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Enhanced Antitumor Activity Induced by Adoptive T-Cell Transfer and Adjunctive Use of the Histone Deacetylase Inhibitor LAQ824

¹ Department of Medicine, Division of Hematology/Oncology; ² Department of Surgery, Division of Surgical Oncology; ³ Department of Neurosurgery; ⁴ Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, California; ⁵ Department of Medicine, Division of Dermatology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; and ⁶ Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland

Requests for reprints: Antoni Ribas, Department of Medicine, Division of Hematology/Oncology, University of California-Los Angeles Medical Center, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095-1782. Phone: 310-206-3928; Fax: 310-206-0914; E-mail: aribas{at}mednet.ucla.edu.

Tumors grow in the presence of antigen-specific T cells, suggesting the existence of intrinsic cancer cell escape mechanisms. We hypothesized that a histone deacetylase (HDAC) inhibitor could sensitize tumor cells to immunotherapy because this class of agents has been reported to increase tumor antigen expression and shift gene expression to a proapoptotic milieu in cancer cells. To test this question, we treated B16 murine melanoma with the combination of the HDAC inhibitor LAQ824 and the adoptive transfer of gp100 melanoma antigen-specific pmel-1 T cells. The combined therapy significantly improved antitumor activity through several mechanisms: (a) increase in MHC and tumor-associated antigen expression by tumor cells; (b) decrease in competing endogenous lymphocytes in recipient mice, resulting in a proliferative advantage for the adoptively transferred cells; and (c) improvement in the functional activity of the adoptively transferred lymphocytes. We confirmed the beneficial effects of this HDAC inhibitor as a sensitizer to immunotherapy in a different model of prophylactic prime-boost vaccination with the melanoma antigen tyrosinase-related protein 2, which also showed a significant improvement in antitumor activity against B16 melanoma. In conclusion, the HDAC inhibitor LAQ824 significantly enhances tumor immunotherapy through effects on target tumor cells as well as improving the antitumor activity of tumor antigen-specific lymphocytes. [Cancer Res 2009;69(22):8693–9]

Key Words: rodent • T cells • tumor immunity • dendritic cells • vaccination