Anti-tumor treatment with immunotherapy has become a reality for many patients and currently, its use is being widespread to more and more cancer types. Among all immunotherapy strategies, immune checkpoint inhibitors have awakened interest in recent years, especially PD-1/PD-L1 blocking drugs, but what are these drugs?
When cells become malignant and begin to grow uncontrollably, our immune system is able to detect them and launch a series of responses aimed at destroying these first tumor cells. However, some of them express proteins in their membrane (e.g. PD-L1) that when interacting with immune cells (through their receptor called PD-1) inhibit their action. Thereby, the interaction between PD-1 and PD-L1, promotes tumor escape from immune system control and the consequent uncontrolled cell growth. Therefore, immune checkpoint inhibitor drugs are molecules that prevent such interaction (PD-1/PD-L1), thus favoring the action of our own immune system on the tumor.
Currently, to determine if a patient is a candidate for immunotherapy treatments, pathologists measure the level of PD-L1 proteins present in their biopsies. To do this, they use traditional immunohistochemistry methods and, depending on the measured amount of this protein (PD-L1), it is determined whether or not these treatments are applied. Unfortunately, this seems not to be a very effective strategy since a significant portion of the selected patients do not respond as expected. Likewise, some of the patients who would not be candidates for these treatments according to the analysis of the presence of PD-L1, improve considerably after being treated with anti PD-1 or PD-L1 therapy.
These findings highlight the lack of efficiency of the diagnostic strategies and our current ability to determine which patients are best suited for the administration of these immunotherapy treatments.
In order to improve diagnostic accuracy and move towards an increasingly personalized medicine, at FASTBASE we have developed the QF-Pro® platform, a quantitative molecular diagnostic technology that on top of quantifying the presence/absence of a marker, it does also precisely determine its functional state.
Based on QF-Pro®, we have designed a repertoire of assays that allow quantitative read-outs of the interaction level of immune checkpoints, providing a quantitative score representing the level of formation of these complexes in the patients’ biopsies. Since inhibition of the interaction of immune checkpoints is the very rationale of ICI immunotherapy treatments, these complexes (PD-1/PD-L1) that we quantify provide a key biomarker for predicting potential patients’ response to these treatments.
The first analyses of QF-Pro® in NSCLC patient samples were published in Cancer Research (Lissete Sanchez Magraner et al, 2020) and show how this technology represents a breakthrough in accuracy compared to other similar state of the art technologies. This study included 40 samples of patients with metastatic NSCLC lung tumors treated with anti-PD1 immunotherapy (nivolumab or pembrolizumab) on which QF-Pro® technology was used to understand the interaction status of PD1/PD-L1 checkpoints. As expected, the expression levels of PD-1 and PD-L1 in these biopsies did not correlate to the state of interaction between these proteins. In fact, it was observed that several of these patients, despite having high levels of PD-L1, presented low interaction between these proteins and their ligands PD-1, and vice versa.
Then, we analyzed the survival data of these patients. As expected, patients with lower QF-Pro® efficiency rate (fewer PD-1/PD-L1 complexes formed) showed a worse response to ICI treatment than those with high efficiency rates. That is, patients whose PD1 and PD-L1 receptors are active and interacting have greater survival after ICI immunotherapy treatment than those, with the same treatment guidelines, who do not have interaction between these proteins. These results demonstrate how QF-Pro® technology is an effective stratification strategy in lung cancer and opens the door to a broader study to validate its use as a common diagnostic tool in this disease.
The analysis of the level of activation of tumor markers may in principle seem logical, but it means a revolution in the field of tumor diagnosis. QF-Pro® technology can determine, more precisely than current strategies, which patients will benefit from treatment and which patients will not. This opens brand new avenues in personalized medicine and better care of patients.
All the results mentioned in this post have been published in the journal Cancer Research and you can read more at this link.