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Updated:05/25/2022 5:00 p.m.
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A new type of cancer vaccine can thwart the defensive response of tumors to vaccine-induced immune attack. The preliminary results, published in “Nature”, demonstrate the efficacy and safety of this vaccine in mice and non-human primates. The preclinical findings could pave the way for further testing to determine clinical applicability.
The approach exploits Z-DNA. This DNA, instead of turning to the right like Watson and Crick’s B-DNA, Z-DNA, has a left turn. One function of Z-DNA is to regulate the immune response to viruses. The key is in the Zα domain that binds to the Z-DNA structure with high affinity. A domain is a specific physical region of a protein that has a specific function.
The Zα domain was originally discovered by Alan Herbert from InsideOutBio, author of the work. The ADAR1 Zα domain turns off the immune response against oneself, while the other ZBP1 Zα activates pathways that kill virus-infected cells, as previously shown by Sid Balachandran, the paper’s other author. Interactions between ADAR1 and ZBP1 determine whether a tumor cell lives or dies
Most cancer vaccines target specific cell surface proteins (antigens) that are expressed by tumor cells, which help the immune system recognize and attack these cells. However, the nature and immunogenicity (ability to stimulate an immune response) of these antigens is unique to each individual, which limits the development of a universal vaccine. In addition, tumors can often escape immune attack by mutating and altering antigen presentation, reducing their recognition.
As the researchers explain, both Zα proteins are induced during inflammation by interferon, although they are not usually present in normal cells. Furthermore, both proteins are also expressed in tumors, especially in cells called fibroblasts that cancer cells use for their growth. Normally, tumors depend on ADAR1 to suppress cell death pathways that would otherwise kill the tumor.
The team has identified a small molecule that could bypass ADAR1 suppression and directly activate ZBP1-mediated tumor cell death. This drug acts independently of the cancer-causing mutation and causes a highly immunogenic form of cell death.
In addition, the response destroys the fibroblasts that support tumor growth, and by doing so, the drug improves the effectiveness of immunotherapy.
The drug is a member of the curaxin family and has already been shown to be safe in Phase I trials, but it still requires more research to confirm its clinical use.
“The work leads us to a new therapeutic approach to cancer treatment,” says Herbert.
The authors conclude that these initial results reveal that this vaccine is capable of promoting a protective immunity against tumors, even those with elusive mutations.
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