Abstract B095: Targeting B Lymphocytes to Improve Therapeutic Outcomes for Pediatric Medulloblastoma

Abstract Group 3 Medulloblastoma (G3MB) is a pediatric brain cancer with poor prognosis, and a median 5-year overall survival of 45-58% in infants and young children, respectively. Moreover, the current standard-of-care therapy – which includes spinal radiation – causes tremendous morbidity. While immunotherapy with immune checkpoint blockade has transformed the treatment of many malignancies, it has yet to show benefit in the most common form pediatric brain tumors. Here we show that B cell depletion using Rituximab; anti-CD20: -- an FDA-approved antibody -- enhances anti-tumor immunity, promote tumor regression and improves overall survival of mice bearing orthotopic murine models of G3MB. By analyzing of human MB transcriptomics datasets, we discovered that pediatric MB patients with elevated B cell signatures have significantly reduced survival rates compared to signatures of other immune cell populations. Using immunohistochemistry and transcriptomic analysis of orthotopic murine models of G3MB, we found that intratumoral B cells are immunosuppressive – they directly inhibit anti-tumor CD8 T cells and reprogram the tumor microenvironment to an immunosuppressive milieu. Furthermore, systemic B cell depletion using murine equivalents of the FDA approved B cell depleting antibody (Rituximab; anti-CD20: 100µg/dose) significantly enhanced animal survival, and improved T cell infiltration and activation – estimated by flow cytometry and single cell RNA-sequencing. Furthermore, systemic B cell depletion enhanced the therapeutic efficacy of murine equivalents of standard-of-care radiation therapy (20.7Gy to tumor bed) and synergized with fractionated low-dose radiation therapy (1.81Gy x 6 daily doses) – which is likely to be less toxic to the developing pediatric brain. Finally, our mechanistic studies done revealed that tumor - derived placental growth factor (PlGF) reprograms B cells toward an immunosuppressive phenotype, characterized by increased IL-10 expression and suppression of CD8+ T cell function. These findings also suggest a potential benefit of anti-PlGF antibody treatment of MB in patient-derived models and its safe use in patients (Snuderl et al, Cell 2013; Sulnier-Sholler et al. Clinical Cancer Research 2022). In conclusion, our findings suggest that targeting B cells systemically represents a promising therapeutic strategy for G3MB treatment while preserving patients’ quality of life. The availability of FDA-approved B cell-targeting drugs for pediatric malignancies offers a path for rapid clinical translation, particularly crucial for this devastating disease. Citation Format: Ashwin S Kumar, Taylor P Uccello, Igor L Gomes dos Santos, Vasiliki Salameti, Sophie C Steinbuch, Sonu Subudhi, Rakesh K Jain. Targeting B Lymphocytes to Improve Therapeutic Outcomes for Pediatric Medulloblastoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B095.