The laboratory of F. Stephen Hodi, MD of Dana-Farber, discovered a possible reason for the less than hoped clinical response of cancer patients involved in a recent trial for MPDL3280A, an immunotherapy drug. It is possible that only patients with tumors expressing programmed death-ligand 1 (PD-L1), a protein that inhibits immune killer T-cells, benefit from MPDL3280A.
As senior author of the team’s paper, “Predictive Correlates of Response to the Anti-PD-L1 Antibody MPDL3280A in Cancer Patients,” published in Nature, Dr. Hodi explained how the findings have implications for not only treating patients but also predicting. “I think this is a launching point to use these findings as a predictive biomarker,” said Dr. Hodi, in a news release.
The study involved tumor tissue samples from 175 patients with a range of cancers: non-small cell lung cancer, melanoma, kidney cancer, and a few others. All patients had been treated previously with MPDL3280A, and the outcome of treatment had been recorded. Of the 175 samples, 18% belonged to patients who showed a clinical response during treatment.
When pre-treatment samples were analyzed, the team discovered a high level of PD-L1 expression by tumor cells and an increased number of infiltrating immune cells in the samples from the patient responders. Piecing everything together, the authors noted, “Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1 and is re-invigorated on antibody treatment.”
Essentially, the proposed mechanism of MPDL3280A’s efficacy in shrinking tumors begins with tumor cell expression of PD-L1 that suppresses T-cell migration, proliferation, and secretion of cytotoxic mediators, preventing the immune response from fighting off the cancer. As an inhibitor of PD-L1, MPDL3280A stops T-cell inhibition, allowing the T-cells to continue their fight against cancer, but only if PD-L1 was first expressed in the area.
As a result, testing a patient for PD-L1 and identifying a positive presence of the biomarker would suggest potential efficacy of treatment, should the patient be placed on MPDL3280A. If the patient does not show high levels of PD-L1, it would be expected that MPDL3280A would not produce as much of a tumor shrinkage response. These findings thus lead to a more patient-tailored approach to cancer therapy.
