• Research

    Guidance Needed on PDL1-Inhibitors

Immunotherapy is a dynamic area of cancer treatment. But while it can provide new options for patients, Aaron S. Mansfield, M.D. and colleagues point out in a recent publication that more research and a cautious approach is warranted, especially when using immunotherapy as a primary treatment.

Aaron S. Mansfield, M.D.
Aaron S. Mansfield, M.D.

While radiation and chemotherapy kill cancer cells when the immune system can’t, immunotherapy uses Y-shaped proteins called antibodies that typically attach to viruses and bacteria to mark them as immune targets. These antibodies work the same way in cancer, to prevent cancer cells from turning off immune cell production.

PDL1 Inhibitors: Unmasking Cancer
Cells have express proteins on their outer surface called the cell membrane. These proteins are a guide for immune cells: are you me, or are you not-me? Some cancer cells have a protein called PDL1 expressed on their membrane. This PDL1 interacts with a PD1 protein on the cell membrane of immune cells. When PD1 and PDL1 link, the immune sentinels think the cancer cell is a normal cell. But by blocking the PDL1 protein on the cancer cell or the PD1 protein on the immune cell, the immune system begins to recognize the cancer and clear it away in a subset of patients.

“Immunotherapy is moving to the front line treatment of lung cancer for a subset of patients,” says Dr. Mansfield. “And that makes our work even more critical. But what we’ve done with our research is poke a hole in the use of PDL1 to select patients. We need a better biomarker than PDL1.”

It’s a new therapy, and the Food and Drug Administration is expanding how it can be used almost monthly. That’s great for cancer treatment in the future, but it poses a dilemma for physicians in the present. Dr. Mansfield and colleagues at Mayo Clinic knew PDL1 in the lab could have variable expression, but they did not have clinical evidence. So they set out to get some by looking at expression of PDL1 in paired biopsies from the same patient but at different time points.

“In lung cancer, unfortunately, a lot of patients develop metastases to the brain,” says Dr. Mansfield. “And when that occurs after their primary diagnosis but they only have one or two lesions in the brain, our neurosurgeons will often remove the lesions.”

Measuring PDL1 Expression
Dr. Mansfield and team were able to identify 73 patients with both primary lung tumors and metastatic lesions in the brain. Some were found only a few months apart from one another, but others were years apart. With these samples the team was able to ask, was expression of PDL1 the same between these paired lesions from the same patient or not?

It was not.

“PDL1 comes, it goes, it’s expressed here but not there,” says Dr. Mansfield. “And based on how you assess its expression, you may miss patients who may benefit from immunotherapy.”

PDL1 can vary based on the size of the biopsy, the specific lesion in question, the time between tests, and the therapies the patient has already undergone. “But currently there’s no guidance as to what size of biopsy is required, what lesion you should look at to determine who should get one of these drugs or another,” says Dr. Mansfield.

Dr. Mansfield and his colleagues Haidong Dong, M.D., Ph.D., and Roxana Dronca, M.D., are working to identify other biomarkers to predict who will benefit from PD1- or PDL1-inhibitors. They are also engaged with the Biomarker Discovery program within the Mayo Clinic’s Center for Individualized Medicine. This project works to discover new biomarkers that will aid in predicting the course of disease.

“There’s more work that needs to be done,” says Dr. Mansfield. “This is one step of many.”

- Sara Tiner, November 10, 2016