Patients do not always respond, as desired, to immune checkpoint blockade (ICB) inhibitors and physicians cannot tell this quick enough. Researchers have now developed biosensors that could make it easier to determine therapy efficacy more rapidly.
Cancer Patient
The treatment of people with cancer has improved significantly since the advent of ICB inhibitors. These drugs, which check proteins that keep the immune system from destroying cancer cells, are more efficacious than the earlier standard of care. Therefore, they have become the leading therapy for a variety of malignancies.
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However, ICB inhibitors still only work on a fraction of cancer patients. It is also currently not easy for physicians to quickly tell if this treatment is working or not.
Researchers from the Georgia Institute of Technology have now produced biosensors to make therapy assessments faster. They reported this in a study that appeared early this month in Nature Biomedical Engineering.
Limited options for efficacy assessment
Physicians currently have two main options for figuring out if patients are responding to cancer medication. These are biopsy and imaging, each of which has its shortcomings.
A biopsy is an invasive procedure that many patients may find to be painful. It also does not produce quick results, with a wait time of some days.
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Imaging, on the other hand, offers a means for assessing tumor changes by taking pictures. But the images taken can often be misleading. They could, for instance, suggest that therapy is not working if the size of a tumor seems to have become bigger.
Gabe Kwong, in whose lab the new synthetic biosensors were created, explained that a bigger tumor size seen with imaging may indicate drug efficacy. Therapy can result in a large number of immune cells (T cells) being driven into the tumor, making it look larger.
Scientists call this tumor increase from therapy “pseudoprogression.”
An increased number of T cells helps to attack a tumor fiercely through the secretion of proteases known as granzymes. The presence of these enzymes, researchers thought, suggests that ICB therapy is working.
Synthetic biosensors to the rescue
Kwong’s lab is not new to synthetic biosensors. It has been developing and fine-tuning them for over 10 years.
The team created sensors capable of detecting proteases secreted by both T cells and tumors for the current study. These would be targeted at the tumor site along with the ICB drug via an injection.
When the sensors get to the targeted tumor location, they are activated by T cells and tumor cell proteases. This sets off the release of fluorescent reporters, which are expected to be concentrated in the urine.
“Basically, these signals would be diluted in blood and would be very hard to pick up, but everything from your blood gets filtered through the kidneys,” explained Kwong, an associate professor in Georgia Tech’s Wallace H. Coulter Department of Biomedical Engineering. “So when we look at the urine, we get very concentrated signals, which increase or decrease, corresponding to whether the patients are responding or not.”
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Machine learning and artificial intelligence methods would also be used to spot signal patterns that mark the diverse ways ICB inhibitors could fail.
Researchers say the biosensors will not only tell whether the drugs are working but also discern between mechanisms involved in cases of intrinsic resistance.
Kwong revealed plans to create similar biosensors for patients who later develop resistance after initially responding to treatment.
References
Mac, Q.D., Sivakumar, A., Phuengkham, H. et al. Urinary detection of early responses to checkpoint blockade and of resistance to it via protease-cleaved antibody-conjugated sensors. Nat. Biomed. Eng 6, 310–324 (2022). https://doi.org/10.1038/s41551-022-00852-y
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