Localized delivery of CAR T cells to treat children with brain tumors

From the Paulovich Lab, Translational Science and Therapeutics Division and Nicholas Vitanza Seattle Children’s Research Institute

The brain, the powerhouse of thought, is not immune to cancer development. This organ is separated from the rest of the body by a strict blood-brain barrier, limiting what can cross from the blood circulating throughout the body to the brain. This biological feature of our anatomy makes treatment of brain tumors particularly challenging. Higher doses of drugs administered into the blood can increase the ability to cross the blood-brain barrier but can also result in significant, potentially negative side effects for the patient. To circumvent the need to cross the blood-brain barrier, reservoirs or shunts are placed in the skull to access the cerebrospinal fluid (CSF) space for localized delivery of therapies to the brain and spinal cord. The Seattle Children’s team optimized a protocol for accessing ports traversing the skull for chimeric antigen receptor (CAR) T cell delivery to children with brain and spinal cord tumors which was published recently in Neoplasia and collaborated with researchers at Fred Hutchinson Cancer Center to perform a limited cohort B7-H3 CAR T cell clinical trial, published in Cancer Discovery.

A malignant brainstem tumor called diffuse intrinsic pontine glioma (DIPG) is a lethal cancer that affects more than 300 children in the United States each year. The treatment plan for these children begins with focal radiotherapy but this only increases survival by an average of 3 months. Advancements in CAR T cell technology present a new therapeutic option for these children and local administration of this therapy to the CSF appears to limit toxicities due to high-dose, systemic delivery. “Thanks to years of planning by Drs. Mike Jensen and Julie Park, Seattle Children’s has implemented a platform to deliver targeted immunotherapy to children who otherwise have very limited or no other treatment options,” commented Dr. Nicholas Vitanza, an Associate Professor and Laboratory PI at Seattle Children’s Ben Towne Center for Childhood Cancer Research.

Advancements in CAR T cell delivery and B7-H3 targeting enabled researchers to conduct an exploratory clinical trial to evaluate B7-H3 CAR T cell therapy for children with brainstem tumors.
Advancements in CAR T cell delivery and B7-H3 targeting enabled researchers to conduct an exploratory clinical trial to evaluate B7-H3 CAR T cell therapy for children with brainstem tumors. Illustration by Katie Vicari

The DIPG tumors have an abundance of B7-H3 glycoprotein decorating the outside of cancer cells that is not found on cells of the normal central nervous system. Other studies have demonstrated the anti-tumor potency of monoclonal antibodies that bind the B7-H3 cell surface protein and recruit immune cells. The collaborating researchers from Seattle Children’s reasoned that engineering T cells to bind the B7-H3 protein (B7-H3 CAR T cells) on the surface of tumor cells could provide a new therapeutic avenue, leading to the first clinical trial of B7-H3 CAR T cell therapy for children with brain tumors. “Our Cancer Discovery article is a genuinely translational report showing that B7-H3 CAR T cells are preclinically effective against [central nervous system] CNS tumors, how a first-in-human trial was designed, and the experience of the first 3 children with DIPG to receive repeated, intracranial B7-H3 CAR T cell dosing,” stated Dr. Vitanza. The B7-H3 CAR T cell therapy reduced the tumor size by about 19% and improved facial nerve palsy for one child who entered the clinical trial immediately following diagnosis. Two other children who were enrolled after initial progression of their cancer, ultimately exhibited increased tumor bulk with cell infiltration after approximately 6 months on the study.

Testing of the CSF samples collected from accessing the port placed in the skull revealed increased cytokine abundance, consistent with immune activation and may signify that the increased tumor bulk and cell infiltration observed for the two children could be due to immune cell recruitment to the tumors. Blood samples taken from the patients did not show signs of systemic immune activation, providing evidence that immune activation is localized to the brain and spinal cord. Additionally, “targeted mass spectrometry from CSF biospecimens was performed by the Hutch’s Paulovich lab and showed that the CAR T cells effect immunoregulatory proteins in the CNS,” commented Dr. Vitanza. The most notable markers included indicators of macrophage maturation and immune cell recruitment, again consistent with immune cell infiltration into the tumors.

These findings from the limited cohort clinical trial demonstrated the capability of intracranial CAR T cell delivery and feasibility of evaluating localized and systemic responses to treatment. However, a common concern with this therapy regimen and others that require frequent access of the port traversing the skull, is infection of the port. “In our Neoplasia article, our excellent partnership with our neurosurgery team helped us characterize the intracranial delivery system and the safety of outpatient, intracranial CAR T cells for children,” explained Dr. Vitanza. The group of researchers administered 307 CAR T cell infusions through Ommaya or shunt reservoirs for 41 patients spanning cohorts from three independent clinical trials for children with brain tumors. The infusions were well tolerated by the patients and no infections were observed. “The procedure we outline is a roadmap for other institutions so these types of treatment options can be available in more places around the country and even globally,” stated Dr. Vitanza.

For the B7-H3 CAR T cell therapy, “we hope to validate these findings in a larger group of patients,” said Dr. Vitanza. This clinical trial showed the feasibility of using mass spectrometry to monitor changes in protein abundance from CSF samples, highlighting an increase in proteins involved in immune cell activation following B7-H3 CAR T cell therapy. Going forward, the researchers will work to “design a panel of proteins that could signal early treatment response, or failure,” added Dr. Vitanza, which would “better describe tumor evolution for potential combinatorial therapies in the future.”

Dr. Vitanza emphasized the collaborative effort that led to these findings, “these publications represent years of work by a large, innovative, dedicated team led by Drs. Mike Jensen, Julie Park, and Rebecca Gardner and by dozens of people across diverse teams preclinically, in research/development, and on the clinical front in the hospital have really come together to make our BrainChild platform of intracranial CAR T cell trials a success. It is a privilege to represent this group and provide care to our brave patients.”

The spotlighted research was funded by Cookies for Kid’s Cancer Young Investigator Grant, DIPG All-In, Matthew Larson Research Grant, Alex’s Lemonade Stand Foundation for Childhood Cancer, National Center for Advancing Translational Sciences, National Cancer Institute, and St. Baldrick’s Stand Up To Cancer Dream Team Translational Cancer Research Grants.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Nicholas Vitanza and Amanda Paulovich contributed to this work.

B7-H3 clinical trial:
Vitanza NA, Wilson AL, Huang W, Seidel K, Brown C, Gustafson JA, Yokoyama JK, Johnson AJ, Baxter BA, Koning RW, Reid AN, Meechan M, Biery MC, Myers C, Rawlings-Rhea SD, Albert CM, Browd SR, Hauptman JS, Lee A, Ojemann JG, Berens ME, Dun MD, Foster JB, Crotty EE, Leary SES, Cole BL, Perez FA, Wright JN, Orentas RJ, Chour T, Newell EW, Whiteaker JR, Zhao L, Paulovich AG, Pinto N, Gust J, Gardner RA, Jensen MC, Park JR. 2023. Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety. Cancer Discov. 13(1):114-131.

Clinical procedure for port access:
Vitanza NA, Ronsley R, Choe M, Henson C, Breedt M, Barrios-Anderson A, Wein A, Brown C, Beebe A, Kong A, Kirkey D, Lee BM, Leary SES, Crotty EE, Hoeppner C, Holtzclaw S, Wilson AL, Gustafson JA, Foster JB, Iliff JJ, Goldstein HE, Browd SR, Lee A, Ojemann JG, Pinto N, Gust J, Gardner RA, Jensen MC, Hauptman JS, Park JR. 2023. Locoregional CAR T cells for children with CNS tumors: Clinical procedure and catheter safety. Neoplasia. 36:100870.