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DNA vaccines target unique cancer mutations
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Researchers at Washington University Medical School in St. Louis have shown that personalized cancer vaccines made with DNA can program the immune system to attack malignant tumors, including breast and pancreatic cancers. The study was carried out in mice with breast cancer and a patient with late-stage pancreatic cancer.
The COVID-19 vaccines, developed using genetic information that direct our immune systems to recognize and fight off viral infections, have become lifesavers in the global battle against the pandemic.
New research from the Washington University Medical School in St. Louis has now shown that a similar vaccination approach can be used to create personalized vaccines that program the immune system to attack malignant tumors, including breast and pancreatic cancers.
The bespoke vaccines target mutated proteins called neoantigens that are only found in a patient’s tumors. Unlike Moderna and Pfizer / BioNTech’s COVID-19 vaccines, which are based on genetic material called mRNA, the personalized cancer vaccines are made using DNA.
“We took a small sample of tissue from a tumor in a 25-year-old male patient with late-stage pancreatic cancer and developed a personalized vaccine based on the unique genetic information in that tumor,” said Dr. William Gillanders. Senior Author and Professor of Surgery in the School of Medicine. “We believe this is the first report of the use of a neoantigen DNA vaccine in a human, and our surveillance confirms that the vaccine successfully triggered an immune response that targets specific neoantigens in the patient’s tumor.”
The study, published April 20 in the journal Genome Medicine, examines how techniques for making personalized cancer vaccines can be improved to help the body produce a more effective, longer-lasting, anti-cancer immune response.
The results also show that a personalized DNA vaccine, when combined with other immunotherapies, can create a robust immune response that can reduce breast cancer in mice. While the DNA vaccine did not shrink the pancreatic cancer patient’s tumors, it produced a measurable immune response that targeted the tumor.
Gillanders, who treats breast cancer patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, said DNA vaccine platforms offer some important advantages over other personalized vaccine platforms currently in early clinical trials, such as on mRNA , dendritic cells and synthetic peptides.
Because the neoantigen DNA vaccine focuses the immune response to neoantigens that are only present in tumor cells, it reduces the risk of dangerous side effects such as damage to normal healthy tissues or triggering an intolerance or poor reaction to the vaccine.
“DNA vaccines are relatively simple and inexpensive to manufacture compared to other neoantigen vaccine platforms, such as those that use dendritic cells or mRNA, which makes the DNA vaccine platform attractive for neoantigen vaccines,” said Gillanders. “The DNA vaccine platform can also be easily constructed to contain multiple neoantigens. Additional immunomodulators can also be incorporated into the vaccine to increase immune responses. “
Like other personalized vaccines currently in development, the DNA vaccine platform targets neoantigens, abnormal protein fragments that are created when cancerous tumor cells mutate and grow. Because each cancer creates unique mutations, each DNA vaccine is also unique and optimized to target multiple neoantigens at the same time.
Each neoantigen in the vaccine sets a red flag for the immune system and sends an army of specialized immune cells called T cells to search for and destroy the tumor.
While the process seems simple in theory, the devil is in the details, and these details lie in the complex inner workings of how cells process the neoantigens and present them to the immune system.
For the vaccine to be successful, the neoantigens must be presented to cells in a precise format that maximizes the likelihood of triggering a complex, step-wise cascade of natural immune responses. Any misstep can lead to a weakened or even failed immune response.
As the new study documents, the neoantigen DNA vaccine can be optimized to improve the presentation process. Small differences in the length of an epitope (the part of the antigen recognized by the immune system), the spacing, and the amino acid sequence can lead to important changes in the way neoantigens are represented in the immune system. Even then, cancers often find ways to evade successful attacks.
In this study, Gillanders and his team attempted to address these challenges using the latest next generation gene sequencing tools, new predictive modeling techniques, and bioinformatics-based computational algorithms, all of which are designed to fine-tune the vaccine manufacturing process.
The results suggest that longer epitope fragments trigger a longer lasting immune response that involves both CD8 and CD4 T cells. that a mutated marker that labels neoantigens and is cloned at the end of an epitope chain can significantly increase its recognition by the immune system; and that even the best-presented epitopes rarely successfully shrink tumors unless accompanied by an additional immunotherapy tool such as an anti-PD-L1 checkpoint block.
“While initial clinical experience is promising, there is still a lot of work to be done to refine the vaccines and evaluate their effectiveness in animal models and clinical trials. However, this is an important first step and points us in the right direction, ”said Gillanders.
This work was supported by Susan G. Komen for the Healing, Grant No. KG111025; the Alvin J. Siteman Cancer Center, 4035 Investment Program Grant; the National Institute of Health (NIH), R01CA240983; the National Cancer Institute, Cancer Center Support Grant P30-CA091842, and SPORE in Pancreatic Cancer, P50-CA196510; NCI Training Scholarship T32 CA 009621; and the Foundation for the Barnes-Jewish Hospital.
Li L, Zhang X, Wang X, Kim SW, Herndon JM, Becker-Hapak MK, Carreno BM, Myers NB, Sturmoski MA, McLellan MD, Miller CA, Johanns TM, Tan BR, Dunn GP, Fleming TP, Hansen TH, Goedegebuure SP, Gillanders WE. Optimized polyepitope neoantigen DNA vaccines trigger neoantigen-specific immune responses in preclinical models and in clinical translation. Genome medicine. April 20, 2021.
The 1,500 faculty physicians at Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching and patient care and is consistently one of the best medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its affiliation with the Barnes-Jewish and St. Louis Children’s Hospitals.
