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

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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Even 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. Methods: In 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. Results: We 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. Conclusions: In 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.

Original languageEnglish
Article number310
Number of pages13
JournalJournal of Experimental and Clinical Cancer Research
Volume42
Issue number1
DOIs
Publication statusPublished - 22 Nov 2023

Keywords

  • CAR
  • CIK
  • CSPG4
  • HLA class-I
  • Immunotherapy
  • Melanoma

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