Australian scientists have created a promising new vaccine candidate against cancers that express the Wilms’ tumor 1 (WT1) gene. These include cancers of the blood, like acute myeloid leukemia (AML), and solid tumors such as certain breast cancers.
The study, “Human CLEC9A antibodies deliver Wilms’ tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1-specific CD8+ T cells,” was published in the journal Clinical and Translational Immunology.
As a vaccine, the new molecule is designed to prime the immune system to recognize and destroy cancer cells whose surfaces contain the WT1 protein, which helps filter blood through the kidneys. WT1 is often expressed at high levels in malignancies of both the blood and solid tissues, including most cases of AML. It is seen as a promising therapeutic target for cancer vaccines.
The potential vaccine consists of a fusion between the WT1 antigen — a molecule that can stimulate an immune response — and the human C-type lectin receptor (CLEC9A) antibody.
CLEC9A is a receptor that plays a critical role in recognizing necrotic cells, which are those dying in an unprogrammed manner, as often occurs in cancer. The receptor presents these cells to a specific type of T cells, called CD8 T cells, as a means of training the immune system to recognize and clear them out.
It is exclusively present in dendritic cells (DCs) that also express a protein called CD141 — so-called CD141 DCs. This particular type of DCs has been found to lead to enhanced immune responses, making the CD141 DCs an attractive target for immune cell activation. Of note, dendritic cells are a type of immune cell required to activate T cells.
The CLEC9A-WT1 fusion protein was designed to specifically target these CD141 dendritic cells, which can then present the WT1 antigen to CD8 T cells. These, in turn, can eliminate cancer cells.
To conduct an in vivo — or in a living organism — test of the potential cancer vaccine, the researchers engineered mice that had human versions of both DCs and naïve CD8 T cells. That means these T cells had not yet “learned” to recognize and attack cancerous cells.
The team then exposed these cells to their experimental vaccine. That triggered the production of interferon gamma, an immune molecule with an established anti-tumor effect, and the expansion of CD8 T cells capable of specifically interacting with the WT1-expressing DCs.
In three out of four samples from donor mice, this WT1-specific CD8 T cell expansion lasted for eight days, providing a measure of lasting protection against malignant cells.
The researchers believe that their potential vaccine has several advantages over existing compounds.
“First,” they write, “it can be produced as an ‘off‐the‐shelf’ clinical‐grade formulation, which circumvents the financial and logistical issues associated with in vitro [in the lab]‐manufactured patient‐specific vaccines. Second, this prototype vaccine targets very precisely the key DC subset required for the initiation of tumor‐specific immune responses, thereby maximising potential efficacy while minimising off‐target effects.”
Kristen Radford, associate professor at the University of Queensland and lead researcher, said the vaccine has the potential to treat a variety of blood cancers.
“We hope our continued work towards finding a safe and effective cancer vaccine will benefit cancer patients in the future,” Radford said in a press release.
“We are hoping this vaccine could be used to treat blood cancers, such as myeloid leukemia, non-Hodgkin’s lymphoma, multiple myeloma, and pediatric leukemias, plus solid malignancies including breast, lung, renal, ovarian, and pancreatic cancers, and glioblastoma,” she added.
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