Immuno-Oncology Resource Center

Immuno-Oncology Resource Center


Healio Interviews

Disclosures: Wang reports a consultant role with Javelin Oncology. Vitanza reports no relevant financial disclosures.
October 06, 2021
6 min read

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


Healio Interviews

Disclosures: Wang reports a consultant role with Javelin Oncology. Vitanza reports no relevant financial disclosures.
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Brain and central nervous system tumors are the second most common malignancy among children and the most prevalent form of solid tumor, according to American Cancer Society data.

Brain and CNS tumors account for approximately one-quarter of childhood cancer cases in the U.S. Five-year survival rates vary considerably depending on disease type and location.

Key study takeaways.
Infographic derived from Vitanza NA, et al. Nat Med. 2021;doi:10.1038/s41591-021-01404-8.

Treatment options are limited for patients with aggressive disease and those who are not candidates for surgery due to tumor location.

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

Photo Nicholas Vitanza 2018
Nicholas A. Vitanza

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, which are exploring strategies to provide CAR T-cell therapy to treat advanced and high-risk brain and CNS tumors among younger patients.

Vitanza and colleagues published an interim analysis of one trial — BrainChild-01 — which is examining the use of locoregionally administered HER2-directed CAR T cells developed at Seattle Children’s. Patients in the BrianChild studies typically have fatal disease that progressed after initial standard treatment.

“There are about 5,000 children a year with brain and spinal cord tumors. Most have malignant tumors that recurred and don't have reliable cures,” Vitanza told Healio. “There are a lot of children in need of novel therapies.”

The local strategy

The primary analysis of BrainChild-01 — published in Nature Medicine — included three patients (age range, 16 to 26 years) who received six to nine doses of HER2-directed 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 not shown evidence of radiographic tumor regression, but the therapy may be both safe and feasible, Vitanza said.

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

The treatment is given weekly as an outpatient via locoregional administration directly into the cerebrospinal fluid or tumor cavity in case of resected tumors.

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

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

Safety results from the analysis showed all patients had manageable treatment-related adverse events. They included mild fever, headache, pain at metastatic sites of spinal cord disease or transient worsening of baseline neurologic deficits, Vitanza said. However, there were no cases of 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 departments of immuno-oncology and pediatrics at City of Hope. His lab also is working on ways to apply CAR T-cell technology to brain and CNS tumors among younger patients.

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

Leo David Wang, MD, PhD
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 adverse event profile, [as patients are experiencing] fever, inflammation [and] C-reactive protein levels are going up,” Wang said, adding that Vitanza and colleagues performed “sophisticated cytokine analysis” that demonstrated cytokine levels fluctuating in concert with the multiple CAR-T infusion cycles.

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

Perhaps the most significant impact of this research is its reinforcement of the effectiveness of locoregional administration of CAR-T for brain and CNS tumors, Wang added. Many ongoing cellular therapy trials use locoregional delivery, but some question whether it is the superior method.

Wang said previous 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 pretty convincing: locoregional delivery is superior to intravenous delivery for brain tumors,” he said. “Many of us in the field are convinced enough that we have shifted over to local delivery.”

Advancing innovation

BrainChild-02, another one of three trials for pediatric CNS and brain tumors being conducted at Seattle Children’s, is using EGFR-specific CAR T cells to treat children and young adults with relapsed or refractory EGFR-positive CNS tumors.

Conversely, BrainChild-03 is using 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 examining the use of interleukin (IL)13R-alpha-2-targeted CAR T cells for younger patients with relapsed or refractory brain tumors.

Researchers at Texas Children’s and Stanford University also are conducting highly innovative clinical trials in hopes of refining CAR T cell therapy for children and young adults with brain or CNS tumors.

Although all trials are using CAR-T, each center aims to address the problem through unique approaches. As results become available, investigators actively share information to advance the pace of innovation, Wang said.

“There's tremendous excitement about CAR-T therapies for pediatric solid tumors and, in particular, brain tumors,” Wang said. “There are many reasons to be very optimistic about the application of this novel technology to what really is a very aggressive and serious set of diseases with no good therapies in the recurrent or refractory setting.”

Vitanza views the BrainChild trials as a stepping-stone to further study. Ideally, they will provide insights 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 likely is not enough.

“The future of CAR T cells for pediatric brain tumors is going to be multi-antigen targeting,” he said.

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

“That's not true for pediatric brain tumors, certainly not the malignant ones,” he said. “They are diverse molecularly and they have surface antigen heterogeneity, so targeting more than one of these at the same time is going to be critical.”

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

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

Despite current obstacles — including the immunosuppressive environment of brain and CNS tumors, and the need to refine an optimal treatment delivery and dosing schedule — Wang remains hopeful about the potential of CAR-T to successfully treat young patients with these malignancies.

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

Having seen 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 honest, the solid tumor CAR-T field has lagged behind the leukemia/lymphoma CAR-T field by a couple of years, but we're playing catch up and we're doing it very quickly.”


American Cancer Society. Types of cancer that develop in children. Last revised Oct. 14, 2019. Available at: Accessed Sept. 29, 2021.
Vitanza NA, et al. Nat Med. 2021;doi:10.1038/s41591-021-01404-8.

For more information:

Nicholas A. Vitanza, 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