Investigators lead first human trials of new immunotherapy drug


PD-L1, expressed at elevated levels in many tumors, binds T cells, white blood cells that protect the body from disease. This inactivates the T cells, protecting tumor cells from immune attack. Avelumab binds to PD-L1, preventing the T cells from being turned off. Avelumab can also trigger tumor killing by natural killer (NK) cells. “You can actually have two shots on the goal,” says James L. Gulley, M.D., Ph.D., Chief, Genitourinary Malignancies Branch, who led the first human trials of avelumab. “You can block this major signal of T cells and also allow NK cells to take out the tumor cells.”

Center for Cancer Research investigators have conducted the first human trials of avelumab, an immunotherapy drug that targets the protein programmed death-ligand 1 (PD-L1). The trials were reported in The Lancet Oncology. The studies provide preliminary evidence that avelumab is safe and can prevent the growth and formation of various advanced solid tumors, including recurrent non-small cell lung cancer (NSCLC).

PD-L1, found on many tumors, binds T cells, white blood cells that protect the body from disease. This inactivates the T cells, allowing tumor cells to evade immune attack. Avelumab binds to PD-L1, preventing the T cells from being turned off so they can still attack tumor cells. Unlike existing anti-PD-1/PD-L1 immunotherapies, used in melanoma and NSCLC, high concentrations of avelumab bound to PD-L1 on tumor cells can trigger natural killer (NK) cells to destroy them - a double whammy.  But disease-fighting immune cells can also express PD-L1, raising the question of whether avelumab spurs NK cells to destroy them, too.

A team led by James L. Gulley, M.D., Ph.D., Chief, Genitourinary Malignancies Branch, and Jeffrey Schlom, Ph.D., Chief, Laboratory of Tumor Immunology and Biology, tested avelumab’s safety in an initial dose escalation study. This type of study starts with a group of patients that get treated with a very low dose. Once it’s shown to be safe, the next group of patients receives a higher dose, and so on.

Out of 53 patients in this study, four had a partial response, or at least 30 percent tumor shrinkage. The disease stabilized in 30 patients, meaning their tumors changed little in size, and no new tumors appeared. The number of PD-L1-expressing immune cells didn’t change significantly, indicating avelumab does not lead to destruction of immune cells.

In a separate study, Gulley and colleagues treated 184 patients whose NSCLC had relapsed after chemotherapy to test avelumab in recurrent NSCLC, for which few treatment options exist. The study provides preliminary evidence that avelumab can also prevent tumors from growing and forming in recurrent NSCLC.  Twenty-one patients had a partial response, and one patient had a complete disappearance of a detectable tumor. The disease stabilized in 70 patients.  Based on these trials, avelumab seems like a promising agent for several types of advanced solid tumors. Ongoing phase III trials will examine the clinical activity of this agent more throughly.

Summary Posted: 04/2017