Q&A With Dr. Sarah White: Expanding the Ablation Zone

sarah whiteAblation offers another treatment option for patients with metastatic colon cancer who are not candidates for resection, but the limited size of the ablation zone currently makes this technique effective only in patients with small tumors.

Researchers, though, are exploring ways to expand the ablation zone. Sarah White, MD, MS, FSIR and colleagues recently published a study that shows a promising method for increasing the ablation zone. Using a rat model of colorectal liver metastases, they compared the size of ablation zones in 3 groups—rats injected with hybrid magnetic gold nanoparticles tagged with monoclonal antibodies, rats injected with hybrid magnetic gold nanoparticles only, and a control group. In a Q&A with IO360, Dr. White discussed the successes and surprises encountered in this research, and she explained how this unique tagging technique may improve patients’ treatment options.

Dr. White is Associate Professor of Radiology at the Medical College of Wisconsin in Milwaukee. She will be presenting on various interventional oncology topics at the 2018 Symposium on Clinical Interventional Oncology (CIO), which takes place February 3-4, 2018 in Hollywood, Florida. 

Can you give a brief overview of your findings?

Nanoparticle work is often difficult because when nanoparticles are injected intravenously they are sequestered in the reticuloendothelial system. For our work, we created biofunctionalized nanoparticles. We tagged the nanoparticles with monoclonal antibodies, which bind to the surface of the nanoparticle and allow them to only find tumor cells and selectively bind to them.

When the nanoparticle encounters the tumor cells, they bind the cells, and the cells engulf and endocytose the nanoparticles. Next, we shine a laser light on the tumor cells that have taken up the nanoparticles. These nanoparticles also contain gold. The gold allows the light to be converted to heat, and thereby increases the zone of heating and thereby increases the amount of tumor cells that are killed.

The idea is that tiny cells that are not visible on imaging are also being killed, leading to a bigger ablation zone. Right now, our ablation zone is limited to 3 to 4 cm. However, if we inject these nanoparticles ahead of time, they can bind to the tumor cells and increase our ablative ability.

A bigger ablation zone will allow us to treat patients with bigger tumors or in more difficult locations. Gold nanoparticles are an innovative way to reach this goal.

How many more steps are there until this research is incorporated into patient care?

There are gold nanoparticles that are already FDA approved for use, and they are being used in clinical trials now. The question remaining is how to get these gold nanoparticles into patients’ tumors. We have a bunch of biologic agents that we know work in humans, and we could potentially tag these biologic agents that are known to work on human cancers with these gold particles and then do laser ablation. That would be the next step in translating from bench to bedside.

Is your team working on any of these next steps?

Absolutely. We are trying to make nanoparticles now using these FDA-approved gold nanoparticles. It usually takes 7 to 10 years for a therapy to develop from bench to bedside.

Can you comment on some of the challenges involved in this research?

If you inject nanoparticles without a biological agent on them, they are pulled into other tissues. However, if you put a biological agent on the nanoparticles, they can home in on the tumor. The question remains though---how do you get these nanoparticles with biological agents to the tumor?

For our research, we injected the nanoparticles intravenously. The problem in humans is that in order to deliver the nanoparticles intravenously, we would have to have a high enough concentration for them to deposit into the tumor even after they are sequestered into the reticuloendothelial system. Therefore, in order to translate this to humans, we could deliver the nanoparticles site-selectively, in a way that is not going to hit other tissues. That’s what we do in interventional radiology—for example, we could infuse these particles into the hepatic artery, which would bathe the tumor, the tumor bed, the tumor vascularity with the nanoparticle.

What makes the rat model a good model at this stage?

It took me about 2 years to get the model up and running. I used a rat model because I’m interested in colorectal liver metastases, and it’s challenging to get a true model of metastatic disease. Most tumor models of colon cancer involve taking colon cancer cells from the colon and injecting them into the liver, which is not a true metastatic model.

The cell line we used, CC-531, was developed by injecting rats with an agent that makes you develop colon cancer. If you keep these rats around long enough, they develop liver metastases.

Those liver metastases, the actual metastatic cells, were harvested to make the cell line we used for this study. That means we used a true metastatic model rather than colon cancer cells that were injected into the liver. This distinction is important because metastatic cells are different from primary cancer cells injected into a different location.

Another way to create a model of metastatic disease is by injecting colon cancer cells into the spleen and waiting for them to go into the liver. However, the disadvantage with that approach is you’re not getting a single, solitary lesion that you can track over time.

So that’s why we chose to use this particular model. I had an interest in using a true liver metastasis model in which I could follow a single, solitary lesion over time. This is important in order to show that this therapy is efficacious.

Did anything surprise you with the experiment, or did it all go as expected?

I don’t think anything goes as expected. I was a little disappointed about one surprise—the temperature measurements--until I saw the histology. According to the measurements, there appeared to be no change in temperature, depending on which nanoparticle we injected. The biologics vs the non-tagged nanoparticles seemed to increase the temperatures at similar rates, which was disappointing because we thought, well, then, there’s no difference between the two particles. We thought it might mean that the biologic agent isn’t necessary.

It turned out that, when we looked at histology, the ablation zones were indeed much bigger with the biologic agents. The zones were actually deeper, and we realized that the thermal camera we were using for the temperature measurement only measured the surface temperature. This meant that we weren’t seeing the depth of the ablation zone.

Looking at histology was a nice surprise because we realized the experiment actually did have an effect.

What’s your takeaway message for people practicing right now?

Nanotechnology has always threatened interventional radiology because it has the ability to supersede what we do. However, I think, in reality, the reticuloendothelial system and the fact that nanoparticles get sequestered and the leaky cancer cells that will take up the EPR effect—all of that isn’t really what in fact happens, and it’s not really what we see in the lab.

I think as interventional oncologists and masters of site-selective delivery, we are the ones that will drive nanoparticle technique forward because if we can get the nanoparticles to the right location and at a high-enough rate, they can do what they’re supposed to do. Whereas, if you just deliver particles intravenously they won’t be present at a high enough concentration. The particles will be sequestered and will not reach the tumor as they should. The bottom line is that we’re in a perfect position to be at the forefront of the field. 

Reference

White SB, Kim DH, Guo Y, et al. Biofunctionalized hybrid magnetic gold nanoparticles as catalysts for photothermal ablation of colorectal liver metastases. Radiology. 2017 Jul 13:161497. doi: 10.1148/radiol.2017161497. [Epub ahead of print],

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