Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Abstract

The OX40 ligand (OX40L), a member of TNF superfamily, is a costimulatory molecule involved in T cell activation. It is expressed on antigen presenting cells including dendritic cells (DC) and activated B cells. This molecule has been reported to provide potent costimulation in APC-T cell interactions upon binding to its cognate receptor, OX40 which is expressed by activated T cells. In this study systemic administration of OX40L fusion protein was used in the treatment of established murine subcutaneous colon and breast carcinomas.Intra-peritoneal injection of mOX40L fusion protein significantly inhibited the growth of subcutaneous 3 day established colon (CT26) and breast (4T1) carcinomas which was dose and route dependent. Effective therapy with OX40L required the the presence of tumour for 3 days prior to OX40L, concomitant therapy, given at the same time (day 0) as tumour cells was less effective. Furthermore, therapy with OX40L fusion protein was effective in significantly reducing CT26 experimental lung metastasis. In addition, inhibition of CT26 and 4T1 tumours in response to therapy with OX40L was significantly enhanced by combination treatment with intra-tumour injection of a DISC-HSV vector encoding mGM-CSF. Tumour rejection in response to OX40L therapy was correlated with splenocyte CTL activity against the gp70 CT26 tumour associated antigen. In vivo depletion studies demonstrated the requirement for both CD4+ and CD8+ T cells for effective OX40L therapy.Collectively these results demonstrate the potential role of the OX40L in cancer immunotherapy.3

OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen

“…This outcome is consistent with data in other systems demonstrating the enhancement of the CD8 ϩ T cell response to exogenous Ags by OX40 costimulation (20,21). Similarly, studies have shown that OX40 costimulation, given in the absence of tumor-targeted vaccination, augments antitumor immunity to poorly immunogenic tumors or tumors expressing model Ags (13)(14)(15)(16)18). In tumor-bearing FVB mice, we also observed anti-OX40 mediated enhancement of the antitumor immune response in mice given a control vaccine.…”

“…In addition to a GM-CSF-dependent increase in the OX40 expression among CD4 ϩ and CD8 ϩ T cell subsets, we also measured an increase in the proportion of OX40-positive T cells in mice given 3T3neu/GM relative to mice vaccinated with 3T3/GM, suggesting that neu-specific T cells comprise a percentage of the OX40-positive T cells. The increased proportion of OX40-postive T cells likely underlies the synergy between GM-CSF administration and OX40 costimulation that has been reported previously (14,16). It is not yet clear whether GM-CSF directly induces OX40 expression on T cells, or whether this is an indirect consequence.…”

“…Previous reports in this model indicate that OX40 costimulation, when given in conjunction with peptide-or tumor lysate-pulsed dendritic cells, does not generate a sufficient immune response to eliminate tumor (24,25). However, because data from other groups have suggested a synergistic relationship between systemic GM-CSF administration and OX40 costimulation in the generation of antitumor immunity (14,16), we sought to explore the effect of combining OX40 costimulation with a neutargeted GM-SCF-secreting whole cell vaccine in the generation of potent antitumor immunity against the immunodominant CD8 ϩ T cell epitope associated with tumor rejection in neu-N mice (26).…”

Development and characterization of recombinant human Fc:OX40L fusion protein linked via a coiled-coil trimerization domain

“…For hFcILZOX40L, inclusion of the ILZ domain may help to stabilize the OX40L trimer as well, although no direct comparison was made to extracellular OX40L domain alone. The mouse Ig:OX40L seems to function without an additional trimerizing domain (Ali et al, 2004;Morris et al, 2001), but the mouse and human sequences are quite different. Compared to the human OX40L extracellular domain, the mouse has only about 40% sequence identity, contains an additional non-homologous 13 amino acids at the C-terminus and has 1.5 times the trimer interface surface area (Compaan and Hymowitz, 2006).…”

“…In animal models for cancer and autoimmune disease, these OX40 + T cells were sorted and shown to recognize tumor or auto antigens respectively (Weinberg, 2002). Strategies to exploit the OX40-OX40L system include agonists such as anti-OX40 monoclonal antibodies or recombinant soluble OX40L, and antagonists, which include monoclonal antibodies to OX40L or OX40:Ig (alShamkhani et al, 1996;Ali et al, 2004;Weinberg et al, 1999). We have initiated a phase I clinical trial using a mouse anti-human OX40 monoclonal antibody in patients with advanced cancer.…”