Researchers ‘extraordinarily optimistic’ about potential of CAR-T for pediatric brain cancer

06 October 2021

6 minutes of reading

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Wang reports a consultant role at Javelin Oncology. Vitaza does not report any relevant financial disclosures.


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Brain and central nervous system tumors are the second most common childhood malignancy and the most common form of solid tumor, according to data from the American Cancer Society.

Brain and CNS tumors are responsible for about a quarter of childhood cancers in the US. Five-year survival varies considerably depending on the type of disease and location.

Treatment options are limited for patients with aggressive disease and for patients who are ineligible for surgery due to the location of the tumor.

Researchers hope to replicate the successes in pediatric acute lymphoblastic leukemia — one of the most common pediatric cancers — by using chimeric antigen receptor T cells to treat brain and CNS tumors. While this modality has significantly improved outcomes for patients with advanced blood cancers, the challenges of treating solid tumors with CAR-T in such sensitive sites will require new approaches.

Nicholas A. Vitanzo

Nicholas A. Vitanza, MD – pediatric neuro-oncologist and assistant professor at Seattle Children’s Hospital – is the primary investigator for the institution’s BrainChild clinical trials, investigating strategies to provide CAR T-cell therapy for the treatment of advanced and high-risk brain and CNS tumors in younger patients.

Vitanza and colleagues published an interim analysis of one trial – BrainChild-01 – investigating the use of locoregional-administered HER2-targeted CAR T cells developed at Seattle Children’s. Patients in the BrianChild studies typically have fatal disease that progresses after initial standard treatment.

“There are about 5,000 children a year with brain and spinal cord tumors. Most have malignant tumors that have recurred and have no reliable cure,” Vitanza told Healio. “There are many children who need new therapies.”

The local strategy

BrainChild-01’s primary analysis – published in Nature Medicine – included three patients (age range, 16 to 26 years) who received six to nine doses of HER2-targeted CAR T cells.

Vitanza and colleagues chose HER2 as the target antigen because it is expressed on a biologically diverse spectrum of CNS tumors, but is not expressed on normal CNS tissue.

Early results have shown no evidence of radiographic tumor regression, but the therapy may be both safe and feasible, Vitanz said.

“It’s too early to really say what the objective radiographic response is and what the effect might be on survival,” he said. “The main takeaway was that it was feasible to produce the CAR T cells and it was feasible to deliver the CAR T cells intracranially in an outpatient setting.”

Treatment is given weekly on an outpatient basis via locoregional administration directly into the cerebrospinal fluid or tumor cavity in case of excised tumors.

BrainChild-01 is the first study to report results with repeated locoregional dosing of CAR T cells for CNS tumors in younger patients, the researchers said.

“We know with brain tumors that, through animal models and adult clinical trials, intracranial local regional delivery is most likely superior to systemic delivery,” Vitanza told Healio.

Safety results from the analysis showed that all patients had manageable treatment-related side effects. They include low-grade fever, headache, pain at metastatic sites from spinal cord disease or transient worsening of neurologic abnormalities at baseline, Vitanz said. However, there were no cases of the cytokine release syndrome, typically one of the most common treatment-related effects of CAR T cell therapy.

Leo David Wang, MD, PhD, is a pediatric oncologist and assistant professor in the immuno-oncology and pediatrics departments at City of Hope. His lab is also working on ways to apply CAR T cell technology to brain and CNS tumors in younger patients.

While BrainChild-01’s results are early and have not shown tumor-reducing capabilities, there is some evidence that the approach is safe and that the CAR T cells used in the study are active, Wang said.

Leo David Wang |

“There are signs and indications of biological activity – that the CAR-T cells are doing something right. You can see that in the side effect profile, [as patients are experiencing] fever, inflammation [and] C-reactive protein levels go up,” Wang said, adding that Vitanza and colleagues performed “advanced cytokine analysis” that showed that cytokine levels fluctuated in concert with the multiple CAR-T infusion cycles.

“There [is considerable] correlative science suggesting there could be biological activity, which is great,” Wang said. “The next challenge is, how do we amplify that?”

Perhaps the most important impact of this study is to enhance the effectiveness of locoregional administration of CAR-T for brain and CNS tumors, Wang added. Many ongoing studies of cellular therapy use locoregional delivery, but some question whether this is the superior method.

Wang said earlier research by his colleague at City of Hope, Christine Brown, PhD, demonstrated in preclinical models that locoregional delivery of targeted CAR T cells for brain tumors is more effective than IV delivery at the same cell dose.

“The preclinical data are quite convincing: locoregional administration is superior to intravenous administration for brain tumors,” he said. “Many of us in the field are confident enough that we’ve switched to local delivery.”

Progress in innovation

BrainChild-02, another of three pediatric CNS and brain tumor studies conducted at Seattle Children’s, uses EGFR-specific CAR T cells to treat children and young adults with relapsed or refractory EGFR-positive CNS tumors.

Conversely, BrainChild-03 uses B7-H3-targeted CAR T cells for all patients with recurrent CNS tumors, as well as those with diffuse intrinsic pontine glioma, a typically fatal brain tumor.

Wang’s lab recently opened a clinical trial investigating the use of interleukin (IL)13R-alpha-2 targeted CAR T cells for younger patients with relapsed or refractory brain tumors.

Researchers from Texas Children’s and Stanford University are also conducting highly innovative clinical trials hoping to refine CAR T-cell therapy for children and young adults with brain or CNS tumors.

While all studies use CAR-T, each center tries to address the problem through unique approaches. As the results become available, researchers are actively sharing information to advance the pace of innovation, Wang said.

“There is tremendous excitement about CAR-T therapies for pediatric solid tumors and brain tumors in particular,” Wang said. “There are many reasons to be very optimistic about the application of this new technology to what is really a very aggressive and serious set of diseases without good therapies in the recurrent or refractory setting.”

Vitanza sees the BrainChild trials as a stepping stone to further research. Ideally, they will provide insight into which target antigens may be effective for CAR-T in pediatric brain and CNS tumors. His group is evaluating more than one antigen at a time in the current studies because, as he emphasized, one is probably not enough.

“The future of CAR T cells for childhood brain tumors will be multi-antigen targeting,” he said.

This is in contrast to the experience with CAR-T in leukemia, which typically uses a single antigenic target for a “highly clonal population” of cells, Vitanza said.

“That’s not true for brain tumors in children, especially not for malignant ones,” he said. “They are molecularly diverse and they have heterogeneity on the surface of antigen, so targeting more than one of these at the same time will be critical.”

Once Vitanza and colleagues have collected safety, feasibility and tolerability data from their current BrainChild studies, they plan to open a new trial that simultaneously targets three antigens with a novel CAR T cell therapy developed in-house.

“It’s really going to be the multi-antigen targeting approach that will help us get over a big bump with solid tumors, especially brain and spinal cord tumors,” he told Healio.

Despite current hurdles – including the immunosuppressive environment of brain and CNS tumors, and the need to refine optimal treatment delivery and dosing schedule – Wang remains hopeful about CAR-T’s potential to successfully treat young patients with these malignancies. .

“We are extremely optimistic and encouraged that at some point immunotherapy and in particular adoptive cellular therapy will be tremendously effective for pediatric solid tumors and brain tumors,” he said.

After seeing the results for CAR-T in hematologic malignancies, the enthusiasm for applying this modality to brain and CNS tumors is palpable among the research community, Wang said.

“We still have a long way to go,” he said. “To be fair, the CAR-T field for solid tumors has lagged a few years behind the CAR-T field for leukemia/lymphoma, but we’re catching up and we’re doing it very quickly.”


American Cancer Society. Types of cancer that develop in children. Last revised October 14, 2019. Available at: Access until September 29, 2021.
Vitaza NA, et al. Nat Med. 2021; doi: 10.1038/s41591-021-01404-8.

For more information:

Nicholas A. Vitanzo, can be reached at Seattle Children’s Hospital, 4800 Sand Point Way NE, MB.8.501, Seattle, WA 98105; email:

Leo David Wang, MD, PhD, can be reached at City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA 91010; email to


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