Dept. of Biological Engineering, Dept. of Materials Science & Engineering, MIT, Cambridge, MA
Koch Institute for Integrative Cancer Research, Cambridge, MA
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
Howard Hughes Medical Institute, Chevy Chase, MD

ABSTRACT
"Engineering immunity via chemistry and materials design: Toward an HIV vaccine and enhanced therapies for cancer"

Our laboratory focuses on applying principles from engineering and technologies from materials science, chemistry, and bioengineering to develop new approaches to study the immune system, create new diagnostics, and create next generation vaccines and cancer immunotherapies. Two examples drawn from our work on HIV vaccines and cancer immunotherapy will be described:

The kinetics of antigen availability following immunization impact follicular helper T cell priming, germinal center responses, and ultimate antibody production, 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 peptide-polymer affinity tag containing repeating phosphoserine (pSer) residues that binds tightly to the most common clinical adjuvant, aluminum hydroxide (Alhydrogel, or alum). Site specific modification of HIV antigens with varying numbers of pSer groups allowed the binding strength to alum to be tuned and alum-bound antigens were presented from alum particle surfaces with a defined orientation. pSer-antigen conjugates in alum could be tuned to steadily release antigen from an injection site over multiple weeks in mice. This persistence led to improved lymph node uptake and colocalization of antigen with B cell follicles. Ultimately, a 20-fold increase in antibody titers relative to the unmodified protein was observed four weeks after primary immunization with both pSer-eOD and pSer-SOSIP conjugates, and long-lived plasma cells in bone marrow were doubled by immunization with pSer-modified immunogens. Additionally, conjugation of pSer linkers to the base of SOSIP trimers minimized the formation of base-specific antibodies, suggesting that antigen arrives in lymph nodes still bound to alum particles.

In a second example, a novel strategy for targeting antigens and immunostimulatory agents to lymph nodes for therapeutic cancer vaccines will be described. Lymph node targeting is achieved clinically is sentinel lymph node mapping in cancer patients, where small-molecule dyes are efficiently delivered to lymph nodes by binding to serum albumin. To mimic this process in vaccine delivery, we synthesized amphiphiles designed to non-covalently bind vaccine antigens and adjuvants to endogenous albumin. These “albumin-hitchhiking” amphiphiles were efficiently delivered to lymph nodes following injection, leading to as much as 30-fold amplified cellular immune responses and anti-tumor immunity. When combined with complementary immunotherapy agents, these lymph node-targeted vaccines are capable of eradicating large established tumors in several mouse models, providing a blueprint for curative immunotherapies. These examples illustrate the power of bioengineering approaches in shaping the immune response in vivo.