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Purpose: 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 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 two- and three-dimensional STS cultures, and in three STS xenograft models.
Results: CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by analysis and on all 16 STS cell lines tested by flow cytometry. CSPG4-CAR.CIK displayed superior 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 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 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710537 | PMC |
| http://dx.doi.org/10.1158/1078-0432.CCR-20-0357 | DOI Listing |
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