Formulation and Quality – Biomolecular
2019 PharmSci 360
The use of formulation design and materials chemistry to control the timing, dose, and location of delivery of immunostimulatory cues is a powerful strategy to enhance immunity induced by vaccines and cancer immunotherapies. Two examples of our recent work utilizing such approaches will be highlighted: First, in infectious disease vaccines, the kinetics of antigen availability following immunization impact many aspects of the antibody response, but clinically-relevant methods to control the duration of antigen delivery to lymph nodes in subunit vaccines are lacking. We conjugated antigens derived from the gp140 HIV envelope trimer with a phosphoserine (pSer) peptide that binds tightly to the most common clinical adjuvant, aluminum hydroxide (Alhydrogel, or alum). Site specific modification of HIV immunogens with varying numbers of pSer groups allowed self-assembly of these antigens on the surfaces of alum particles to be tuned. Tight binding to alum converted alum itself into a nanoparticle delivery vehicle, eliciting a 30-fold increase in germinal center responses and enhanced neutralizing antibody responses relative to the unmodified antigens.
In a second area of research, we recently developed a strategy to enhance chimeric antigen receptor (CAR) T cell therapy for cancer, via targeted delivery of ligands for the CAR T cell to lymph nodes to “vaccine boost” CAR T cells. Small molecules or peptides are normally rapidly dispersed in the bloodstream following parenteral injection, but linking these compounds to an albumin-binding lipid moiety retargets these molecules to lymph nodes. In addition, these lipid-conjugated molecules can also partition into cell membranes. We hypothesized that by attaching a small molecule, peptide, or protein ligand for a chimeric antigen receptor (CAR) to such albumin-binding lipid tails (forming an “amph-vax” molecule), CAR ligands could be delivered efficiently to lymph nodes by albumin and subsequently partition into membranes of resident antigen presenting cells (APCs), thereby co-displaying a CAR T cell ligand from the cell surface together with native cytokine/receptor costimulation. In syngeneic mouse models of adoptive cell therapy, we demonstrated that this approach effectively concentrates CAR T ligands on the surfaces of dendritic cells in lymph nodes, leading to profound expansion of amph-vax-boosted CAR T cells in vivo. Amph-vax boosting safely increased the polyfunctionality of CAR T cells in parallel with T cell expansion, and dramatically enhanced the efficacy of CAR T cell therapy in solid tumors. This concept provides a strategy to regulate the expansion and function of CAR T cells directly in vivo to enhance adoptive cell therapy of cancer.