Researchers at the University of Zurich have modified a widespread
respiratory virus called adenovirus so that it functions like a Trojan horse
and transports genes for therapeutic agents directly into tumor cells. In
contrast to chemotherapy or radiation therapy, this approach does not harm
normal, healthy cells. Once in the tumor cells, the genes supplied serve as
templates for therapeutic antibodies, cytokines and other messenger
substances that are produced by the cancer cells themselves and eliminate
the tumor from within.
Channel adenoviruses undetected by the immune system
"We get the tumor to eliminate itself by causing its cells to produce
therapeutic agents," says postdoc Sheena Smith, who led the development of
the approach. Research group leader Andreas Plückthun explains: "The active
ingredients such as therapeutic antibodies or messenger substances stay
exactly where they are needed in the body, instead of being distributed in
the bloodstream where they can damage healthy organs and tissues."
The UZH researchers call their technology SHREAD: for SHielded, REtargeted
ADenovirus. It builds on key technologies that the Plückthun working group
had previously developed to guide adenoviruses that no longer carry viral
genes past the immune system to specific points in the body.
High levels of antibodies in the tumor, low levels in other tissues
The scientists used the SHREAD system to induce a tumor in the breast of a
mouse to produce a clinically approved antibody called trastuzumab
(Herceptin®) for the treatment of breast cancer. They found that after a few
days, SHREAD produced a greater amount of the clinical antibody in the tumor
than when the drug was injected directly. At the same time, the
concentration in the bloodstream and in other tissues, in which side effects
can occur, was significantly lower. With the help of a sophisticated,
high-resolution 3D imaging process and tissue made transparent, they were
able to show how the therapeutic antibody produced in the body creates pores
in blood vessels in the tumor, destroys cells there and treats it from the
inside out.
Use to fight Covid-19 is being investigated
Plückthun, Smith and their colleagues emphasize that SHREAD technology is
not only suitable for fighting breast cancer. Since healthy tissue no longer
comes into contact with significant amounts of medication, the technology
can also be used to administer a wide range of so-called biologics -
powerful protein-based drugs that would otherwise be too toxic.
The members of the Plückthun Group are currently using their technology in a
project funded by the Swiss National Science Foundation that aims at a
Covid-19 therapy. Adenoviral vectors are already used in several Covid
vaccines, including those from Johnson & Johnson, AstraZeneca, China's
CanSino Biologics and Russia's Sputnik V - but without SHREAD technology.
“By administering the SHREAD treatment to the patient via an inhaled
aerosol, our approach could allow the targeted production of Covid antibody
therapies in lung cells. In other words, where it is needed most, ”explains
Smith. "This could reduce costs, increase the accessibility of Covid
therapies and, with the inhalation approach, also improve the administration
of vaccines."
Reference:
Smith SN, Schubert R, Simic B, et al. The SHREAD gene therapy platform for
paracrine delivery improves tumor localization and intratumoral effects of a
clinical antibody. Proc Natl Acad Sci USA. 2021;118(21):e2017925118. doi:10.1073/pnas.2017925118