March 6, 2024 | A team of researchers from Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard are developing priming agents to temporarily boost levels of cell-free DNA (cfDNA) for cancer diagnostics. It’s an entirely new concept that could do for liquid biopsies what contrast agents have done for ultrasound and MRI, according to Christopher Love, Ph.D., MIT professor of chemical engineering.
“No amount of sequencing can detect what’s not in a tube of blood,” says Viktor Adalsteinsson, Ph.D., director of the Gerstner Center for Cancer Diagnostics at the Broad Institute. “That’s why we turned our attention to addressing the biology of tumor DNA in the bloodstream and finding ways to recover more from the body.”
Encouragingly, their priming agents produced orders of magnitude jumps in the amount of cfDNA recovered from the blood of tumor-bearing mice, as recently reported in Science (DOI: 10.1126/science.adf2341). Injecting the agents one to two hours before blood draws increased the amount of recovered analyte by more than 10-fold, but the amplification endured for less than 24 hours, Adalsteinsson reports. “That’s exactly what we would want when thinking about clinical translation, agents that act in the timescale of a doctor’s visit... but also have a transient effect.”
Although the potential of the priming agents was demonstrated with a single assay, he notes, the ability to obtain quantitatively higher recovery of tumor DNA from a blood draw is generalizable to many liquid biopsy tests. “We have reason to believe this will boost the performance of therapy selection tests in advanced cancer, minimal residual disease tests, and... perhaps someday as well in the early detection setting. We have high enthusiasm for the impact it could make across the cancer care continuum.”
Use of the priming agents would be a good fit with standard clinical practice where patients are routinely giving blood, adds Love. In the case of cancer, they could have a single injection about an hour before a blood draw to learn if their cancer has returned and inform their doctor of potential treatments.
The MIT and Broad Institute team has been working together on liquid biopsies for almost a decade now, but shifted its focus to include priming agents about two years ago after recognizing the limitations of sequencing technologies when samples don’t contain the information of greatest interest, says Love. His contribution to this study has revolved largely around antibody design and testing.
As Adalsteinsson explains it, the technique employed by the priming agents is to separately target the two ways the body removes circulating DNA from the blood—deoxyribonuclease (DNases), via a monoclonal antibody, and macrophages, using a dummy nanoparticle to distract them from their normal job. The rationale for the affinity reagent (antibody) is to bind and protect cfDNA from the enzymes in circulation and uptake by liver macrophages. Similarly, the idea with the decoy nanoparticle was to temporarily keep liver macrophages busy so they weren’t consuming cfDNA instead.
These priming agents reflect two drug classes—monoclonal antibodies and nanomedicines—that are well established in humans and therefore better positioned to overcome the hurdles to clinical translation. “Our goal was to come up with agents that would be familiar in medicine, and we could conceivably imagine being applied someday in humans,” says Adalsteinsson.
The priming agents developed here are agnostic to the analyte being measured by a liquid biopsy, Love says, drawing an analogy to water being held and released by a kitchen sink. The shedding of cfDNA and other analytes can be likened to water flowing through the faucet that drains normally because of the “fairly generic” degradation mechanisms (macrophages and enzymes) unless they are temporarily blocked so their concentration accumulates in the circulating blood.
Love and Adalsteinsson—together with MIT professor Sangeeta Bhatia, M.D., Ph.D.—recently cofounded Amplifyer Bio to further develop the technology and bring the priming agents to market. Todd R. Golub, M.D., director of the Broad Institute, is also a key participant in the blood biopsy work and co-founder of the company. One key next step is to see if the effects observed in the preclinical study hold in humans, and to hopefully demonstrate that the priming agents can be safely and effectively used for clinical diagnostic purposes.
The focus on monoclonal antibodies and nanoparticles, modalities that are generally regarded as safe and efficacious for the approved indications, provides a strong starting point, Adalsteinsson reiterates. The development process is therefore expected to follow the usual timelines so that results from early clinical studies in oncology begin emerging over the next two years.
The goal here is to attenuate temporarily the biology for clearing circulating DNA from the bloodstream, the possibility of which has now been demonstrated, to boost the performance of a downstream diagnostic like liquid biopsy, says Adalsteinsson. “We don’t envision reinventing the downstream tests, rather we... envision a future where liquid biopsies will be ordered with or without priming and that with priming will be able to detect what may otherwise be challenging to [find].”
Priming agents could in principle enhance liquid biopsies not only for cancer but also for neurodegenerative diseases, metabolic disorders, deep-seeded infectious diseases, and prenatal genetic testing, as well as for the detection of other scarce analytes of clinical significance, Adalsteinsson says. “Boosting circulating tumor DNA in blood is just the tip of the iceberg.”