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Forging Therapies for Pediatric Patients for Whom Progress Has Stalled

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000574912.39221.e2
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Robbie G. Majzner, MD; pediatric cancer; CAR T-cell therapy; blood cancers

Robbie G. Majzner, MD; pediatric cancer; CAR T-cell therapy; blood cancers

Robbie G. Majzner, MD, is out to prove a point. And it's a potential game-changer. He wants to demonstrate that chimeric antigen receptor (CAR) T-cell therapy can be instrumental in knocking out pediatric solid tumors, just as it does in blood cancers.

“We have only seen the beginning of CAR T-cell use. Right now it is reaching only blood cancer patients who are at the end of the therapeutic line and have already been through chemotherapy. When CAR T-cell therapy is pushed up closer to frontline use—in patients who have undergone less chemotherapy and less exposure to toxicities—it will be revolutionary. I firmly believe this will also work for solid tumors,” Majzner told Oncology Times resolutely.

Successful use of CAR T cells in solid tumors is something that has been considered unlikely in some medical research circles. But pessimists take note: Majzner, an instructor in pediatric oncology at Stanford University School of Medicine, and colleagues have already had success in engineering immune cells able to attack a variety of solid tumors in mice. They published their optimistic findings in Clinical Cancer Research in January (2019 Apr 15;25(8):2560-2574).

The study provided evidence that CAR T cells can target many types of pediatric solid tumors, including brain tumors. It's a hopeful development in light of the imperative need for better treatments for children with these cancers.

“The prognosis for children with relapsed or metastatic solid tumors generally is dismal,” said Majzner. “There have been great strides for almost all other classes of patients; survival has increased with the advent of chemotherapy, radiation, and effective surgery. But in pediatric solid tumors and brain tumors, there have been few advancements for decades. Patients with metastatic and relapsed disease have been confronted by 40 years of limited success. We need to use new technologies to change outcomes and give those patients treatment options, and hope.”

Majzner, lead author of the referenced study, and his team set about making CAR T cells for pediatric brain tumors and solid tumors, including tumors found in bone and muscle. Because these cancers do not carry the same surface markers as leukemia, the investigators had to look for another marker that the CAR T cells could target.

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Search for a Target

“You need very high amounts of the target on the tumor cells, and you may need the target to be on every cell in a tumor,” Majzner said. “We really struggled to identify a good target because, while we needed something that is highly expressed on the tumor, we also needed it to be hardly expressed at all on normal tissue.”

Though traditionally it had been thought that the target could not be expressed at all in normal tissue, the investigators now believe CAR T cells may ignore the target when there are only low levels of expression.

“We've seen that demonstrated in different clinical trials.” Majzner confirmed. “We think that as long as there is a big difference between tumor and normal tissue, CAR T cells will attack the target on the tumor but may not bother to attack the target on normal tissue.

“Even in leukemia, we have disease that comes back. And in a clinical trial targeting CD22—the next-generation target after CD19—in patients who relapsed, their mechanism of relapse was with lower levels of CD22,” he detailed. “So the patient still has CAR T cells and has leukemia cells, but CARs could no longer attack the leukemia cells because they had lowered their amounts of CD22. The therapeutic window requires something that is screaming high on the tumor, and low enough on normal cells that the T cells won't attack it.”

Researchers in the published study screened 388 pediatric tumor samples for expression of a surface marker called B7-H3, which prior studies suggested might be a good candidate, according to information provided by Stanford. “B7-H3 was found on 84 percent of the samples, and it was present at high levels in 70 percent of the samples. Many types of pediatric cancer were found to express high levels of B7-H3, including Ewing sarcoma, rhabdomyosarcoma, Wilms tumor, neuroblastoma, and medulloblastoma.”

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Early Success in Mice

According to the Stanford report, “The scientists then developed six types of CAR T cells to target B7-H3 and tested them in a dish. The type of B7-H3 CAR T cells that performed best was used for further studies. The researchers tested these B7-H3 CAR T cells against several xenograft models of pediatric cancer, in which human tumors were implanted in mice. In mice with osteosarcoma or Ewing sarcoma, B7-H3 CAR T cells eradicated the tumors. The treated mice lived significantly longer than animals that received a control treatment. “The tumor just goes away,” Majzner said. “It's very consistent. It happened in all the mice, and that's exciting.”

Initial tumors were surgically removed from mice with osteosarcoma, and then the mice received B7-H3 CAR T cells to test whether the cells could treat cancer that had spread to their lungs. Again the CAR T cells worked. Additionally, when mice implanted with a pediatric brain tumor called medulloblastoma were treated, the injected B7-H3 CAR T cells crossed the blood-brain barrier and eradicated the tumors.

Majzner and colleagues are planning a series of phase I clinical trials for the B7-H3 CAR T cells, starting with adult brain tumor patients. He cautioned that the treatment may leave behind a few rare cancer cells that do not carry B7-H3, opening the door to relapse. “We're already making combination CAR T cells that combine several targets for future clinical trials,” he said.

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A Target for DIPG

In another effort, Majzner and team discovered that disialoganglioside GD2, known in many cancers, was “screaming high” on a disease called diffuse intrinsic pontine glioma (DIPG), discussed in a spring paper published in Nature Medicine. “DIPG is basically the worst diagnosis in pediatric oncology. It is a high-grade glioma in the brain stem of children typically between 4 and 10 years old. It is completely unresectable,” said Majzner, noting there has never been a positive clinical trial showing clear clinical benefit, except radiation, which is just a temporizing measure.

“We took GD2 CAR T cells and put them in mouse models of that disease and they worked very well. We did not see toxicity in our mice, even though GD2 is expressed on their normal tissue also. We think that it is because the level was lower than the threshold needed to activate the CAR T cells,” reprised Majzner.

“So we are going to open a trial,” he said, admitting with caution, “however there are certainly other risks with toxicity when generating a massive immune response in the brain—especially the brain stem. Those risks include cytokine storm, harm to normal tissue, and the chance of pressure caused by inflammation in such a closed space. Too much pressure can cause major damage to the brain, including herniation that can result in death. We call it ‘neuroanatomic toxicity,’ a new type of toxicity that we have to watch for now. This will be done very carefully in the hospital under intensive care monitoring, but because the disease is so lethal we are willing to take these risks.”

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A Look Back & Ahead

Majzner, originally from Morris Plains, N.J., is married and father to young two children. Self-described as having been “a normal kid into sports, video games, and TV,” he parlayed an intellectual capacity for science and love of people into training at Harvard Medical School, a pediatric residency at Columbia University (also his undergraduate alma mater), followed by combined fellowships at the NCI/NIH and Johns Hopkins. He followed an esteemed mentor, Crystal Mackall, MD, who had earlier been the head of the pediatric oncology branch at the NIH, to Stanford where she founded a program on cell therapy.

From there it has been full steam ahead with research efforts. “My goal is to make things in the laboratory and bring them to young patients with metastatic or relapsed solid tumors or brain tumors. Fortunately, the environment is ripe now to bring therapies rapidly to kids,” said Majzner optimistically. “Through a combination of advocacy by pediatric groups and effective legislation, there has been encouragement in the form of tax benefits for companies to bring therapies—especially for children—to fruition. Companies get a financial boost from it and there are markets for it—even in rare diseases.

He added that in the case of the B7-H3 CAR T, “The fact that the same marker exists across so many tumor types increases the chance that it could serve as the basis for a commercially viable therapy.” He explained that, while only a few hundred children in the U.S. are afflicted with each tumor, together they form a larger patient population.

“In pediatric oncology, we have stalled in our treatment of patients with metastatic and relapsed disease. I'm hopeful that cellular immunotherapy will be one of those new technologies that will change paradigms of care and improve outcomes,” said Majzner. “One therapy will not be the answer and the cure in itself, but just to start to move the needle for these patients who have had so little progress made on their behalf would be a wonderful thing.”

Valerie Neff Newitt is a contributing writer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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