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Herpes Simplex Virus (HSV) Amplicon-mediated Codelivery of Secondary Lymphoid Tissue Chemokine and CD40L Results in Augmented Antitumor Activity¹

James P. Wilmot Cancer Center [K. A. T., J. M., V. H.], Departments of Medicine [K. A. T.], Neurology [W. J. B., H. J. F.], Microbiology and Immunology [H. J. F.], and the Center for Aging and Developmental Biology [W. J. B., R. E. G., H. J. F.], University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida 33136 [J. D. R.]

Development of effective antitumor immune responses depends on timely interactions of effector cells. A bimodal approach that involves coexpression of chemokines and costimulatory molecules within the tumor bed may elaborate a more optimal antitumor response. One candidate includes secondary lymphoid tissue chemokine (SLC), which promotes the colocalization of naïve, nonpolarized memory T cells and dendritic cells (DCs) within lymph nodes and Peyer’s patches. CD40L-mediated DC activation could induce maturation, enhance antigen presentation, and facilitate priming of the recruited naïve T cells. To this end, the antitumor activity of SLC and CD40L expressed singly or in combination using the herpes simplex virus (HSV)-derived amplicon was examined in two murine models: A20, a B-cell lymphoma, and CT-26, an adenocarcinoma. Administration of amplicons encoding SLC (HSV-SLC) into s.c. tumors established previously resulted in heavy infiltration of CD4⁺ and CD8⁺ T cells, and DCs, and the generation of cytolytic T-cell activity. Combined transduction of either tumor with HSV-SLC and HSV-CD40L resulted in a more enhanced antitumor activity that was CD8⁺ T cell-dependent than observed with either vector alone. mRNA expression of the Th1 markers IFN-, perforin, and interleukin 12 was detectable only in transduced regressing tumors. In addition to identifying a potent antitumor immune strategy, we show that amplicon-mediated SLC and CD40L delivery may mimic lymph node conditions necessary for priming naïve T cells within the tumor bed, and demonstrate the importance of DC activation status on antigen presentation and cytokine expression for priming of newly recruited T cells.

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