Ann Houghton

Background: Medulloblastoma (MB) is the most prevalent malignant brain cancer in children under ten¹. MB is characterized by unregulated growth and proliferation of cerebellar precursor cells with metastasis to the cerebrospinal fluid. There are four subgroups (WNT, SHH, Group 3 and Group 4) that attribute their uncontrolled growth to mutations in different regulatory pathways and the presence of quiescent cancer stem cells². Current treatments, including surgical resection, radiation, and chemotherapy, show long-term pediatric toxicity with little tumor reduction^1,2,3. Treatment resistance is conferred by barriers, such as the blood-brain barrier (BBB) and the blood-tumor barrier (BTB), that prevent drug delivery and reduce immune recognition^4,5,6. Immunotherapy research highlights the use of CAR T-cells and various proteins involved in blood barrier integrity to improve targeted drug delivery⁴. These findings show potential for improving treatment efficacy in MB.

Objectives: In this narrative review, we focus on immunotherapy methods that have been tested in various treatment resistant brain tumor animal models to improve drug delivery across blood barriers.

Search Methods: An online database search was conducted in Pubmed from 2018-2026 with the key words: “medulloblastoma”, “immunotherapy”, “blood-tumor barrier”, “blood-brain barrier”.

Results: CAR T-cell therapy increases targeted drug delivery by genetically engineering T-cells to express antigen receptors specific to tumor cells. A study showed that MB tumor cells preferentially expressed GPC2 oncofetal antigen. The use of GPC2 CAR T-cells showed in vivo tumor reduction in mice along with selective homing and proliferation of T-cells in the cerebellum⁷. Other studies have identified genes involved in vascular integrity as a means of improving drug delivery to the tumor site. One study noted that in SHH MB, cancer cells expressed a mechanically activated cation channel, Piezo2, that facilitated BTB formation by sensing tissue stiffness gradients. Piezo2 knockouts showed a compromised BTB and increased immune cell response⁵. Another study showed that the Rab27 GTPase regulates vascular development and tight junctions. Double knockout mice models exhibited a hyperpermeable BBB and BTB, decreased brain vasculature, and increased lymphocyte infiltration⁶. Additionally, studies have noted that intracerebroventricular drug delivery, compared to intravenous delivery, showed less toxicity, greater tumor eradication, and increased T-cell potency and memory^7,8. Similarly, a clinical trial in 2018 used convection enhanced intratumoral delivery of a G207 oncolytic virus in 6 pediatric patients with malignancies. They noted tumor regression, treatment tolerance, and no toxicities or viremia⁹. This clinical trial is promising for the use of immunotherapies in pediatric patients and the potential in changing the standard of care for patients with brain malignancies.

Conclusion: Medulloblastoma is prevalent among pediatric CNS cancers. Current treatments are deterred by reduced drug delivery and tumor susceptibility due to the BBB and BTB. Immunotherapy enhances tumor specificity via CAR T-cell therapy and surface receptor expression. Key proteins, such as Rab 27 and Piezo2, are crucial in maintaining brain vasculature and angiogenesis and show potential for modifications. Immunotherapies and varied treatment delivery methods have shown tumor reduction in early clinical trials and may be involved in changing the standard of care for pediatric patients.

Works Cited:

1. Abdel-Rasol MA, El-Sayed WM. Advancing Medulloblastoma Treatment: Molecular Mechanisms, Drug Repurposing, and Precision Therapies. Mol Diagn Ther. 2026;30(1):75-90. doi:10.1007/s40291-025-00817-2
2. Abballe L, Spinello Z, Antonacci C, et al. Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives. Pharmaceutics. 2023;15(2):505. Published 2023 Feb 2. doi:10.3390/pharmaceutics15020505
3. Malbari F, Lindsay H. Genetics of Common Pediatric Brain Tumors. Pediatr Neurol. 2020;104:3-12. doi:10.1016/j.pediatrneurol.2019.08.004
4. Alaseem AM, Alrehaili JA. Overcoming the blood-brain barrier (BBB) in pediatric CNS tumors: immunotherapy and nanomedicine-driven strategies. Med Oncol. 2025;42(10):431. Published 2025 Aug 19. doi:10.1007/s12032-025-02984-y
5. Chen X, Momin A, Wanggou S, et al. Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity. Neuron. 2023;111(1):30-48.e14. doi:10.1016/j.neuron.2022.10.007
6. Adnani L, Meehan B, Kim M, et al. Immune cell infiltration into brain tumor microenvironment is mediated by Rab27-regulated vascular wall integrity. Sci Adv. 2025;11(21):eadr6940. doi:10.1126/sciadv.adr6940
7. Okada R, Fanuzzi M, Rodriguez C, et al. GPC2-CAR T cells have potent preclinical activity against orthotopic medulloblastoma xenografts. Mol Ther Oncol. 2025;33(4):201067. Published 2025 Sep 30. doi:10.1016/j.omton.2025.201067
8. Wang X, Huynh C, Urak R, et al. The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma. Cancer Immunol Res. 2021;9(1):75-88. doi:10.1158/2326-6066.CIR-20-0236
9. Friedman, Gregory, et al. “IMMU-08. PHASE I TRIAL (NCT02457845) SAFETY, TOLERABILITY and PRELIMINARY EFFICACY of IMMUNOVIROTHERAPY with HSV G207 in CHILDREN with PROGRESSIVE MALIGNANT SUPRATENTORIAL BRAIN TUMORS.” Neuro-Oncology, vol. 20, no. suppl_2, 1 June 2018, pp. i100–i100, https://doi.org/10.1093/neuonc/noy059.324. Accessed 1 Dec. 2025.