A recent collaboration between researchers from the Dana-Farber Cancer Institute (MA, USA) and the Yale University School of Medicine (CT, USA) has demonstrated that an experimental immunotherapy drug is most effective in patients whose immune response is initially activated against their cancer but then shut down by the molecular brake protein, PD-L1.
The findings, recently published online in Nature, demonstrate that the antibody drug MPDL3280A inhibits PD-L1, restarting the immune response. Clinical trials involving the PD-L1 inhibitor have witnessed the shrinkage of kidney, melanoma and lung tumors; however, there were also patients who saw no effect.
The researchers state that the treatment was most effective when immune cells adjacent to tumors expressed PD-L1, indicating that a pre-existing immune response has been halted by PD-L1. Conversely, patients who had not developed an immune response to the cancer had less PD-L1 in adjacent cells and subsequently had less tumor shrinkage.
“I think this is a launching point to use these findings as a predictive biomarker,” stated senior author F Stephen Hodi of the Dana-Farber Cancer Institute.
The team collected tumor samples from 175 individuals treated with MPDL3280A for advanced non-small-cell lung cancer, melanoma and kidney cancer, among others. Upon analysis, an average of 18% of patients exhibited complete or partial tumor shrinkage, with fluctuating rates observed for different cancer types. It is reported that the treatment was well tolerated, with few severe side effects.
Tumor samples that had been removed prior to treatment were marked with an antibody stain, which indicated the presence of PD-L1. This revealed that PD-L1 was present not only in the cancerous cells, but also in tumor-infiltrating immune cells (ICs).
The researchers observed greater responses to MPDL3280A in patients who had high levels of PD-L1 in their tumor cells and ICs. In addition to this, tumor samples taken during treatment had PD-L1 levels investigated. Shrunken tumors were observed to have increased PD-L1 in the cancer cells and ICs.
For MPDL3280A to be effective, the research team concluded that the patient had to have mounted an immune response that was subsequently suppressed. It is asserted that this initial response creates a target for MPDL3280A, which then inhibits PD-L1 and allows for the restarting of the immune response.
In calling for further studies to define predictors of the response to PD-L1 blockers, the researchers commented: “Understanding the profile of nonresponders will likely provide even more valuable information,” stating that these studies could potentially reveal the diversity of mechanisms controlling antitumor immunity.