Agonistic anti-CD137 mAb need a certain degree of immunogenicity in the tumor in order to be able to exert their antitumor effects (Wilcox et al., 2002a). It became clear that transplantable tumors could be categorized into responsive and not responsive to anti-CD137 therapy, in a fashion that correlated with the intrinsic degree of immunogenicity of the tumor cells. It is still unknown if this basal immunization takes place upon presentation by endogenous dendritic cells (cross-presentation or surrogate presentation of the antigens) (Chen et al., 2004; van Mierlo et al., 2004) or directly by tumor cells reaching the draining lymph nodes (Ochsenbein etal., 1999). Whatever the case, itwas conceivable that artificial vaccination with tumor antigens would be capable of starting the immune response generating antigen-specific activated T cells that would start to express CD137. A compelling study addressed this concept using peptide vaccination plus agonistic anti-CD137 mAb treatment (Wilcox et al., 2002a). It was demonstrated that several poorly immunogenic tumors, including C3 sarcoma, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, were refractory to treatment by anti-CD137 mAb due to immunological ignorance, rather than anergy or clonal deletion of tumor antigen-specific CTLs. Breaking CTL ignorance by immunization with tumor antigen-derived peptides, although insufficient to stimulate a curative CTL response, was necessary for anti-CD137 mAb to induce a CTL response leading to the regression of established tumors (Wilcox et al., 2002a). In this case, a well described epitope of the E7 oncogene of human papillomavirus 16 (HPV-16) was used as a surrogate tumor antigen (Wilcox et al., 2002a). There was evidence that under the conditions tested, this antigen remains ignored by the immune system without signs of immunization or toler-ization (Melero et al., 1997b). This situation of immune ignorance is postulated to be a frequent type of relationship of potential tumor antigens and the immune system (Chen, 1998).
However, in certain experimental examples the tumor antigens specifically cripple the immune system leaving it disabled to mount a proper immune response. This could be a result of deletion (physical elimination) of the lymphocytes with antigen receptors displaying relevant avidity for the antigen, but also a result of the induction of a paralysis in still viable specific lymphocytes, a status known as T-cell anergy. The deleting scenario is quite dire for immunotherapy, but not so much in the second case. It has been recently demonstrated that repeated treatment with anti-CD137 mAb can certainly revert a status of anergy induced against a tumor antigen. This remarkable effect was demonstrated for three surrogate tumor antigens towards which this status of anergy had been induced by peptide immunization (Wilcox et al., 2004).
Active immunization using antigen-presenting dendritic cells as adjuvants has generated an impressive amount of preclinical and clinical results (Banchereau and Palucka, 2005). In these settings agonistic anti-CD137 mAb have been observed to display a truly synergistic effect (Ito et al., 2004; Tirapu et al., 2004) Important ongoing research will tell if anti-CD137 augments the efficacy of conventional treatments that destroy tumor cells releasing antigens, such as local radiotherapy or systemic chemotherapy.
The concept of using an immunostimulating antibody and a procedure of immunization is not unique to anti-CD137 mAb. In the preclinical development of anti-CTLA-4 monoclonal antibodies, it became apparent that there was synergy of anti-CTLA-4 mAb with vaccination (Hurwitz et al., 1998), that even could lead to autoimmunity by breaking tolerance (i.e., vitiligo) (Phan et al., 2003). Clinical trials with a humanized anti-CTLA-4 mAb have only been conducted in combination with vaccination strategies such as GM-CSF transfected allogenic tumor cells (Hodi etal., 2003) and peptides (Phan etal., 2003). The overall concept of vaccination plus an immunostimulating monoclonal antibody could become very important for clinical translation (Murillo et al., 2003).
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