Development of a B7-H3 nanoCAR-T cell therapy for recurrent glioblastoma (GlioCAR)

Glioblastoma (GB) is the most common primary brain tumor in adults. Despite first-line therapy, consisting of a maximal safe resection followed by concomitant radiotherapy and temozolomide followed by 6 cycles of adjuvant temozolomide, the outcome of GB patients is poor with a median progression-free survival of less than 7 months. To date, there are no treatment options to enhance the overall survival (OS) of patients with recurrent GB (rGB) following standard-of-care therapy.
Our group is conducting a clinical trial sponsored by the UZ Brussel, the GLITIPNI trial (NCT03233152), studying immune checkpoint blockade (ICB) to treat rGB patients and improve their survival. This trial is the first to combine intracerebral (IC) and intravenous (IV) delivery of PD-1 and CTLA-4 blocking monoclonal antibodies (mAbs) during surgical resection of rGB. This experimental immunotherapy proved to be safe and resulted in a prolonged OS compared to a large Belgian historical population of rGB patients. Despite this, most patients eventually progressed on therapy. Analysis of tumor samples from the GLITIPNI trial showed that high expression of B7 homolog 3 (B7-H3, CD276) correlated significantly with a shorter OS, suggesting that B7-H3 has a gate-keeping function, preventing rGB from responding to PD-1/CTLA-4 ICB.
Given these findings, we propose B7-H3 as a marker for a targeted therapy in GB patients that have tumors with high B7-H3 expression. We aim to develop and validate a GMP compliant B7-H3 targeting nanoCAR-T cell product. Herein, T cells are lentivirally transduced to express a chimeric antigen receptor (CAR) that specifically binds B7-H3 using a nanobody (Nb) as a targeting moiety. These B7-H3 nanoCAR-T cells will allow to generate a new combination treatment regimen for rGB patients, refractory to PD-1/CTLA-4 ICB. The developed GMP workflow will help accelerate transition of the B7-H3 nanoCAR-T cells to the clinic.
The project has the following hypothesis-driven aims: (1) Validate the cytolytic potential of B7-H3 nanoCAR-T cells using GB-derived cell lines with distinct B7-H3 expression levels. (2) Assess the administration route and dose levels of B7-H3 nanoCAR-T cells for optimal homing to and infiltration in GB tumors. (3) Test the functionality and activity of B7-H3 nanoCAR-T cells in a preclinical setting using xenograft mouse models and patient-derived GB cell lines that show varying levels of B7-H3 expression. (4) Combine B7-H3 nanoCAR-T cells with immune checkpoint inhibitors (ICIs) to examine their complementarity to ICB as applied in the current GLITIPNI clinical trial for rGB patients. (5) Fast track this novel B7-H3 nanoCAR-T therapy to the clinical setting via a parallel workflow focusing on GMP-production and regulations. Upon success, the proposed project will lead to the development of a new targeted therapy for rGB patients that are refractory to PD-1/CTLA-4 ICB.