Scientists have been trying to use the body’s natural defenses to fight successfully against cancer, a promising idea still in development. There has been limited success in this immunotherapeutic approach, but researchers have potentially made a breakthrough. Investigators working at The Wistar Institute and Inovio Pharmaceuticals, Inc. have engineered a DNA vaccine so the immune system will recognize a common cancer marker in a way that stimulates a major effect. Their results, which are summarized in the following video, were reported in the journal Molecular Therapy.
DNA vaccines are made up of a synthetic genetic sequence, one which instructs the immune system to mount a response against an antigen or marker. In this case, the antigen is one strongly associated with tumors. The relatively recent discovery of those antigens has inspired researchers to try using vaccines, obviously not a new tool in the biomedical repertoire but one that is not useful without the critical information about antigens. Already, this method has worked to clear neoplasia in people that have tumors because of a viral infection.
There have been serious limitations to the vaccine approach that have been exposed as more are attempted. Those antigens that indicate tumors often only result in a mild immune response; even though they are unique to tumors, the body can also recognize that they are part of the host’s body. So-called self-antigens are protected in order to prevent the immune system from attacking its own cells and harmless neighbors. The ability of the immune system to tolerate other cells that belong to the host thus dampen the efficacy of these vaccines.
Wilm’s tumor gene 1 (WT1) is one such antigen that is abundant in many types of cancerous tumors. Scientists speculate that it’s likely to have an important part in tumor growth. However, vaccines that aim to target WT1 have not worked well; the immune system is not up to the fight.
To improve the body’s fight against the WT1 antigen, Wistar scientists utilized an edited DNA sequence, one which makes the host target the WT1 antigen as a foreign invader. This technique, broke the immune tolerance of WT1 in animal models.
“This is an important time in the development of anti-cancer immune therapy approaches. This team has developed an approach that may play an important role in generating improved immunity to WT1 expressing cancers,” explained the senior author of the work, David B. Weiner, Ph.D., Executive Vice President and Director of the Vaccine Center at The Wistar Institute and the W.W. Smith Charitable Trust Professor in Cancer Research. “These immune responses represent a unique tool for potentially treating patients with multiple forms of cancer. Our vaccine also provides an opportunity to combine this approach with another immune therapy approach, checkpoint inhibitors, to maximize possible immune therapy impact on specific cancers.”
This new vaccine with the optimized DNA sequence, one which tags WT1 for destruction but maintains enough similarity that only WT1 is targeted, has shown success in both mice and non-human primates. There did not appear to be any toxic effects on the test subjects. The vaccine did result in the establishment of immune memory against the antigen. In mice, the vaccine elicited an immune response to leukemia. Testing in human subjects will be another step on the road to clinical use.