It was around 2010 and neurosurgeon Michael Lim, MD, was taking a patient to the operating room to remove a brain tumor. Prior to the surgery, the patient received an experimental drug to stimulate his immune system to attack his cancer, which had begun as kidney cancer and metastasized.
“I remember taking him to the OR and thinking this was going to be a routine case,” recalled Lim, now chair of the Stanford University School of Medicine’s Department of Neurosurgery.
“I took his tumor out. But when the pathology report came back, it indicated the mass was just inflammatory cells and no active cancer. And over the next months, the tumors in his body started to melt away. My interest was piqued by that finding and I became very interested in that drug.”
The drug, which became known as Opdivo, belongs to a new class of medications called checkpoint inhibitors. Although our immune systems are honed to recognize and kill developing tumors, the tumors can evade them by exploiting biological safety valves called checkpoints, which normally tamp down any overactive immune responses that could lead to autoimmune disorders or inflammation.
Lim, who trained at Stanford Medicine but was working at Johns Hopkins University School of Medicine at the time, wondered if checkpoint inhibitors might also be effective against tumors that start in the brain, like glioblastomas.
Although subsequent experiments in mice and clinical trials in patients uncovered some significant stumbling blocks, Lim said he is excited to see a way forward for patients with the devastating cancer.
“It’s clear that brain cancers are different from other types of cancers,” Lim said. “For example, we’ve found that, although all tumors suppress the immune response in the microenvironment, tumors that originate in the brain cause a global immune suppression that affects the whole body. This makes it very hard to induce an immune response to the tumor.”
Targeting the culprits behind the immune suppression — a class of cells called myeloid cells — could reverse this phenomenon, researchers believe.
Another approach focuses on reviving a kind of immune cell called a T cell that leads the charge against cancers but can become exhausted and ineffective over time.
A series of experiments in Lim’s lab suggested that combining a checkpoint inhibitor with a molecule to combat T cell exhaustion is safe.
A study of the combo’s effect on patients confirmed the treatment’s safety and found it resulted in longer survival times for some of the participants.
“Now we’re going back to the lab bench to try to learn why some patients responded to the combination treatment and some didn’t,” Lim said. “We hope to go on to a larger clinical trial. There’s so much amazing science here at Stanford — we’re able to go from the bench to bedside and back to the bench to solve these problems.”
Lim and his colleagues hope to one day see outcomes for glioblastoma patients that are similar to those experienced by patients with metastatic brain cancer.
“Glioblastoma is such a malignant disease. I’ve treated hundreds of these patients, and every conversation I’ve had with them fueled me to try to do better for them. Each one gives me a new sense of urgency,” he said.
“Right now, we are understanding cancer at a level we’ve never achieved before. As we learn how to assess a patient’s tumor, we can become more and more precise with the therapies we can offer. We’re not just wielding blunt tools anymore. I’m optimistic and excited about the future for these patients.”