Data from GD2-Targeting CAR T-cell Therapy for Patients with GD2<sup>+</sup> Medulloblastoma

Abstract

<div>AbstractPurpose:<p>Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects.</p>Experimental Design:<p>GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In <i>in vitro</i> and <i>in vivo</i> models, GD2<sup>+</sup> MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9.</p>Results:<p>GD2 was expressed in 82.68% of MB tumors. The SHH and G3–G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In <i>in vitro</i> coculture assays, CAR.GD2 T cells were able to kill GD2<sup>+</sup> MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2<sup>dim</sup>MB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood–brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells.</p>Conclusions:<p>Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients.</p></div>