Immune checkpoint blockade inhibitors have changed the treatment of cancer and have become the frontline therapy for a wide range of malignancies. Its because they perform better than the previous standard of care.
Despite the fact that less than 25% of patients benefit from these therapies, which are designed to block proteins that hinder the immune system from attacking cancer cells. In many cases, the benefit is temporary. It''s difficult to tell in a timely manner, if the treatment is effective. That kind of critical feedback can help determine whether a patient should continue the course or pursue an alternative therapy.
We don''t have an effective way of delivering that information early enough, and that''s a huge problem, according to an associate professor at Georgia Tech and Emory University. Even for patients who respond to the therapy, there will likely be a point when they develop a resistance and stop responding.
So Kwong and his team have developed a variety of synthetic biosensors that will allow a patient and doctor to quickly discover if an ICB therapy is doing well in a non-invasive urinalysis. In a study published March 3, the researchers found that the findings are positive.
When physicians wish to know if their patients are using cancer medications, they have two basic options: they can perform a biopsy, but that is invasive, and the results may take a few days. Or they can then record a CT scan, for example, and actually see the tumor. However, it may seem that the medication isn''t working for the patient.
If youre successful in activating the immune system, you''ll get a lot of immune cells into the tumor, and it will look like the tumor has grown bigger, according to Kwong. In reality, the patient is responding to the therapy.
The ICB drug activates protective T cells, which attack the tumor in large part with a deadly secretion of proteases called granzymes, a class of enzymes found in the stomach that are used to digest food. Potent stuff.
If patients are attempting to take the medication, we understand that these T cells are making proteases, and if they are not responding, these proteases are not present, so the T cells are not active, according to Kwong, the team of coulter Associate Professor Peng Qiu and top authors, Quoc D. Mac and Anirudh Sivakumar, both grad students when the study was conducted.
During ICB therapy, Kwongs lab has been experimenting and improving their synthetic biosensors for over a decade.
The sensors are connected to the ICB medication that makes its way toward the tumor environment after the injection. Upon arrival, they are activated by proteases produced by both T cells and tumor cells, which causes the release of signaling fluorescent reporters that are intended to concentrate into urine.
These signals would be diluted in blood and would be very difficult to pick up, but everything from your blood is filtered through the kidneys, according to Kwong. So when we look at the urine, we receive very concentrated signals, which increase or decrease, corresponding to whether the patients are responding or not.
A second medium of reading biosensor reporters involves artificial intelligence and machine learning techniques to identify signal patterns that differ from the various ways the drug may fail. The second part of the paper focuses mainly on this part, teasing apart two different mechanisms of intrinsic resistance.
Es are several forms of resistance, according to Kwong. A patient may be intrinsically resistant to the therapy that is, and it would never work for them. There are individuals who have acquired resistance the medication initially worked for them, but with time it stops working.
Biosensors at Kwongs are able to tell if the drug works and can discriminate between two forms of intrinsic resistance, owing to mutations in different protein coding genes.
Next we would like to develop the same biosensor approach for patients who develop resistance, according to Kwong. We endeavour to discern the patient journey in our work: the person who receives a bad diagnosis, initiates a new therapy, responds to the medication, and then three months down the road theyre no longer responding. It''s a subtle difference, but a serious issue.