GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma.

Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE

Original Publication: Denville, NJ : The Association, c1995-

Medulloblastoma*/therapy ; Medulloblastoma*/immunology ; Medulloblastoma*/pathology ; Medulloblastoma*/genetics ; Medulloblastoma*/metabolism ; Gangliosides*/metabolism ; Gangliosides*/immunology ; Receptors, Chimeric Antigen*/immunology ; Receptors, Chimeric Antigen*/genetics ; Receptors, Chimeric Antigen*/metabolism ; Immunotherapy, Adoptive*/methods ; Immunotherapy, Adoptive*/adverse effects ; Xenograft Model Antitumor Assays*; Humans ; Animals ; Mice ; Cell Line, Tumor ; Child ; Female ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Cerebellar Neoplasms/therapy ; Cerebellar Neoplasms/immunology ; Cerebellar Neoplasms/pathology ; Cerebellar Neoplasms/metabolism ; Morpholines/pharmacology ; Male ; Child, Preschool ; Benzamides ; Biphenyl Compounds ; Pyridones

Purpose: 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.
Experimental Design: 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.
Results: 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.
Conclusions: 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.
(©2024 The Authors; Published by the American Association for Cancer Research.)

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Accelerator Award – Fondazione AIRC per la ricerca sul cancro ETS (AIRC); Special Project 5× Fondazione AIRC per la ricerca sul cancro ETS (AIRC); AIRC IG 2018 id. 21724 Fondazione AIRC per la ricerca sul cancro ETS (AIRC); MFAG 21979 Fondazione AIRC per la ricerca sul cancro ETS (AIRC); Ricerca Corrente Ministero della Salute (Italy Ministry of Health); Ricerca Corrente Ministero della Salute (Italy Ministry of Health); Grant PRIN 2017 Ministero dell'Università e della Ricerca (MUR); PRIN2020 Ministero dell'Università e della Ricerca (MUR); PRIN 2022 Ministero dell'Università e della Ricerca (MUR); CAR T RCR-2019-23669115 Ministero della Salute (Italy Ministry of Health); GR-2016-02364546 Ministero della Salute (Italy Ministry of Health); RF-2016-02364388 Ministero della Salute (Italy Ministry of Health); RF-2021-12374120 Ministero della Salute (Italy Ministry of Health); 2016 call Agenzia Italiana del Farmaco, Ministero della Salute (AIFA); Italian PNRR CN3 “ Ministero dell'Università e della Ricerca (MUR); LSH-TA Ecosistema innovativo della Salute Ministero della Salute (Italy Ministry of Health); Lazio-Innova project IMMUNO (CUP code: E82F20000200002 Regione Lazio (Lazio Region); project CARSA (CUP code: E82F20000240002 Regione Lazio (Lazio Region); Young Investigator Award in Pediatric Oncology Drug Development CureSearch for Children's Cancer (CSCC); "le risorse cellulari della vita" Associazione "Raffaele Passarelli" Onlus; ricerca medulloblastoma laboratorio di Chiara; IMI JU/T2EVOLVE with grant number 945393 European Federation of Pharmaceutical Industries and Associations (EFPIA)

0 (Gangliosides)
0 (Receptors, Chimeric Antigen)
65988-71-8 (ganglioside, GD2)
Q40W93WPE1 (tazemetostat)
0 (Morpholines)
0 (Benzamides)
0 (Biphenyl Compounds)
0 (Pyridones)

Date Created: 20240329 Date Completed: 20240603 Latest Revision: 20240724

20240726

PMC11145172

10.1158/1078-0432.CCR-23-1880

38551501