ArticleNeuro-oncology advances
A fluorescein-conjugated somatostatin receptor antagonist adapter for chimeric antigen receptor T cell therapy of meningioma.
Article in Neuro-oncology advances. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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 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. 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.
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