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SHREADing Tumours From Inside Out by Producing Anti-Cancer Agents in situ

The SHREAD gene therapy platform, which allows the body to generate therapeutic agents on demand at precise locations, is expected to reduce the side effects of anti-cancer treatments and facilitate better delivery of COVID-19 drugs to the lungs.

One of the biggest challenges faced in cancer therapy is delivering high levels of therapeutics to tumours consistently without compromising neighbouring cells and tissues with toxic drugs. Protein-based therapeutics, which often use antibodies, are usually delivered via the bloodstream and require several doses to produce demonstrable results. However, normal tissues often suffer as a consequence since exposure to such drugs can also induce death and destruction in healthy cells.

To alleviate the problems of toxicity, researchers have been investigating ways to produce therapeutic agents directly within tumour tissues, or in situ. A group of scientists from the University of Zurich has developed a novel gene therapy platform using a common respiratory virus, called adenovirus, to deliver genes for cancer therapeutics directly into tumour cells. As opposed to chemotherapy or radiotherapy, this novel approach poses minimal toxicity to normal healthy cells.

Their novel technology SHREAD (or SHielded, REtargetted ADenovirus) leverages a specially engineered adenovirus to deliver genes to exact areas of the body, specifically cancerous tissues. Upon entry inside tumour cells, the delivered genes can act as a blueprint to synthesise therapeutic antibodies, such as cytokines and other signalling substances. These therapeutics activate self-destructive pathways in the tumours, thus eliminating them from inside out.

Postdoctoral fellow Sheena Smith, who led the development of the delivery approach, explained the basic premise of their technique, “We trick the tumour into eliminating itself through the production of anti-cancer agents by its own cells.”

Research group leader Andreas Plueckthun explained that therapeutic agents usually remain in areas of the body where they are most needed. By targeting the adenovirus to specific tumours, the therapeutics are unlikely to spread throughout the bloodstream and damage healthy organs and tissues.

To test the efficacy of their SHREAD system, they used a mouse tumour model and found that they were able to stimulate the tumour to produce trastuzumab, a clinically approved breast cancer antibody, in the mammary of the mouse. After a few days, they found that the number of antibodies produced with SHREAD was reportedly higher than when trastuzumab was directly injected, making it an attractive and powerful alternative to direct administration of therapeutics. Furthermore, the team observed that most of the antibodies were centralised in tumour tissues, and only low levels were detected in the bloodstream and other tissues, demonstrating its low toxicity.

Using a high-resolution 3D imaging method and rendering the tumour tissues transparent, they demonstrated how SHREAD initiates tumour destruction. The therapeutic antibody, produced within the body, creates pores in the blood vessels of the tumour, thus destroying tumour cells from the inside.

Besides cancer therapeutics, the SHREAD system bears good prospects to be used for other medical purposes. Plueckthun, Smith and colleagues believe that it can become a useful tool to deliver a wide range of biologics, which are protein-based drugs with potentially high levels of toxicity, without the worry of healthy tissues being compromised by therapeutic agents.

Presently, members of the Plueckthun group are exploring ways to apply SHREAD to COVID-19 therapies. With the adenovirus already being used in several COVID-19 vaccines like Johnson & Johnson, AstraZeneca, China’s CanSino Biologics, and Russia’s Sputnik V vaccines, the team see potential in incorporating their SHREAD technology to reduce side effects and offer better-targeted therapeutics.

“By delivering the SHREAD treatment to patients via an inhaled aerosol, our approach could allow targeted production of COVID antibody therapies in lung cells, where they are needed most,” Smith explained. “This would reduce costs, increase [the] accessibility of COVID therapies and also improve vaccine delivery with the inhalation approach.” [APBN]

Source: Smith et al. (2021). The SHREAD gene therapy platform for paracrine delivery improves tumour localization and intratumoral effects of a clinical antibody. Proceedings of the National Academy of Sciences, 118(21).