Every cell in our body presents part of its peptide repertoire to our immune system so that it can distinguish between self and non-self-cell. As cancer cells unceasingly mutate their DNA as well as produce altered form of normal proteins that having small changes in their peptide sequences. Due to these changes when cancer cell present their faulty neopeptides (or neoantigens), the immune system’s dendritic cells (DCs) can initiate strong T cell responses to attack the very cancer cells that express them.
A new study led by Harvard’s Wyss Institute have recognized the potential of neoantigens as vaccine targets and recognized a new approach that uses an injectable scaffold loaded with a selection of tumor-expressed peptides. using mouse models, they show that vaccines eliminated the large tumors and tumor metastases as well as creating a memory so that in future tumor rejections can be enabled and strongly synergize with checkpoint therapy, a different immune therapy approach that is used clinically to restimulate fading anti-tumor immunity in cancer patients.
“There is tremendous enthusiasm for using neoantigens in immunotherapy as predicting them in individual tumors becomes more and more reliable. Our materials approach is able to mix and match predicted neoantigens very easily and efficiently in a single scaffold that as a delivery vehicle could be plugged into existing pipelines to enable more effective personalized cancer treatments,” said Wyss Institute Core Faculty member David Mooney, Ph.D., who led the study. He is also the leader of the Wyss Institute’s Immunomaterials Platform and the Robert P. Pinkas Family Professor of Bioengineering at SEAS.
During their research, the scientists used their previously developed programmable biomaterial made from tiny mesoporous silica rods (MSRs) that can be injected under the skin where they spontaneously assemble into a 3-dimensional scaffold that is able to attract and stimulate DCs. They coated the MSRs with polyethyleneimine (PEI) which is a polymer used as a delivery vehicle for delivering DNA and protein into the cell. Using this technique multiple peptides were easily absorbed without any further modifications and regardless of their inherent and were taken up by DCs together with the peptides, PEI enhanced the stimulation of DCs and the ensuing tumor-directed cytotoxic T cell responses in our mouse models.
The vaccine also contained boosting factors besides PEI which can help them attract DCs and boost immune functions. The team compared them with controlled vaccine lacking boosting factors and found that they were more efficient in activating DC populations, stimulating their interactions with T cells in nearby lymph nodes, and driving the generation of circulating killer T cells that are capable of recognizing the tumor-specific peptides.
For studying the potential of clinical strategy, a collaborative team designed a vaccine that presented a model peptide of the well-known E7 oncoprotein from human papillomavirus (HPV), which causes cervical and other cancers. During their research, they found out that a single injection of the vaccine was curing HPV tumors in mice completely and with 80% of the animal’s lifespan increased to more than 150 days. They also found out that the animals vaccinated with the PEI formulation could still destroy tumor cells even after injection, demonstrating that they had formed a robust immunological memory of the tumors.
The team mimicked potential future neoantigen approaches in human patients more closely by carrying out studies in more aggressive and difficult-to-treat tumor models. According to the author Li “We introduced up to five neoantigens that had been recently identified in mouse melanoma and colorectal tumors into our biomaterial scaffold, and found that a single injection of the vaccines cleared tumor metastases and provided strong immune responses against the tumors that were comparable to multiple injections with existing vaccines.” When combined with immune checkpoint therapy it boosted both the effects of the vaccine and the checkpoint therapy. In the light of this study, team wants to combine them with their biomaterial-supported neoantigen and have a hope that it could help treat many patients more effectively.
“This new biomaterials-based cancer vaccine therapy has enormous clinical potential as it markedly enhances our ability to attack tumors by harnessing the very process that lets them arise in the first place. It is an exciting next step in the immuno-oncology field,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at SEAS.