Immune checkpoint blockade (ICB) inhibitors have transformed cancer treatment and have become the first-line treatment for a wide range of malignancies. This is because they work better than the previous standard of care.
Yet less than 25% of patients benefit from these drugs, which are designed to block proteins that prevent the immune system from attacking cancer cells. And in many cases, this benefit is temporary. Added to all of this is the difficulty of telling, in a timely manner, whether the treatment is working. This type of critical feedback can determine whether a patient should stay the course or switch to an alternative therapy.
We don’t have an effective way to provide that information early enough, and that’s a big problem. Another problem is that even for patients who respond to therapy, there will likely come a time when they develop resistance and stop responding.”
Gabe Kwong, Associate Professor, Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University
Kwong and his team have therefore developed a system of synthetic biosensors that will allow a patient and a doctor to quickly know if an ICB therapy is working through non-invasive urinalysis. The research team shared their work in a study published March 3 in the journal Nature Biomedical Engineering.
Generally, when doctors want to know if their patients are responding to cancer drugs, they have two basic options: they can perform a biopsy, but this is invasive, can be painful, and results can take a few days. Or they can take pictures -; a scanner, for example -; and actually look at the tumor. But imaging can be misleading when monitoring immunotherapies. For example, if the tumor appears to have grown, it may appear that the medication is not working for the patient.
“But if you’re successful in activating the immune system, you’re going to get a flood of immune cells into the tumor, and it looks like the tumor has grown,” Kwong said. “In reality, the patient responds to the therapy.”
This is called the “pseudo progression” of the disease. By blocking the activity of these hostile proteins, the ICB drug activates protective T cells, which attack the tumor en masse. The T cells kill it with a deadly secretion of proteases called granzymes, which are part of the same class of enzymes found in the stomach that are used to digest food. Powerful stuff.
“We thought that if the patients are responding to the drug, that means those T cells are making proteases, and if they don’t respond, those proteases aren’t there, so the T cells aren’t active,” Kwong said. , whose collaborators included Associate Professor Coulter Peng Qiu and lead authors Quoc D. Mac and Anirudh Sivakumar, both graduate students when the study was conducted.
Kwong’s lab has been manufacturing and improving its synthetic biosensors for more than a decade. For this study, they developed sensors to detect both T cells and tumor proteases (tumors also secrete a type of protease) during ICB treatment.
The sensors are attached to the ICB drug which travels to the tumor environment after injection. Upon reaching their destination, the sensors are activated by proteases produced by both T cells and tumor cells, triggering the release of fluorescent signaling reporters designed to concentrate in urine.
“Basically, these signals would be diluted in the blood and would be very difficult to pick up, but whatever is in your blood is filtered out by the kidneys,” Kwong said. “So when we look at urine, we get very concentrated signals, which increase or decrease depending on whether patients are responding or not.”
A second way to read biosensor reporters involves artificial intelligence and machine learning techniques to identify signal patterns that distinguish between different ways the drug may fail. The second part of the article mainly focuses on this part, distinguishing between two different mechanisms of intrinsic resistance.
“There are several versions of the resistance,” Kwong said. “A patient can be inherently resistant to therapy – that is, it would never work for them. And there are patients who have acquired resistance – the drug worked for them first, but over time it stops working.”
Kwong’s biosensors can indicate whether the drug is working and can discriminate between two intrinsic resistance mechanisms -; both due to mutations in different protein-coding genes.
“We would then like to develop the same biosensor approach for patients who acquire resistance,” Kwong said. “We try to think about the patient journey in our work: the person who gets the wrong diagnosis, starts a new treatment, responds to the medication, and then three months later they’re not responding. It’s a subtle difference, but a big problem.”