A team of researchers, led by scientists at Yale and the biotech company Genentech, have completed a phase I clinical trial for a new cancer immunotherapy and developed biomarkers to predict its efficacy in patients. The trial’s results look promising for the potential to use personalized medicine and immunotherapies to treat cancer.

The drug tested in the clinical trial works by inhibiting a molecule that suppresses the immune system, preventing it from effectively identifying and destroying cancer cells. That molecule, present on many immune and cancer cells, is called programmed death-ligand 1 (PD-L1). The treatment was given to patients with lung cancer, melanoma, renal cell carcinoma and other tumors, including gastric and colorectal cancer. The results of the study were published in the journal Nature on Nov. 27.

“It shows for the first time that immunotherapy could be used in a major cancer indication outside of the expected cases like melanoma,” said one of the study’s senior authors and Vice President of Cancer Immunology at Genentech Ira Mellman GRD ’78. “This study extended this observation to many new cancers.”

Of 175 eligible patients, 18 percent exhibited complete or partial responses. These results add legitimacy to a growing field of cancer research focused on immunotherapies, drugs that either inhibit the suppression of the immune system or enhance the patient’s already existing response to the cancer.

“In many cases, as soon as you turn on the immune system to fight a tumor, you engage breaks like PD-L1. And this, in theory, is one of the main reasons why these strategies haven’t worked so well,” said Ron Winslow, deputy bureau chief of health and science at The Wall Street Journal, who also covers cancer research. “As a result, there has been some skepticism and even cynicism among oncologists until recently that this was even a viable strategy to pursue.”

The researchers developed biomarkers for responses to this treatment based on a surprising finding. Jamie Harden, a postdoctoral associate at Rockefeller University who was not involved in the study, explained that, for the treatment to be effective, it is more important that the immune cells express PD-L1 than the actual tumor cells themselves.

The expression of PD-L1 on infiltrating immune cells could then be used to screen patients for this treatment.

“We found that those patients [whose immune cells were expressing PD-L1] prior to treatment would have a significantly higher chance of responding to the treatment than those patients not expressing a marker,” said Mellman. He added that these biomarkers are readily testable by doctors.

According to Associate Director of the Yale Cancer Center and Professor of Medical Oncology and Pharmacology Roy Herbst ’84, who is also the study’s lead author, the researchers were able to develop these biomarkers by adding basic science research to a clinical study. They not only treated patients and recorded responses, but also attempted to understand the mechanisms by which the treatment worked in some patients but not others. Herbst said the development of this biomarker opens up the door for personalized treatment.

“We can know who will benefit in advance,” he said.

The study challenges the commonly held assumption that PD-L1 expression on tumor cells, not the infiltrating immune cells, would dictate the immune system’s response to the cancer. Mellman said that this crucial finding would not have been made in mouse models.

“When you study patient populations at this level of detail you get insights into how the immune system works in humans that can be significantly different from what you see in mice, and it emphasizes the important of doing basic science using humans as your organism,” Mellman said. “It’s not enough to do it in mice and try to translate it to humans. It often doesn’t work.”

Mellman said the researchers at Genentech plan to investigate why some patients did not respond to the drug and whether a combination of treatments would improve responses. Herbst said Yale researchers will continue to work with Genentech to answer those questions, and also investigate why certain patients’ tumors did not express PD-L1, and why those patients did not respond well to the treatment.

Although the results of the study and the potential for personalized medicine and combination immunotherapies are encouraging, Winslow said some caution is necessary.

“The percentage of patients who responded both overall and in the individual cancers was still a pretty small fraction, so there’s a lot of work to be done,” he said.

According to the NIH, there are approximately 800 immunotherapy drug clinical trials underway nationwide.