Adoptive transfer of antigen specific T lymphocytes is certainly a promising strategy for cancer treatment (Dudley and Rosenberg, 2003), as well as for chronic or latent viral infections (Moss and Rickinson, 2005). Several approaches are possible which share in common the obtainment of autologous lymphocytes that are stimulated with antigen in vitro and then artificially expanded for infusion. In these treatments interleukin-2 is commonly coadministered to keep injected lymphocytes alive and activated. There is strong experimental evidence that Interleukin-15 would probably substitute with advantage these effects of IL-2 (Waldmann,
2003). Lymphodepletion of the host previously to lymphocyte infusion helps the antitumor effect correlating with less competition for T cell growth and survival factors, as well as with the removal of suppressor regulatory T cells (Treg cells) (Klebanoff et al., 2005). Activated T lymphocytes as those commonly infused in adoptive T cell therapies express CD137 and can receive costimulationby agonistic antibodies (Kim et al., 2001). Experimental proof of the concept for synergistic effects of adoptive T cell therapy and systemic treatment with agonistic anti-CD137 mAb is available (May et al., 2002), although there is controversy on whether the effect is exerted at promoting lymphocyte survival, activation and/or proliferation (May et al., 2002). Adoptive T cell therapy is potentiated by anti-CD137 mAb even in a transgenic model of spontaneous breast cancer in which the tumor expresses MUC-1 while the mouse is tolerant for this antigen (Mukherjee et al.,
2004). CD137 can help adoptive T cell therapy also during in vitro expansions of T cells. An interesting paper using K562 as artificial antigen presenting cells shows much better in vitro induction of CTLs for adoptive therapy if the artificial antigen presenting cells are endowed with the ability to stimulate simultaneously the TCR, CD28, and CD137 (Maus et al., 2002).
Allogeneic bone marrow transplantation is a procedure with success against many hematological malignancies. Its curative potential relies on high dose chemotherapy but importantly also on the function of the donor immune cells that attack the allogeneic malignant cells (Graft versus leukemia effect). However, this frequently pays the price of damage to certain host organs that are also attacked, giving rise to acute and chronic graft versus host disease. This is an area in which agonistic monoclonal antibodies against CD137 might find an important niche for application. As previously commented, anti-CD137 mAb can treat autoimmune conditions that share the property of a pathogenic role of autoreactive CD4 T cells. In this setting of bone marrow transplantation, it became apparent since the earliest studies with agonistic anti-CD137 mAb that they could find an application, because these antibodies enhanced CD8 dependent graft versus host reactions while inhibiting CD4 responses (Shuford et al., 1997). Indeed, subsequent reports point to the conclusion that anti-CD137 treatment can enhance acute graft versus host reactions including the graft versus leukemia effect (Blazar et al., 2001), while greatly ameliorating chronic graft versus host disease by inhibiting a pathogenic CD4+ mediated T-cell response (Kim et al.,
Infusion of donor T lymphocytes is common practice upon relapse of the malignancy after bone marrow transplantation and there are experimental indications that suggest that anti-CD137 mAb could also enhance this form of adoptive T cell therapy.
With regard to NK cells, there is increasing evidence that these cells can mediate alloreactive recognition of target cells in certain mismatches of class IMHC alleles between donor and recipient through "missing self" recognition (Ruggeri et al., 2005). This is known to be clinically efficacious in haploidentical bone marrow transplantation both to prevent graft versus host disease by killing the host dendritic cells that initiate the reaction, and by killing leukemia cells thus preventing the relapse (Ruggeri et al., 2002). These findings have raised considerable expectancy at exploiting the strategy for adoptive NK cell therapy with semiallogeneic NK cells (Miller et al., 2005). The fact that CD137 is expressed on cytokine-activated NK cells in such a way that its ligation further promotes NK activation, cytokine secretion and proliferation has not been explored in the alloreactive scenario (Melero et al., 1998b; Wilcox et al., 2002b). These investigations could become important for the future of these protocols of adoptive cell therapy with NK cells, that are already in clinical trials (Miller et al., 2005).
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