American Association for Cancer Research
10780432ccr200357-sup-236387_3_supp_6499398_qf1khx.avi (1.54 MB)

Suppl. Video 1 from CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes

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posted on 2023-03-31, 22:08 authored by Valeria Leuci, Chiara Donini, Giovanni Grignani, Ramona Rotolo, Giulia Mesiano, Erika Fiorino, Loretta Gammaitoni, Lorenzo D'Ambrosio, Alessandra Merlini, Elisa Landoni, Enzo Medico, Sonia Capellero, Lidia Giraudo, Giulia Cattaneo, Ilenia Iaia, Ymera Pignochino, Marco Basiricò, Elisa Vigna, Alberto Pisacane, Franca Fagioli, Soldano Ferrone, Massimo Aglietta, Gianpietro Dotti, Dario Sangiolo



Associazione Italiana Ricerca sul Cancro

Ricerca corrente Progetto





No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CAR.CIK) are effective in eliminating tumor cells derived from multiple STS histotypes in vitro and in immunodeficient mice. The experimental platform included patient-derived CAR.CIK and cell lines established from multiple STS histotypes. CAR.CIK were transduced with a retroviral vector encoding second-generation CSPG4-specific CAR (CSPG4-CAR) with 4-1BB costimulation. The functional activity of CSPG4-CAR.CIK was explored in vitro, in two- and three-dimensional STS cultures, and in three in vivo STS xenograft models. CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by in silico analysis and on all 16 STS cell lines tested by flow cytometry. CSPG4-CAR.CIK displayed superior in vitro cytolytic activity against multiple STS histotypes as compared with paired unmodified control CIK. CSPG4-CAR.CIK also showed strong antitumor activity against STS spheroids; this effect was associated with tumor recruitment, infiltration, and matrix penetration. CSPG4-CAR.CIK significantly delayed or reversed tumor growth in vivo in three STS xenograft models (leiomyosarcoma, undifferentiated pleomorphic sarcoma, and fibrosarcoma). Tumor growth inhibition persisted for up to 2 weeks following the last administration of CSPG4-CAR.CIK. This study has shown that CSPG4-CAR.CIK effectively targets multiple STS histotypes in vitro and in immunodeficient mice. These results provide a strong rationale to translate the novel strategy we have developed into a clinical setting.

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