Biomimetic Glyconanoparticle Vaccine for Cancer Immunotherapy

Cancer
immunotherapy aims to harness the immune system to combat
malignant processes. Transformed cells harbor diverse modifications
that lead to formation of neoantigens, including aberrantly expressed
cell surface carbohydrates. Targeting tumor-associated carbohydrate
antigens (TACA) hold great potential for cancer immunotherapy. N-glycolylneuraminic acid (Neu5Gc) is a dietary non-human
immunogenic carbohydrate that accumulates on human cancer cells, thereby
generating neoantigens. In mice, passive immunotherapy with anti-Neu5Gc
antibodies inhibits growth of Neu5Gc-positive tumors. Here, we designed
an active cancer vaccine immunotherapy strategy to target Neu5Gc-positive
tumors. We generated biomimetic glyconanoparticles using engineered
αGal knockout porcine red blood cells to form nanoghosts (NGs)
that either express (NGpos) or lack expression (NGneg) of Neu5Gc-glycoconjugates in their natural context. We
demonstrated that optimized immunization of “human-like”
Neu5Gc-deficient Cmah–/– mice with NGpos glyconanoparticles induce a strong, diverse
and persistent anti-Neu5Gc IgG immune response. The resulting anti-Neu5Gc
IgG antibodies were also detected within Neu5Gc-positive tumors and
inhibited tumor growth in vivo. Using detailed glycan
microarray analysis, we further demonstrate that the kinetics and
quality of the immune responses influence the efficacy of the vaccine.
These findings reinforce the potential of TACA neoantigens and the
dietary non-human sialic acid Neu5Gc, in particular, as immunotherapy
targets.