Future Directions for Idiotype Specific T Cell Immunotherapy

The Revised Authoritative Guide To Vaccine Legal Exemptions

Vaccines Have Serious Side Effects

Get Instant Access

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.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment