Personalized cancer vaccines made using DNA can program the immune system to attack malignant tumors, including breast and pancreatic cancers. That is the conclusion of researchers at Washington University School of Medicine in St. Louis in Missouri who have conducted a study on mice with breast cancer and one patient with late-stage pancreatic cancer.

Therapeutic DNA vaccines have emerged as an attractive immunotherapeutic approach against cancer due to their simplicity, stability, and safety. In numerous clinical trials, researchers have demonstrated that therapeutic DNA vaccines are generally well tolerated by patients and do not trigger major adverse effects. [1]

However, therapeutic DNA vaccines have often demonstrated only modest therapeutic effects in clinical trials. The modest effects are partly due to the immunosuppressive mechanisms developed by the tumor. To enhance the vaccine-induced immune response and the treatment efficacy, researchers are improving DNA vaccines by using two different strategies. The first strategy is to increase their immunogenicity by selecting and optimizing the best antigen(s) to be inserted into the plasmid DNA. In the second strategy, researchers combine DNA vaccines with other complementary therapies designed to improve their activity by attenuating immunosuppression in the tumor microenvironment or by increasing the activity/number of immune cells.[2]

Personalized vaccine strategy
The COVID-19 vaccines, designed using bits of genetic information that prime our immune systems to recognize and fight off viral infections, have become real lifesavers in the global fight to end the SARS-Cov-2 pandemic.

By using their understanding of therapeutic DNA vaccines in the treatment of cancer, combined with a better understanding of COVID-19 mRNA vaccines, researchers from Washington University School of Medicine in St. Louis, Missouri, have shown that a similar vaccine approach can be used to create personalized vaccines that program the immune system to attack malignant tumors, including breast and pancreatic cancers.

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DNA vs mRNA
The personalized, tailor-made vaccines are designed to target mutated proteins called neoantigens that are unique to a patient’s tumors. Unlike the COVID-19 mRNA vaccines made by Moderna and Pfizer/BioNTech that rely on genetic material called mRNA, personalized cancer vaccines are made using DNA.

“We took a small tissue sample from a tumor in a 25-year-old male patient with late-stage pancreatic cancer and used it to develop a personalized vaccine based on the unique genetic information in that tumor,” said William Gillanders, MD, senior author, and professor of surgery at the School of Medicine.

“We think this is the first report of the use of a neoantigen DNA vaccine in a human, and our monitoring confirms the vaccine was successful in prompting an immune response that targeted specific neoantigens in the patient’s tumor,” Gillanders added

Published April 20, 2021 in the journal Genome Medicine, the study, funded by the Susan G. Komen for the Cure, Alvin J. Siteman Cancer Center, the National Institute of Health, SPORE in Pancreatic Cancer, and The Foundation for Barnes-Jewish Hospital, explores how novel techniques used to create personalized cancer vaccines can be improved to help the body unleash a more effective, longer-lasting, tumor-fighting immune response.[3]

Robust immune response
The findings also show that a personalized DNA vaccine coupled with other immunotherapies can generate a robust immune response capable of shrinking breast cancers in mice. While the DNA vaccine did not shrink tumors in the pancreatic cancer patient, it did produce 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 now in early clinical trials, such as those relying on mRNA, dendritic cells, and synthetic peptides.

Because the neoantigen DNA vaccine focuses the immune response on neoantigens that exist only in tumor cells, it lowers the risk of dangerous side effects, such as damage to normal healthy tissues or the triggering of intolerance or a bad reaction to the vaccine.

Cost-effective
“DNA vaccines are relatively easy and cost-effective to manufacture compared with other neoantigen vaccine platforms such as those that use dendritic cells or mRNA, for example, making the DNA vaccine platform attractive for neoantigen vaccines,” Gillanders explained.

“The DNA vaccine platform also can be readily engineered to include multiple neoantigens. Additional immune modulators can also be integrated into the vaccine to increase the immune responses.”

Like other personalized vaccines now under development, the DNA vaccine platform targets neoantigens, abnormal protein fragments that are created as cancerous tumor cells mutate and grow. Since each cancer generates unique mutations, each DNA vaccine is also unique and optimized to simultaneously target multiple neoantigens.

Each neoantigen included in the vaccine raises a red flag for the immune system, sending an army of specialized immune cells called T cells to seek and destroy the tumor.

While the process seems simple in theory, the devil is in the details, and those details reside within the complex inner workings of how cells process and present the neoantigens to the immune system.

For the vaccine to be successful, the neoantigens must be presented to cells in a precise format that maximizes the odds of triggering a complex, step-by-step cascade of natural immune responses. Any misstep may result in a weakened or even failed immune response.

The new study documents that 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), spacing, and amino acid sequence can result in important changes in how neoantigens are presented to the immune system. Even then, cancers often find ways to evade successful attacks.

In this study, Gillanders and his team address challenges using the latest in next-generation gene sequencing tools, new predictive modeling techniques, and bioinformatics-based computational algorithms — all designed to fine-tune the vaccine creation process.

The findings suggest that longer epitope fragments are more effective at triggering a longer-lasting immune response that includes both CD8 and CD4 T cells; that a mutant marker that tags neoantigens and is cloned to the end of an epitope string can significantly increase its recognition by the immune system; and that even the most well-presented epitopes are seldom successful at shrinking tumors unless accompanied by an additional immunotherapy tool, such as anti-PD-L1 checkpoint blockade.

“Although the initial clinical experience is promising, there is more work to do to refine the vaccines and evaluate their effectiveness in animal models and clinical trials. But this is an important first step and points us in the right direction,” Gillanders noted.

Reference
[1] Yang B, Jeang J, Yang A, Wu TC, Hung CF. DNA vaccine for cancer immunotherapy. Hum Vaccin Immunother. 2014;10(11):3153-64. doi: 10.4161/21645515.2014.980686. PMID: 25625927; PMCID: PMC4514137.
[2] Lopes A, Vandermeulen G, Préat V. Cancer DNA vaccines: current preclinical and clinical developments and future perspectives. J Exp Clin Cancer Res. 2019 Apr 5;38(1):146. doi: 10.1186/s13046-019-1154-7. PMID: 30953535; PMCID: PMC6449928.
[3] 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 elicit neoantigen-specific immune responses in preclinical models and in clinical translation. Genome Medicine. April 20, 2021.

Featured image courtesy: © 2021 WUST/Washington University School of Medicine in St. Louis in Missouri.

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