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Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma

¹ Myeloma Institute for Research and Therapy, Section for Gene and Immunotherapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas; ² Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama; and ³ Department of Surgery, University of Basel, Switzerland

Requests for reprints: Frits van Rhee, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 776, Little Rock, AR 72205. Phone: 501-296-1503, ext. 1547; Fax: 501-686-6442; E-mail: vanrheefrits{at}uams.edu.

Myeloma vaccines, based on dendritic cells pulsed with idiotype or tumor lysate, have been met with limited success, probably in part due to insufficient cross-priming of myeloma antigens. A powerful method to introduce myeloma-associated antigens into the cytosol of dendritic cells is protein transduction, a process by which proteins fused with a protein transduction domain (PTD) freely traverse membrane barriers. NY-ESO-1, an immunogenic antigen by itself highly expressed in 60% of high-risk myeloma patients, was purified to near homogeneity both alone and as a recombinant fusion protein with a PTD, derived from HIV-Tat. Efficient entry of PTD-NY-ESO-1 into dendritic cells, confirmed by microscopy, Western blotting, and intracellular flow cytometry, was achieved without affecting dendritic cell phenotype. Experiments with amiloride, which inhibits endocytosis, and N-acetyl-L-leucinyl-L-norleucinal, a proteasome inhibitor, confirmed that PTD-NY-ESO-1 entered dendritic cells by protein transduction and was degraded by the proteasome. Tetramer analysis indicated superior generation of HLA-A2.1, CD8⁺ T lymphocytes specific for NY-ESO-1_157-165 with PTD-NY-ESO-1 compared with NY-ESO-1 control protein (44% versus 2%, respectively). NY-ESO-1-specific T lymphocytes generated with PTD-NY-ESO-1 secreted IFN- indicative of a Tc1-type cytokine response. Thus, PTD-NY-ESO-1 accesses the cytoplasm by protein transduction, is processed by the proteasome, and NY-ESO-1 peptides presented by HLA class I elicit NY-ESO-1-specific T lymphocytes.

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