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

AbstractPurpose: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.Experimental Design: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.Results: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.Conclusions: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.

Journal of Experimental & Clinical Cancer Research

CSPG4 CAR-redirected Cytokine Induced Killer lymphocytes (CIK) as effective cellular immunotherapy for HLA class I defective melanoma

Article

Author: Centomo, Maria Laura ; Marchiò, Caterina ; Paruzzo, Luca ; Donini, Chiara ; Biolato, Andrea Michela ; Poletto, Stefano ; Iaia, Ilenia ; Massa, Annamaria ; Ferrone, Cristina R ; Ventin, Marco ; Berrino, Enrico ; Merlini, Alessandra ; Gammaitoni, Loretta ; Landoni, Elisa ; Picciotto, Franco ; Giraudo, Lidia ; Pisacane, Alberto ; Sangiolo, Dario ; Carnevale-Schianca, Fabrizio ; Leuci, Valeria ; Cattaneo, Giulia ; Basiricò, Marco ; Dotti, Gianpietro ; Vigna, Elisa ; Caravelli, Daniela ; Aglietta, Massimo ; Bortolot, Valentina

AbstractBackgroundEven acknowledging the game-changing results achieved in the treatment of metastatic melanoma with the use of immune checkpoint inhibitors (ICI), a large proportion of patients (40–60%) still fail to respond or relapse due to the development of resistance. Alterations in the expression of Human Leukocyte Antigen class I (HLA-I) molecules are considered to play a major role in clinical resistance to ICI. Cellular immunotherapy with HLA-independent CAR-redirected lymphocytes is a promising alternative in this challenging setting and dedicated translational models are needed.MethodsIn this study, we propose an HLA-independent therapeutic strategy with Cytokine Induced Killer lymphocytes (CIK) genetically engineered with a Chimeric Antigen Receptor (CAR) targeting the tumor antigen CSPG4 as effector mechanism. We investigated the preclinical antitumor activity of CSPG4-CAR.CIK in vitro and in a xenograft murine model focusing on patient-derived melanoma cell lines (Mel) with defective expression of HLA-I molecules.ResultsWe successfully generated CSPG4-CAR.CIK from patients with metastatic melanoma and reported their intense activity in vitro against a panel of CSPG4-expressing patient-derived Mel. The melanoma killing activity was intense, even at very low effector to target ratios, and not influenced by the expression level (high, low, defective) of HLA-I molecules on target cells. Furthermore, CAR.CIK conditioned medium was capable of upregulating the expression of HLA-I molecules on melanoma cells. A comparable immunomodulatory effect was replicated by treatment of Mel cells with exogenous IFN-γ and IFN-α. The antimelanoma activity of CSPG4-CAR.CIK was successfully confirmed in vivo, obtaining a significant tumor growth inhibition of an HLA-defective Mel xenograft in immunodeficient mice.ConclusionsIn this study we reported the intense preclinical activity of CSPG4-CAR.CIK against melanoma, including those with low or defective HLA-I expression. Our findings support CSPG4 as a valuable CAR target in melanoma and provide translational rationale for clinical studies exploring CAR-CIK cellular immunotherapies within the challenging setting of patients not responsive or relapsing to immune checkpoint inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Preclinical	Italy	Candiolo Cancer Institute Irccs	22 Nov 2023

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