journal contribution
posted on 2024-06-03, 07:20 authored by Roselia Ciccone, Concetta Quintarelli, Antonio Camera, Michele Pezzella, Simona Caruso, Simona Manni, Alessio Ottaviani, Marika Guercio, Francesca Del Bufalo, Maria Cecilia Quadraccia, Domenico Orlando, Stefano Di Cecca, Matilde Sinibaldi, Mariasole Aurigemma, Laura Iaffaldano, Andrea Sarcinelli, Maria Luisa D'Amore, Manuela Ceccarelli, Francesca Nazio, Veronica Marabitti, Ezio Giorda, Marco Pezzullo, Cristiano De Stefanis, Andrea Carai, Sabrina Rossi, Rita Alaggio, Giada Del Baldo, Marco Becilli, Angela Mastronuzzi, Biagio De Angelis, Franco Locatelli Supplemental Figure 10. In vivo experiment of NSG mice bearing D283 Med-GFP-FF-Luc cells treated with NT or CAR.GD2 T-cells.
Funding
Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
Ministero della Salute (Italy Ministry of Health)
Ministero dell'Università e della Ricerca (MUR)
Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
Regione Lazio (Lazio Region)
CureSearch for Children's Cancer (CSCC)
Associazione "Raffaele Passarelli" Onlus
laboratorio di Chiara
European Federation of Pharmaceutical Industries and Associations (EFPIA)
History
ARTICLE ABSTRACT
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.
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 in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9.
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 in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB 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.
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.
