A Fluorescein-Conjugated Somatostatin Receptor Antagonist Adapter for Chimeric Antigen Receptor T Cell Therapy of Meningioma.

Background:A significant proportion of meningiomas are resistant to current treatments. Somatostatin receptor 2 (SSTR2) is highly and consistently expressed in most meningiomas, providing a promising target for localized chimeric antigen receptor (CAR)-T cell therapy. Short-lived small-molecule CAR adapters can potentially prevent CAR-T cell exhaustion in solid tumors by alternating between active and resting states. Methods:We developed the CAR adapter peptide Octofluo, which combines fluorescein-5-isothiocyanate (FITC) with a high-avidity SSTR2 antagonist. After determining its biodistribution, killing efficiency of CAR-T cells plus Octofluo against human meningioma was evaluated in vitro and ex vivo. Therapeutic capacity was assessed in vivo against xenograft and syngeneic genetically engineered mouse meningioma models. Results:We herein demonstrate rapid tissue diffusion and transient tumor persistence for only a few hours after intravenous administration of Octofluo, making a suitable switch for on-demand CAR-T cell activation. Nanomolar concentrations of Octofluo effectively directed FITC-specific CAR-T cells against SSTR2-expressing meningioma cells. Combined intratumoral CAR-T cell delivery and intravenous octofluo infusion at periodic intervals showed limited efficacy in an immunocompromised xenograft model but cured most mice with an intact immune system harboring highly aggressive, genetically induced higher grade meningiomas. Cures were accompanied by CAR-T cell expansion and an endogenous T cell response, suggesting a role for the host immune system in tumor elimination. Ex vivo lysis of patient-derived meningioma cells was observed. Conclusions:The combination of systemic octofluo administration and locally applied CAR-T cells is a promising strategy for future clinical development for patients with refractory meningiomas.