P12.13.B LOCOREGIONAL BI-SPECIFIC CAR-T CELLS TARGETING CD44 AND CD133 IN RECURRENT GLIOBLASTOMA: THE FIRST IN-HUMAN CLINICAL TRIAL RESULTS

Abstract BACKGROUND Recurrent glioblastoma (rGBM) remains no standard of care exists, with a median overall survival of less than 1 year. Here, we report the pre-clinical data and the first four patients with rGBM in a phase I study of locoregionally administration of newly developed tandem CAR-T cell, targeting CD44 and CD133, armored with a modified IL7Ra intracellular domain (Tris-CAR-T). MATERIAL AND METHODS Target screening and verification were based on primary glioma stem cells, GBM patient samples, and corresponding sequencing datasets. The antitumor activity of Tris-CAR-T cells was verified in patient-derived tumor stem cells, intracranial xenograft models, GBM patient-derived xenograft models and glioblastoma organoids. Single-cell RNA sequencing and mass spectrometry were used to assess the immune phenotype of Tris-CAR-T cells. The study’s primary outcomes were safety and any adverse events associated with Tris-CAR-T administration. Secondary outcomes include the distribution and persistence of Tris-CAR-T cells, cytokine concentration, and the therapeutic effect according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria. RESULTS CD44 and CD133 are two inverse-correlated targets. Locoregionally administered Tris-CAR-T cells in vivo induced long-term tumor control with preferable safety. Patient-derived autogenous CAR-T showed robust antitumor capacity in the matched glioblastoma organoid model. All four patients had progressive disease at the time of treatment. At present, the first patient had 1 dose of 107 Tris-CAR-T cells administration, the second patient had multiple doses of 107 Tris-CAR-T cells administration, and the third and fourth patient had multiple doses of 108 Tris-CAR-T cells administration. No neurotoxicity or adverse event greater than grade 2 was observed until now. Radiographic tumor regression or suppression was observed within days after the first dose infusion. The improvement of signs and symptoms were also recorded. CONCLUSION The newly constructed Tris-CAR-T cells are capable of GBM suppression with limited side effects. The inspiring early-stage efficacy requires confirmation with subsequent doses of administration, additional patients, biospecimen investigation, and follow-up. The therapeutic response may mainly correlated with tumor burden, product quality, and dose level. ClinicalTrials.gov identifier: NCT05577091.