Future Directions for Idiotype Specific T Cell Immunotherapy

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For 30 years, idiotype vaccination has been shown to generate a protective immune response against lymphoma and myeloma tumors, mainly in preclinical models. Future directions will focus on how to improve the effect of the T cell response generated by idiotype vaccination in human patients. As shown by the example of the idiotype-KLH-GMCSF vaccine, an effective vaccine will depend on three factors: tumor antigen, carrier molecules, and vaccine adjuvant. Because KLH has a large molecular weight and is more immunogenic than other molecules, it has become the most widely employed carrier protein for idiotype vaccination. Recently, the alternative conjugation using the maleimide-based method has been reported to significantly enhance the immunogenicity of both human and murine Id-KLH vaccines in preclinical studies (Kafi et al. 2009). The mechanism of GM-CSF in the enhancement of T cell response in idiotype vaccination involved dendritic cell differentiation, migration, and maturation by GM-CSF through the STAT5 signaling pathway (Esashi et al. 2008). Dendritic cells are the most potent antigen presenting cell (APC) to induce antigen-specific T cells in vivo. Recent studies demonstrated that Toll-like receptor signaling pathways also play important roles in the differentiation, maturation, and activation of dendritic cells (Biragyn et al. 2002; Schjetne et al. 2003). Activation of Toll-like receptor signaling by CpG strongly enhances dendritic cell-mediated vaccine efficiency (Speiser et al. 2005). How to incorporate the growing knowledge of Toll-like receptor signaling pathway and dendritic cell activation into our idiotype T cell generation will be important for idiotype vaccination.

The observation that over 50% cancer patients can respond to the adoptive T cell transfer has made the adoptive immunotherapy one of the most attractive strategies (Dudley et al. 2002). A previous study has demonstrated that it is feasible to transfer idiotype-specific T cells from healthy donors to recipients (Kwak et al. 1995). The transferred idiotype-specific T cells protected mice against established tumor in mouse model (Hornung et al. 1995). T cells can also be generated in large number in vitro for adoptive T cell transfer. It has been demonstrated that the success of T cell transfer will depend heavily on the quality of transferred T cells. T cells that belong to central memory (TCM) type but not terminal differentiated type (TEM) can proliferate well and exert a protective role after adoptive transfer (Wherry et al. 2003; Gattinoni et al. 2005). Generating T cells that have a high percentage of TCM cells is essential for the success of adoptive T cell transfer. IL-15 and IL-7 have been reported to increase the percentage of TCM cells in the T cell population (Ku et al. 2000; Schluns et al. 2000; Tan et al. 2002). Recent studies also have demonstrated CD28 and CD27 expression and 4-1BB ligand interaction to increase the pool of Tcm cells (Acuto and Michel 2003; Oelke et al. 2003; Topp et al. 2003). Telomeres of TCM cells are characteristically longer than those of TEM cells, which make TCM capable of going through multiple cell divisions (Weng et al. 1997; Rufer et al. 2003). IL-15 is capable of activating telomere synthesis in memory CD8 T cells via Jak3 and PI3K signaling pathways (Li et al. 2005). Further studies of the T cell population will help us to achieve the best culture conditions for preparing idiotype specific TCM cells for adoptive T cell transfer. Moreover, CD4 T cells have proven to be able to improve and expand CD8 T cell function through cytokine- and CD40L-dependent pathways (Bevan 2004). Adoptive transfer of both CD4 and CD8 T cells produced a greater effect than single CD8 T cell transfer

(Ossendorp et al. 1998). Therefore in the future, idiotype-specific adoptive T cell transfer may involve both CD4 and CD8 T cells.

A healthy microenvironment has been demonstrated to be extremely important for the T cell response in vivo. For example, an increase in CD4+CD25+ Treg cell has been observed in lymphoma and myeloma patients (Beyer et al. 2006; Yang et al. 2006). In normal healthy donors, this group of T cells can suppress the autoimmunity mediated by T cells. However, in a tumor environment, this group of T cells can inhibit the immune response of tumor-specific T cells. In both human and mouse studies, it has been shown that the depletion of Treg can drastically increase the antitumor effect of immune system (Sutmuller et al. 2001; Dannull et al. 2005). Moreover CTLs have been reported to express inhibitor molecules, such as PD-1, CTLA4, and B7-1. These molecules can interfere with the cytotoxic function of CTLs, and the inhibition of these molecules has been shown to improve the antitumor immunity by tumor antigen-specific CTLs (Sutmuller et al. 2001; Iwai et al. 2002; Curiel et al. 2003). Taken together, these studies demonstrate that the combination therapy of active immunization and adoptive T cell transfer, together with immune suppressive pathway inhibition, may be the ideal immuno-therapy strategy for hematologic malignancies in the future.

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