This trial on medulloblastomas was co-funded by the Enfants sans Cancer 2021 race and was selected as part of our European Fight Kids Cancer grant call.
About Medulloblastomas in Children
Medulloblastoma is the most common embryonal tumor of the central nervous system. This pathology develops in the cerebellum, which is important for motor control, balance, and certain cognitive functions such as attention and spatial learning.
Medulloblastoma is a malignant tumor that resembles embryonic tissue and is invasive. Metastases can be found throughout the entire central nervous system, as tumor cells migrate via cerebrospinal fluid. At diagnosis, nearly half of the children have metastases that are rarely symptomatic. The majority of these tumors occur before the age of 10 (40% before 5 years and 75% before 10 years), but they can also affect adolescents and young adults.
Treatment decisions are based on risk group, determined by surgical quality, presence of metastases, and intrinsic biological tumor factors. For high-risk patients, prognosis has significantly improved with therapeutic strategies including multiple courses of high-dose chemotherapy and craniospinal irradiation. However, there remains substantial room for improvement in therapies, particularly through the advancement of immunotherapy.
About Carbemed
Among the various subtypes of medulloblastomas, group 3 tumors have the poorest prognosis. These tumors are characterized by MYC oncogene amplifications, known to inhibit immune cells in the tumor microenvironment. These immune brakes are activated through various pathways, including TGF-β, a well-known cytokine in our immune system that plays a crucial role in tumor progression by regulating cell growth, tumor vascularization, and inhibiting immune cells within the tumor.
Medulloblastoma is generally described as immunologically “cold,” with low mutational burden (thus low antigenicity and immune responsiveness) and minimal immune cell infiltration. However, CAR T-cell therapy represents a potentially promising strategy for medulloblastoma.
The research team leading the CARBEMED project has identified B7H3 as a promising antigenic target in pediatric brain tumors due to its absence in normal tissues and expression in these tumors, including group 3 medulloblastomas. While CAR T-cell therapy has shown promising results in hematologic malignancies, its efficacy in solid tumors has been more limited, partly due to the presence of a highly immunosuppressive tumor microenvironment. Therefore, within CARBEMED, researchers will explore the hypothesis that a combination approach with anti-B7H3 CAR T-cells and TGF-β inhibitors could have synergistic effects to support medulloblastoma regression. Moreover, CAR T-cells will be modified to be insensitive to TGF-β inhibitory actions.
Project Progress
New anti-B7H3 CAR T-cells have been generated and tested in vitro and in vivo. They have shown short-term insensitivity to TGF-β actions and demonstrated significant efficacy in eliminating tumor cells in the cerebellum in vivo. Combination tests with TGF-beta inhibitors are currently ongoing, and optimizations have been necessary to enhance their inhibitory effects further.
About Carbemed
- Lead Investigator: Prof. John Anderson
- Program Duration: September 2022 – January 2025
- Fight Kids Cancer Funding: €500,000, including Imagine for Margo funding: €300,302
- Principal Investigator: John Anderson
