocytes, the entire process occurs in 1 hour, and yields very rapidly systemic T cell immunity. Characteristic of this approach is the induction of memory T cell responses of the central memory type. Transgenic lymphocyte immunization (TLI) has been used to induce protective T cell responses in mouse models of cancer and influenza virus infection. Predicated on these successes, TLI has been used in a Phase 1 clinical study to vaccinate prostate cancer patients against telomerase reverse transcriptase. The model is exemplified by, which can be activated by clicking…