Interleukin-2 is the most extensively investigated cy-tokine in clinical use at present. Interleukin-2 enhances the proliferation, cytokine production, and cytolytic activity of T and NK/LAK cell populations, various aspects of monocyte/macrophage function and global measures of immune responsiveness in vivo (Hladik et al. 1994; Foa et al. 1992; Higashi et al. 1991; Verstovsek et al. 1995; Nishimura et al. 1992; Cox et al. 1992). IL-2 has demonstrated anti-tumor activity in neuroblastoma (Lode et al. 1997) and may also have synergy when used in combination with IFN-g to treat murine tumors, including neuroblastoma (Sigal et al. 1991). A total of 15 studies have reported on the use of IL-2 to treat pediatric patients with solid tumors, including over 100 patients with neuroblastoma (Frost et al. 1997; Negrier et al. 1991; Pardo et al. 1996;Valteau-Couanet et al. 1995; Bauer et al. 1995; Chien and Hsieh 1990; Nasr et al. 1989; Pais et al. 1992; Favrot et al. 1990; Truitt et al. 1992; Ribeiro et al. 1993; Roper et al. 1992; Toren et al. 2000; Pession et al. 1998). The majority of these early studies evaluated the use of chronic, intermittent dosing of IL-2 delivered as an intravenous bolus over periods ranging from 15 min to 2h. Fever, vascular leak, and hypotension are common side effects, seen more frequently at the higher intravenous dosing schedules.
IL-2 alone has had little activity in relapsed bulky disease in any solid tumor other than renal cell carcinoma (Bauer et al. 1995), and has therefore been more extensively tested in the post-transplant setting. For relapsed disease, IL-2 may be more effective in combination with other immunotherapeutic agents, such as the anti-GD2 antibody or other cy-tokines. Recent preclinical evidence suggests that in combination, IL-12 with IL-2 may possess potent im-munomodulatory and anti-tumor activity that exceeds the effect of either agent alone. IL-12 and IL-2 reciprocally upregulate the expression of their respective receptors (Bacon et al. 1995; Desai et al. 1992; Yanagida et al. 1994) and can greatly enhance T and/or NK cell proliferation, cytokine production, and cytolytic function. Systemic administration of IL-12 in combination with intermittent,weekly doses of IL-2 (pulse IL-2) is not only well tolerated, but can induce rapid and complete regression of established primary and/or metastatic tumor in several murine models (Wigginton et al. 1996, 2001a,b). Several reports have also demonstrated that IL-12 gene therapy administered alone or in conjunction with tumor-targeted IL-2 possesses anti-tumor activity in trans-plantable murine neuroblastoma tumor models (Lode et al. 1999; Davidoff et al. 1999). Based on pre-clinical data of the combination therapy in murine neuroblastoma models and the adult human trial data, a phase-I dose escalation trial of IL-12 combined with IL-2 is now underway in the NANT consortium.
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