Priming Agents Show Potential to Improve Liquid Biopsies in Oncology

Shervin Tabrizi, MD

A novel 2-part priming strategy to enhance the sensitivity of liquid biopsies for cancer detection and monitoring shows potential, according to a study published in Science.

Though liquid biopsies hold promise in detecting and tracking cancer, their sensitivity remains a challenge. Specifically, this is an issue when conventional tests fail to detect cancerous DNA in patients. To address this limitation, Shervin Tabrizi, MD, and colleagues took inspiration from contrast agents used in medical imaging to develop injectable agents to slow down the clearance of cell-free DNA (cfDNA) from the body, helping to find more circulating tumor DNA (ctDNA) in blood samples and improve the sensitivity of liquid biopsies.

They developed 2 priming agents: nanoparticles to inhibit cfDNA uptake by liver-resident macrophages and DNA-binding monoclonal antibodies to protect cfDNA from degradation by circulating nucleases and clearance from plasma.

Findings showed that there was a significant increase in ctDNA recovery by over 10-fold in preclinical models. This enhanced recovery enabled more comprehensive tumor molecular profiling and substantially improved the sensitivity for detecting small tumors in these models, from 10% to 75%. The clinical implications of this research are promising, and the safety of these priming agents should be confirmed through further research in order to potentially be utilized in clinical settings in the future.

“We found with our approach that we could recover over 10 times more circulating tumor DNA from a blood draw compared with before. Now, these are all experiments that were done in preclinical models…but this improved recovery of circulating tumor DNA translates to significantly higher sensitivity,” Tabrizi, attending radiation oncologist at Mass General Cancer Center, researcher at the Broad Institute Gerstner Center for Cancer Diagnostics and the Koch Institute at MIT, told Targeted Oncology^TM, in an interview.

In an interview, Tabrizi discussed the development of a 2-part priming strategy aimed at enhancing the sensitivity of liquid biopsies for cancer detection and monitoring.

Targeted Oncology: Can you provide an overview of your research and the rationale behind it?

Tabrizi: Liquid biopsies are a promising technology that could help us better detect and monitor cancer. The big limitation in the field is that for many clinical applications, they are just not sensitive enough. In a lot of patients who still have cancer in their body, the tests come back negative. We were thinking of ways of overcoming this limitation and we took inspiration from the use of injectable contrast agents, like iodine and gadolinium, that we already use in CT and MRI scans. We thought, what if we could develop a similar agent, but for liquid biopsy diagnostics, that could boost the sensitivity of these diagnostics in relevant clinical situations? We thought, perhaps we could develop agents that can attenuate the clearance of cell-free DNA in the body temporarily and help us recover more circulating tumor DNA from a blood draw, and hence, boost the signal.

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What is the observed improvement in ctDNA detection sensitivity with your approach compared with conventional methods?

We found with our approach that we could recover over 10 times more circulating tumor DNA from a blood draw compared with before. Now, these are all experiments that were done in preclinical models of cancer as these are brand new agents, but this improved recovery of circulating tumor DNA translates to significantly higher sensitivity, especially in situations where the tumor DNA level is very low at baseline.

How does your approach compare with other emerging methods for increasing ctDNA detection?

Most of the existing approaches focus on optimizing how we can improve ctDNA detection from a sample after it has already been collected. Our method is one of the first to intervene upstream of this step by increasing the amount of ctDNA that ends up in the blood sample in the first place. The way we have been able to do that is by developing agents that can attenuate the clearance of cell-free DNA from the body, in plasma. This is a new approach that in many ways is complementary to existing approaches, and I think could open new avenues for using liquid biopsy tests.

What types of cancers have you tested this approach on? Are there any specific cancer types where it shows greater promise?

We have tested our approaches in preclinical cancer models. Models that we have used are tumors in the lung. Further testing and other models are going to be important. That is a part of our ongoing work. Because our approaches affect ctDNA that is already in the plasma, we anticipate that they should show a benefit for a wide variety of tumor types, because, again, they are working with molecules that are already in circulation in the plasma rather than affecting the release of tumor DNA from the tumor itself.

Based on your current findings, what are the next steps for translating this technology into clinical trials?

The side-effect profile of these new agents needs to be further tested rigorously in both preclinical testing and then eventually first-in-human testing. There is also further preclinical development work and optimization to go from agents that demonstrate a proof of concept to agents that can be safely tested in clinical trials. These are the next steps for getting this technology eventually to the clinic.

Do you anticipate any challenges in adapting this approach for use in humans?

Just as with any agent, I think that there is further development work and investment needed to establish safety and efficacy. This would be in preclinical settings, but then eventually in first-in-human trials, and I think that is going to be the major next step. The next hurdle, so to speak, for us is to work on ways of translating this technology to the clinic one day.

Are you exploring other strategies to further enhance ctDNA detection sensitivity beyond this primary method?

We think there are opportunities for further improvements in performance of ctDNA tests in multiple domains, both analytical improvements in downstream steps, but also in the context of our new priming strategy. We are exploring several of these approaches. For the priming strategy we are doing further follow-up work to better understand this new way to improve ctDNA recovery, to better understand the biological processes that are going on, and to get clues to potentially improve these even further.

In your opinion, what are the most significant implications of your research for early detection and monitoring of cancer?

We think that primary agents could make liquid biopsy tests more effective for the many patients whose blood samples just do not have high enough levels of ctDNA to be able to be detected by current technologies. For patients with cancer, which is my specialty, this includes a lot of critical points in cancer care, such as when we need to make a decision about whether someone needs adjuvant treatment after they have had surgery or definitive radiation, for diagnosis of early-stage or indeterminant lesions that are found in imaging scans, and for early detection of recurrence after a patient has completed cancer treatments. All of those are potential situations where this added boost in sensitivity could make a difference.

What should other oncologists know about this research?

I want to emphasize that this work leverages a truly multidisciplinary team involving people with expertise in bioengineering, next generation sequencing, protein engineering, nanotechnology, and disease modeling, as well as clinicians. I think for liquid biopsies and cancer diagnostics in general, this sort of multidisciplinary approach is going to be critical for developing the most promising technologies in the lab, and then getting them to patients. I am excited about this work and I think it is a great way and a great model for how we can push the needle on these technologies.

REFERENCE

Martin-Alonso C, Tabrizi S, Xiong K, et al. Priming agents transiently reduce the clearance of cell-free DNA to improve liquid biopsies. Science. 2024;383(6680):eadf2341. doi:10.1126/science.adf2341