CD137 Acting in Synergy with Cytokines and Other Costimulatory Molecules

Interleukin-12 as a recombinant protein has been one of the most promising anti-cancer agents arising from preclinical models. Unfortunately an underestimated maximal tolerated dose led to serious adverse effects in a phase II clinical trial that halted development. However systemic toxicity and local efficacy made IL-12 an excellent candidate for local gene therapy (Colombo and Trinchieri, 2002; Murphy et al., 2005). Tumor cell gene transfer of IL-12 has remarkable antitumor effects in mouse models that are dependent on increases of antitumor CTL, NK cells and on antiangiogenic effects triggered by this cytokine and its downstream mediators. A very exciting series of experiments demonstrated that IL-12 gene transfer by intratumor injection of a recombinant adenovirus syner-gizes with systemic agonistic monoclonal antibodies against CD137 (Chen et al., 2000). Although co-transduction of the gene encoding CD137 ligand with IL-12 genes had some effect, it was not as potent as the one achieved by systemic anti-CD137 mAb (Martinet et al., 2000, 2002). The therapeutic effect in this case was in great part mediated by NK cells. These synergistic effects are also observed upon injection into the tumor tissue of dendritic cells that have been engineered to produce IL-12 by means of recombinant adenovirus (Tirapu et al., 2004). Direct intratumoral injection of both a recombinant adenovirus encoding IL-12 and dendritic cells engineered to produce IL-12 have been tested in pilot clinical trials demonstrating safety but modest clinical results (Mazzolini et al., 2005; Sangro et al., 2004). Hence, the road is paved for testing the combination of IL-12 gene therapy with anti-CD137 mAbs.

The modest effect of CD137 ligand transfection either into tumor cells (Martinet et al., 2000, 2002) or into dendritic cells (Wiethe et al., 2003) has strikingly contrasted with the outstanding efficacy achieved by introducing into tumor cells a gene encoding for a transmembrane attached version of an agonist single chain (ScFv) antibody against CD137 (Ye etal., 2002). This artificial ligand promotes tumor rejection and generates systemic immunity in which both NK and CD4 T cells have a central role (Ye et al., 2002).

CD137/CD137 ligand relatives in the TNF/TNF-Receptor family have also immunestimulating antitumor properties if stimulated with antibodies or if trans-fected into tumor cells. These include OX-40(CD134)/OX40 ligand, CD40/CD40 ligand, CD27/CD27 ligand (CD70). This issue has been recently reviewed (Croft, 2003; Watts, 2005) and exceeds by far the coverage of this chapter. It must be said that some of the most exciting experiments in the field of CD137 in immunotherapy involve the reported synergy of OX40 and CD137 at inducing cellular immune responses upon concomitant stimulation. Enforced dual costim-ulation through CD137 and OX40 induced profound specific CD8 T cell clonal expansions (Dawicki et al., 2004; Lee et al., 2004). The synergistic response of the specific CD8 T cells persisted for several weeks, and the expanded effector cells resided throughout lymphoid and nonlymphoid tissue. Dual costimulation through CD137 and OX40 did not augment the number of rounds of T cell division in comparison to single costimulators, but rather enhanced lymphocyte accumulation in a cell-intrinsic manner. It was shown that CD8 T cell clonal expansion and effector function did not require T cell help, but accumulation in non-lymphoid tissue was predominantly CD4 T cell-dependent (Lee et al., 2004). Dual costimulation mediated rejection of an otherwise resistant established murine sarcoma. Importantly, effector function directed towards established tumors was CD8 T cell dependent, while being entirely CD4 T cell independent. Available data suggest that OX40 seems to preferentially costimulate CD4 Th1, cells mirroring the effects of CD137 costimulation on CTLs (Lee et al., 2004). These observations with anti-OX40 mAb and OX40L are reminiscent of the synergis-tic effects reported upon cotransfection into tumor cells of two costimulatory molecules CD137 ligand and B7-1 (CD80) (Guinn et al., 1999; Melero et al., 1998a).

In addition, some surface glycoprotein interactions are coinhibitory, as opposed to costimulatory for the T cell response. For instance the B7-H1 molecule that binds to PD-1 and some other non-identified surface T cell ligand can strongly inhibit the T cell response (Dong et al., 2002). In fact B7-H1 is expressed by many experimental and human tumors in vivo as an escape mechanism (Dong et al., 2002). Interestingly blocking B7-H1/PD-1 interactions with antibodies has antitumor effects (Dong et al., 2002) that are truly synergistic with the administration of anti-CD137 mAb to induce complete tumor eradication (Hirano et al., 2005). The mechanism involves a prevention of the resistance of tumor cells to the local killing by infiltrating lymphocytes (Hirano et al., 2005), but other mechanistic possibilities such as tolerance induction cannot be definitively excluded.

Figure 8.1. Schematic representation of the different sites and modes of action of agonistic anti-CD137 mAb, gene transfer of CD137 ligand, and combination strategies.

As mentioned before, there is no synergy between blocking the CTLA-4 inhibitory receptor and treatment with anti-CD137 mAb. Finding the reason could be informative for designing therapies based on CD137 and the concept of multiple costimulation. Combination immunotherapy, in other words, the sequential or simultaneous combination of several mechanisms can be one way to eventually reach curative treatments for humans (Pardoll et al., 2004). We have previously suggested that if immunotherapy were a car, the engine should be started (immunization), the gas pedal should be pressed (costimulation) and the brakes should be released (by disconnecting co-inhibitory receptors). This car can take us to success, but we will probably will have to face autoimmunity in our race (Tirapu et al., 2002). In Figure 8.1, a schematic representation ofthe explored combinations that exploit the CD137/CD137 ligand pathway has been represented.

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