Host Lymphodepletion Enhances the Therapeutic Activity of an Oncolytic Vaccinia Virus Expressing 4-1BB Ligand

Abstract

Oncolytic viral vectors have shown promise as antitumor therapeutic agents but their effectiveness is complicated by induction of antiviral antibody responses and rapid host clearance of recombinant vectors. We developed a recombinant oncolytic vaccinia virus expressing the 4-1BBL T-cell costimulatory molecule (rV-4-1BBL) and showed modest tumor regression in the poorly immunogenic B16 murine melanoma model. To improve the therapeutic potential of this vector, we tested the antitumor activity of local intratumoral injection in the setting of host lymphodepletion, which has been shown to augment vaccination and adoptive T-cell therapy. In this model, rV-4-1BBL injection in the setting of lymphodepletion promoted MHC class I expression, reduced antiviral antibody titers, promoted viral persistence, and rescued effectormemory CD8 + T cells, significantly improving the therapeutic effectiveness of the oncolytic vector. These data suggest that vaccination with rV-4-1BBL in the setting of host nonmyeloablative lymphodepletion represents a logical strategy for improving oncolytic vaccination in melanoma, and perhaps other cancers as well. [Cancer Res 2009;69(21):8516-25]

The New Era of Cancer Immunotherapy

“…For example, expression of the ligands of TNF receptor superfamily such as OX40L, 4-1BBL, and GITRL by has been demonstrated to enhance the efficacy of adenovirus and vaccinia vectors delivered intratumorally (Andarini et al, 2004;Calmels et al, 2005;Kim, Kim-Schulze, Kim, & Kaufman, 2009). Most of the studies demonstrated that such viruses could induce stronger infiltration of immune cells into the virus-injected tumors; however, the question remained whether this was merely a reflection of an enhanced antiviral immune response and whether this would translate into a more effective systemic antitumor immunity.…”

Immune cells: more than simple carriers for systemic delivery of oncolytic viruses

“…These antigen-presenting cells in turn stimulate a Th1 response, which promotes T-cell-based tumor killing. 18,19 …”

In Vivo Programming of Tumor Antigen-Specific T Lymphocytes from Pluripotent Stem Cells to Promote Cancer Immunosurveillance

“…These studies concluded that administration of naïve and early effector T cells, in combination with a lymphodepleting pretreatment regimen, g c cytokine administration, and vaccination, resulted in the eradication of established tumors (18)(19)(20). A conditioning treatment of mice (e.g., sublethal irradiation) prior to iPS cell transfer or cytokine treatment (IL-2 or IL-15) may benefit iPS cell-based therapies.…”