Liquid biopsy offers ‘meaningful approach’ to understanding CAR-T
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Key takeaways:
- Liquid biopsy identified CAR T cells with superior sensitivity compared with traditional DNA testing.
- Liquid biopsy could help answer questions regarding CAR-T success and toxicity in the future.
Liquid biopsy could provide enhanced information about chimeric antigen receptor T-cell therapy compared with normally used DNA, RNA and protein assays, according to findings published in Journal for ImmunoTherapy of Cancer.
Researchers said liquid biopsy could measure quality and quantity of the cells in patients as opposed to just their presence, and that information may be used to define the impact of CAR-T on cancer as well as its connection to treatment-related toxicities.
“The questions that the therapeutic developers are asking are, what happens to these cells when I inject a bolus of these cells into the patient?” Peter Kuhn, PhD, founding member of the USC Michelson Center for Convergent Bioscience and director of the Convergent Science Institute in Cancer at USC, told Healio.
“What happens in the first hour? In the first 24 hours? In the first 7 days? What happens in the first 3 months? How many of these cells live in the body over a long period of time? Do they start changing as well? Why does that matter?,” he continued, adding “This is a meaningful approach to monitor CAR T-cell therapy.”
‘Much deeper insights’
CAR-T has been approved for treatment of hematologic malignancies, and many studies are exploring their efficacy in treating other cancers and diseases.
The rapid expansion has caused a need for deeper understanding of the therapy — particularly its long-lasting effects.
“CAR-T has traditionally been monitored with just a [polymerase chain reaction]-based approach. The problem with that is when you do that, you just have a bulk measure[ment],” Kuhn said.
“That seemed OK in the beginning of this whole CAR-T world, but it doesn't enable you to study that CAR-T product as it persists over time,” he added. “We are demonstrating that we can find the actual CAR T cell and we can characterize them at the single-cell level. We get a much higher complexity readout and, with that, much deeper insights.”
Researchers detected, on average, one cell in 3 million with a 91% sensitivity using liquid biopsy, or one in a milliliter of blood, Kuhn said.
“Traditionally, you would characterize the cancer by bone marrow sampling and blood sampling, but with methods that would have sensitivities in the one in 10,000 to one in 1,000 ranges because that was good enough to diagnose the disease and monitor treatment efficacy,” he said.
Kuhn described the difference with a produce analogy: In a picture of a bowl of fruit, almost anyone can identify an apple, banana or kiwi. But make a smoothie, and detecting the individual flavors is much more difficult — liquid biopsy can do that, he said.
“We really need to get deeper insights into the CAR T cells as a functional unit and not just into one piece of DNA,” he said.
‘A not-to-distant future’
Kuhn hopes liquid biopsy can help characterize which patients respond well to CAR-T, allowing clinicians to change treatments for those who are not improving. Additionally, tracking CAR T cells could identify toxicity clusters, which patients are affected and why.
“In a not-too-distant future — without sounding too sci-fi-ish here — the CAR-T won’t work in 100% of patients, but I want to know which patient it is going to work with, the likelihood it will work, and then monitor it to figure out whether I was right or wrong,” Kuhn said. “If I was wrong and it’s not working, then I want to switch, and I want to switch by either adapting the CAR-T approach to a different CAR-T construct, or by switching to a different therapeutic approach altogether. That is what this technology allows us to do.”
Kuhn noted his team plans on working with Carl H. June, MD, Richard W. Vague professor in immunotherapy and director of the Center for Cellular Immunotherapies at Perelman School of Medicine at University of Pennsylvania, and Saul J. Priceman, PhD, associate professor in the department of hematology and hematopoietic cell transplantation and associate director of translational sciences and technologies in the T Cell Therapeutics Research Laboratories at City of Hope, to further examine the capabilities of liquid biopsy.
“[If we are] going alongside clinical trials and figuring out whether we are simply an aid to that science and we just need to answer the scientific questions within these clinical trials and then we bow out, that’s great stuff,” Kuhn said. “If, on the flip side, in these clinical trials we learn that we actually need to do this for CAR-T to be successfully deployed in the clinic and run alongside, then we also know how to get this test out into centralized laboratories to make it available to everybody.”
For more information:
Peter Kuhn, PhD, can be reached at pkuhn@usc.edu.
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