CD44v6 as innovative sarcoma target for CAR-redirected CIK cells

V. Leuci, G. M. Casucci, G. Grignani, R. Rotolo, U. Rossotti, E. Vigna, L. Gammaitoni, G. Mesiano, E. Fiorino, C. Donini, A. Pisacane, L. D. ambrosio, Y. Pignochino, M. Aglietta, A. Bondanza, D. Sangiolo

Research output: Contribution to journalArticle

Abstract

Purpose of our study was to explore a new immunotherapy for high grade soft tissue sarcomas (STS) based on cytokine-induced killer cells (CIK) redirected with a chimeric antigen receptor (CAR) against the tumor-promoting antigen CD44v6. We aimed at generating bipotential killers, combining the CAR specificity with the intrinsic tumor-killing ability of CIK cells (CAR+.CIK). We set a patient-derived experimental platform. CAR+.CIK were generated by transduction of CIK precursors with a lentiviral vector encoding for anti-CD44v6-CAR. CAR+.CIK were characterized and assessed in vitro against multiple histotypes of patient-derived STS. The anti-sarcoma activity of CAR+.CIK was confirmed in a STS xenograft model. CD44v6 was expressed by 40% (11/27) of patient-derived STS. CAR+.CIK were efficiently expanded from patients (n = 12) and killed multiple histotypes of STS (including autologous targets, n = 4). The killing activity was significantly higher compared with unmodified CIK, especially at low effector/target (E/T) ratios: 98% vs 82% (E/T = 10:1) and 68% vs 26% (1:4), (p<0.0001). Specificity of tumor killing was confirmed by blocking with anti-CD44v6 antibody. CAR+.CIK produced higher amounts of IL6 and IFN-γ compared to control CIK. CAR+.CIK were highly active in mice bearing subcutaneous STS xenografts, with significant delay of tumor growth (p<0.0001) without toxicities. We report first evidence of CAR+.CIK's activity against high grade STS and propose CD44v6 as an innovative target in this setting. CIK are a valuable platform for the translation of CAR-based strategies to challenging field of solid tumors. Our findings support the exploration of CAR+.CIK in clinical trials against high grade STS.

Original languageEnglish
Article numbere1423167
JournalOncoImmunology
Volume7
Issue number5
DOIs
Publication statusPublished - May 4 2018

Keywords

  • adoptive immunotherapy
  • CAR
  • CD44v6
  • CIK
  • soft tissue sarcoma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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