Sounding Out Effective Cancer Treatments

OxSonics Therapeutics was spun out of the University of Oxford’s Institute of Biomedical Engineering in 2013. Its proprietary technology platform, SonoTran, combines innovative particles co-administered independently with an anticancer drug. CEO Jérôme Marzinski tells us how this technology can benefit the anticancer research community.

What is SonoTran and what can it do?
 

The SonoTran particles carry a pre-formed, stabilized air bubble that creates sustained levels of “inertial cavitation” (bubble expansion and collapse) when exposed to ultrasound at the tumor site. The SonoTran System, an ultrasound device, “activates” the particles, creating an inertial cavitation effect that produces localized pumping to enhance anticancer drugs’ penetration into and throughout tumors, thereby improving efficacy and reducing toxicity.

SonoTran is drug-agnostic and requires no drug reformulation, enabling its use with both existing and novel therapies. Treatment can be imaged and monitored in real time using proprietary mapping technology overlaid onto medical images to allow healthcare professionals to see as they treat.

What stage of development are you at?
 

SonoTran is currently in a phase I/IIa clinical trial in patients with liver metastases from colorectal cancer. We are combining the technology with standard-of-care anticancer therapy, which includes cetuximab. This first-in-human clinical trial started in January 2022 after nine years of work to get the technology to this point. Data from the initial safety cohort show that, as anticipated, SonoTran is well tolerated.

What led you to focus on solid tumors?
 

There is a need for new technologies to address the performance limitations of current anticancer drugs, which are restricted in their ability to penetrate solid tumors – particularly in the case of targeted biologics such as mAbs, ADCs, and oncolytic viruses.

Several factors combine to make solid tumors a challenging environment for anticancer biologics delivery. The tumor vasculature is tortuous, highly heterogeneous, and leaky, with endothelial gaps in the range of 200–1,200 nm (many times larger than the 5 nm gaps typical of healthy vasculature). This causes increased interstitial fluid pressure through unregulated extravasation of fluid. In colorectal liver cancer metastases, fluid pressures are reported to be 10 times higher on average than in normal tissue (21 mmHg versus 2 mmHg). Although the peak distance between a cell and the nearest blood vessel in healthy tissues rarely exceeds 100 μm, this almost doubles to 180 μm in tumors, rendering drug penetration ineffective. The result is that less than 0.01 percent of the administered drug gets into the tumor.

What are your hopes for the future of your approach?
 

SonoTran could be harnessed in multiple ways. As well as heightening the efficacy of a given anticancer drug dose, we could also potentially administer a lower systemic dose, lowering systemic toxicity. This might make certain therapeutics viable for patients who cannot tolerate them at the doses required for efficacy. It could even help salvage failed therapeutics by enhancing the efficacy of these drugs at or below the maximum tolerated dose.

Although we are currently focused on cancer, our drug delivery technology could also have potential in other diseases such as atherosclerosis, the major cause of morbidity and mortality in cardiovascular disease, where we would look to get more drug out of the blood vessel and into the plaques.

How did SonoTran improve tumor penetration in the murine test model?
 

This two-part project was a collaboration between OxSonics Therapeutics and two biopharma companies to assess SonoTran’s ability to enhance the delivery and efficacy of an “unarmed” oncolytic vaccinia virus in a murine bladder cancer model.

The initial pilot study evaluated high and low doses of vaccinia virus, which were intravenously administered with or without SonoTran. The results showed that mice treated with SonoTran demonstrated higher viral spread in their tumors at both dose levels than those treated with the virus alone. In the second study, this increase in viral spread in the tumor translated into better efficacy, with 78 percent of mice treated with vaccinia virus and SonoTran surviving to the end of the study versus 56 percent of mice treated with vaccinia virus alone. Both studies showed that SonoTran resulted in a smaller average tumor size and increased the number of responders to the treatment.

Was it easy to find a partner willing to collaborate?
 

We received a lot of interest in SonoTran because of the known issue of tumor interstitial pressure acting as a barrier to drug delivery. A variety of approaches are being explored in the life sciences to get more drug into a tumor, but the problem they all face is getting the drug to reach throughout the tumor tissue.

We now have plenty of data to show that, even with different anticancer drugs, we can deliver more of the therapeutic throughout the tumor using SonoTran and achieve reductions in tumor size. Prior to securing our two biopharma companies, we had previously shown that we could get 50 times more vaccinia virus into a tumor 24 hours after treatment, which resulted in a 10,000-fold increase in vaccinia virus activity by day six of the study.

A collaboration with ADC Therapeutics in which we combined their ADCT-601 with SonoTran showed that SonoTran increased ADCT-601’s potency 3.3-fold.

When do you expect to progress to the next phase of testing?
 

Once we’ve completed the safety cohort in the ongoing clinical study, we can move into recruiting patients into a delivery cohort to generate clinical data that demonstrate how SonoTran increases delivery of an anticancer drug into liver tumors. Alongside this, we will also have an efficacy cohort in which patients are randomized to receive a standard-of-care anticancer treatment with or without SonoTran. We will follow these patients to see whether SonoTran can improve the reduction in tumor size over the anticancer therapy alone.

We are also looking to start another clinical trial next year that will involve SonoTran in combination with other cancer therapies, but in a different type of cancer – potentially breast cancer.