Department of Pathology

Montefiore’s IHC Lab and Clinical Oncology

Teaming Up to Bring Life-Saving Immunotherapy to Cancer Patients


Drs. Changcheng Zhu, left, and Balazs Halmos

When the world learned, in the summer of 2015, that Jimmy Carter had been diagnosed with metastatic cancer, the prognosis looked grim. The melanoma had spread to the then 91-year-old former president’s brain and liver. Just months later, Mr. Carter’s doctors pronounced him cancer-free. The secret to his miraculous rebound? Treatment with radiation and an immunotherapy drug called Keytruda.

Immunotherapy, a revolutionary approach to cancer treatment, uses a new class of drugs known as checkpoint inhibitors to harness the patient’s immune system to fight tumor cells. It’s an effective alternative to conventional chemotherapy, with fewer toxic side effects. But immunotherapy doesn’t work for everyone.

Manufactured by Merck, Keytruda (pembrolizumab) has been approved by the U.S. Food and Drug Administration (FDA) as a first- and second-line treatment for non-small cell lung cancer (NSCLC), the most aggressive form of lung cancer. Doctors have also used it to successfully treat several other cancers, including melanoma.

How do clinicians decide which patients are likely to benefit from Keytruda? They rely, in part, on a diagnostic tool called the PD-L1 test. Fortunately for Montefiore oncologists and their patients, a PD-L1 test--PD-L1 IHC 22C3 pharmDx, developed by DAKO and approved by the FDA—is now available in-house through the Pathology Department’s Immunohistochemical (IHC) Laboratory. This companion test for administering Keytruda is regarded as the gold standard for PD-L1 testing. Test results are delivered within 24 to 72 hours—a time frame that can make a critical difference for patients with advanced NSCLC.

A Fruitful Collaboration

zhu-team  PD-L1 stain 
Dr. Zhu and members 
of the IHC Lab team. 
PD-L1 stain.

“Montefiore was the first and is now one of only three academic medical centers in the New York metropolitan area to offer the PD-L1 test,” notes Changcheng Zhu, MD, PhD, director of the IHC lab and an associate professor of clinical pathology at Einstein.

“We used to order the PD-L1 test through a commercial reference laboratory, but it took 10 days to get the results,” says Balazs Halmos, MD, MS, director of thoracic oncology at Montefiore and a professor of medicine and director of clinical genetics at Einstein. “The clock is ticking for these patients. Sending the test to an outside reference lab wastes tissue—and precious time. The more we can streamline the process, the better it will be for our patients.”

With this in mind, Dr. Halmos and his team reached out to Dr. Zhu’s lab in 2015 and asked if they could develop the process in-house.

“We wanted to answer the call from our oncologists,” recalls Dr. Zhu, “but it was a challenge.” To validate the test, the lab needed positive cases with known PD-L1 status, as well as negative cases, and it took time to collect them from a commercial laboratory. After a 10-month implementation process, the PD-L1 test went live at Montefiore in July 2016.

Unleashing the Immune Response

“Keytruda is a humanized monoclonal antibody that increases the immune system’s ability to help detect and fight tumor cells,” Dr. Zhu explains.
The PD-L1 test detects the percentage of PD-L1—the target antigen for Keytruda—expressed in the patient’s tumor cells. Based on the test results, the pathologist reviews the stains and assigns the patient a Tumor Proportion Score (TPS). A TPS of greater than 50% PD-L1 expression is considered positive; however, a recent clinical trial showed that even patients with a score as low as 1% can benefit.
“If you think about it logically, tumor cells should be killed by the patient’s own immune system,” says Dr. Zhu. “But tumor cells are smart. When they grow, they go undetected and suppress the patient’s immune system to prevent the immune cells from attacking them.

“PD-L1, an immune checkpoint protein, regulates the immune response by keeping cytotoxic T cells from attacking healthy tissue as well as tumor cells. Keytruda unleashes the suppressed immune reaction against the tumor cells, and kills them.

“We don’t interpret test results as either positive or negative,” he adds, “we just report the percentage of cells expressing the target as a TPS. We give this information to the oncologist. The oncologist then uses his or her judgment to assess whether or not a particular patient is a good candidate for the drug.”

The Power of Immunotherapy: Case in Point

“Patients who show evidence of the protein do much better on immunotherapy,” says Dr. Halmos. “They maintain their functionality better and experience long-term benefits.” To illustrate this point, he recounts a remarkable story: “One of our patients, a contractor and family man in his mid-40s, presented with NSCLC. Our initial treatment approach, targeted chemotherapy with detailed sequencing, was unsuccessful. Then we ran the PD-L1 test. The results showed that the patient was in the highest category of PDL expression, making him an excellent candidate for Keytruda.

“By the time he started treatment his life expectancy was measured in days. He actually ‘died’ and was resuscitated, twice. We began prepping him for hospice care when, suddenly, he started to improve. He got better and better, and has continued ever since. He’s running his business again, and he’s still receiving immunotherapy.” Dr. Halmos shared the story with a global audience, as a guest contributor to the U.S. News & World Report

Impact on Patient Care

Currently, the IHC lab performs 5 PD-L1 tests per week. That volume will be increasing, say Drs. Halmos and Zhu, because PD-L1 will soon be a reflex test—that is, instead of being requested at the discretion of an individual oncologist, it will be performed as a routine test whenever the lab receives a tissue sample with a lung cancer diagnosis.

“We don’t dismiss chemotherapy completely, but it’s better for the patient to receive something more effective and less toxic, whenever possible,” says Dr. Halmos.

“PD-L1 is not a consistent or reliable predictive biomarker to exclude patients from checkpoint inhibitor treatment,” he adds, “but it can be used to predict how well a particular patient will respond to treatment. It can also help identify patients who are candidates for more aggressive, combined treatment strategies.”

Pathology’s Critical Role

“As oncologists, we’re committed to providing our patients the best possible care,” says Dr. Halmos. “And we’re relying more and more on our colleagues in the Pathology lab as an integral part of our team.

“We’ve been lucky to work with Dr. Zhu and his staff. They’ve been incredibly responsive. They steward the tissue specimens, maintain reasonable timelines and avoid running unnecessary tests. They read the results in a way that we can trust the information. Their expert interpretation is critical.”

For some patients, immunotherapy can have a downside. As recently reported in the New York Times, certain individuals whose cancer has been arrested by checkpoint inhibitors go on to develop unexpected, severe or life-threatening reactions such as a new type of acute-onset diabetes. Still, says Dr. Halmos, he and his colleagues in the oncology field remain optimistic.

“We’re finding that patients treated with immunotherapy do much better than those receiving conventional chemotherapy,” he says. “We’re just at the dawn of this exciting new era in cancer treatment. Obviously, more research has to be done.”

“The ability to do the PD-L1 test in-house is a win-win for our clinical staff, and for our patients,” says Dr. Halmos. “Our collaboration with Dr. Zhu and his team has put Montefiore on the cutting edge of cancer treatment. I am super happy with that.”

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