The Arrival of Agonistic AntiCD137 Monoclonal Antibodies

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Current tumor immunotherapy includes a series of approaches that intend to destroy malignant tissue by means of the cell destructive armamentarium with which the immune system is endowed. Priming and enhancing the cellular immune response against cancer cells or critical components of the tumor stroma is a difficult endeavor, but recent advances have achieved complete regressions of established transplantable rodent malignancies. Among these experimentally successful approaches we can list: (i) vaccinations with dendritic cells pulsed with tumor antigens and other vaccine formulations (Banchereau and Palucka, 2005); (ii) adoptive transfer of in vitro-preactivated lymphocytes into a tumor bearing host in whom lymphopenia has been induced (Dudley et al., 2002); (iii) systemic or local treatment with cytokines, including gene therapy approaches, that augment the cellular immune response (Murphy et al., 1996, 2005); (iv) transfection of costimulatory molecules for T cells into cancer cells; (v) molecular interference with physiological mechanisms that negatively regulate the immune response. The latter is a particularly fertile field of investigation that encompasses: (a) interference with T cell co-inhibitory molecules such as PD-1 (Dong et al., 2002; Hirano et al., 2005) and CTLA-4 (Egen et al., 2002), (b) the depletion or inactivation of regulatory T cells (Sakaguchi, 2005), and (c) the inhibition of enzymes whose activity locally interferes with T cell activation (Muller et al., 2005).

Translation towards human therapy is slowly progressing although, in general, the results in mice tend to be more efficacious than the observations that are being made in the early clinical trials. Nonetheless, there is great hope that the

Ignacio Melero, Oihana Murillo, Iñigo Tirapu, Eduardo Huarte, Ainhoa Arina, Laura Arribillaga, and Juan Jose Lasarte • Centro de Investigación Medica Aplicada y Clínica Universitaria. Universidad de Navarra. Pamplona, Spain.

CD137 Pathway: Immunology and Diseases. Edited by Lieping Chen, Springer, New York, 2006

combination of several of these approaches in a stepwise fashion would optimize results and become standard clinical practise (Pardoll et al., 2004).

In 1995, the field of costimulation in the immune response against tumors was a hot topic. Exciting experiments had shown that transfection of tumor cells with costimulatory ligands such as B7-1 (CD80) increased their immunogenicity in such a fashion that those tumor cells became rejected and were able to control the growth of untransfected tumor cells injected elsewhere in the mouse (Chen et al., 1992; Townsend and Allison, 1993). A key feature of these systems is that tumor cells had to present tumor rejection antigens in order to be enhanced by the artificial costimulation (Chen et al., 1994).

Monoclonal antibodies directed toward lymphocyte membrane molecules can potentially act as artificial agonistic ligands for such receptors, providing signals that could mimic those received from the natural costimulatory ligands (Murillo et al., 2003). Following this simple reasoning, a number of experiments screened for an antitumor effect of monoclonal antibodies of this kind. This screening was performed by administering a series of this type of agents to mice bearing established mastocytomas in the peritoneal cavity. One of such antibodies, that was able to prevent tumor progression, was identified as directed against CD137 (4-1BB) (Melero et al., 1997a). Immediately after, two other monoclonal antibodies of the same specificity (Shuford et al., 1997) were tried in mice bearing the P815 mastocytoma either intraperitoneally or subcutaneously. The rapid progression of tumors in the control groups contrasted with the almost constant rejection in the treated groups. Some of the shrinking subcutaneous tumors were surgically removed to show a clear lymphocyte infiltrate entering the tumor nodules from the periphery Tumor infiltrates chiefly contained T cells (both CD8+ and CD4+), as well as macrophages. Accordingly, a series of experiments clearly showed an increase of tumor specific cytotoxic T cell activity in the spleen of the treated mice (Melero et al., 1997a). It was surprising to observe that such cytotoxicity was detectable in the freshly isolated splenocytes even without restimulation with irradiated tumor cells in culture. Successful treatment and similar mechanistic observations were made in established tumors derived from the Ag104A sarcoma, a spontaneous malignancy considered of low intrinsic immunogenicity (Melero et al., 1997a). In the P815 mastocytoma model, it was noticed that selective depletion of either CD4 or CD8 T cells gave rise to a complete loss of the antitumor effect (Melero et al., 1997a). Subsequent studies have found that the requirement for CD4 T cell help is tumor model dependent (Miller et al., 2002). Selective depletion studies showed that NK cells were also absolutely necessary for the antitumor effect of agonistic anti-CD137 monoclonal antibodies (Melero et al., 1998b). CD137 is not detectable on the surface of resting NK cells but was found to be readily expressed on cytokine-activated Natural Killer cells (Melero et al., 1998b; Wilcox et al., 2002b).

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