Three case reports published in the New England Journal of Medicine demonstrate the promise of cancer immunotherapy in gray zone lymphoma, a rare subtype that mixes characteristics of Hodgkin and Non–Hodgkin forms of the disease. In one case from the University of Colorado Cancer Center using nivolumab and two from the National Institutes of Health using pembrolizumab, treatment with immune therapy “checkpoint inhibitors” followed unsuccessful therapies and was based on clinicians’ ability to match the mechanism of the drug with the known molecular alterations in this lymphoma. These three cases represent the first successful uses of immune therapies in gray zone lymphoma, potentially paving the way for clinical trials utilizing this strategy in this and related conditions.

Bobbie Flexer, PhD, a retired mathematics education professor from CU Boulder, had not improved after multiple rounds of chemotherapy and radiation therapy.

Genetic testing of Flexer’s tissue showed focal over–expression of the protein PD–L1. This protein displayed on a tumor cell’s surface acts as a white flag telling the immune system’s T cells not to attack. Specifically, T–cells probe other cells with their own cell–surface protein, PD–1, and it is the interaction between PD–1 and PD–L1 that can disarm the immune system against a marked cell. A major strategy of cancer immunotherapy is to block this interaction between a T cell’s PD–1 and a cancer cell’s PD–L1. If one is blinded from seeing the other, the immune system can be reactivated to attack cancer cells.

This is the strategy of nivolumab. It blocks PD–L1 from binding to PD–1 (it inhibits this checkpoint) thus removing the immune system’s blinders to cancer. The drug is approved as a first–line therapy for metastatic melanoma and has also been used to treat non–small cell lung cancer, Hodgkin disease and renal cancer. It had not previously been used against gray zone lymphoma.

“Within one dose, she was in less pain and she looked much better,” said Flexer’s oncologist, Manali Kamdar, MD, investigator at the CU Cancer Center and Clinical Director of Lymphoma Services at University of Colorado Hospital. A PET scan after six doses showed that Bobbie’s gray zone lymphoma was in complete remission.

Of course, the treatment hasn’t been without side–effects.

“When they put you on a drug at the hospital, they tell you how it’s supposed to act and they tell you all the side effects. They hand you a written sheet of what can go wrong. For nivolumab, they said think of every organ in your body – any one or more may become inflamed,” Bobbie says.

The goal of the drug is to cajole the immune system into specifically attacking a patient’s cancer. But with brakes removed, the immune system may also attack other tissues that use PD–L1 to keep themselves safe. For Bobbie, this meant two bouts of pneumonitis, an inflammation resulting from her immune system’s activation against her lungs.

“They treated it successfully with a prednisone burst each time,” Bobbie says. She also experienced an uptick in pancreas enzymes that caused high blood glucose levels. Bobbie is learning to treat that side–effect with insulin. And dietitians at University of Colorado Hospital helped her manage expected gut related side effects.

Bobbie Flexer has now been on nivolumab for over half a year. To Kamdar, the case was striking enough to warrant submitting a report to the New England Journal of Medicine. Interestingly, the editor at the journal had just received two similar case reports from the National Institutes of Health, using the related immune therapy pembrolizumab to target the condition in a nearly identical way.