Abstract #LB-154: Identification of novel helper epitopes of MAGE-A4 and Survivin tumor antigen: Useful tool for the propagation of Th1 cells
Authors: Takayuki Ohkuri, Daiko Wakita, Daisuke Noguchi, Minoru Kobayashi, Kazutaka Masuko, Junya Ohtake, Kenji Chamoto, Yuji Togashi, Hidemitsu Kitamura, Takashi Nishimura
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumor immunotherapy. It has been well accepted that T helper type 1 (Th1)-dominant immunity is critical for the successful induction of antitumor immunity in a tumor-bearing host. The adoptive Th1 cell therapy has been demonstrated to be an attractive strategy for inducing tumor eradication in mouse systems. However, no clinical trial of Th1 cell therapy has carried out. Here, we first identified MAGE-A4-derived promiscuous helper epitope peptide bound to both HLA-DPB1*0501 and DRB1*1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 cells in vitro. Culture of CD4+ T cells with IFN-\#947;-treated peripheral blood mononuclear cells (PBMC)-derived adherent cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th cells producing IFN-\#947; but not IL-4. Moreover, it was demonstrated that ligation of MAGE-A4-reactive Th1 cells with the cognate peptide caused the production of IFN-\#947; and IL-2. Using this expansion procedure, we identified two novel survivin helper peptides, SU21 and SU22. The survivin molecule is known as one of the most desired target molecules for tumor immunotherapy. Therefore, survivin-specific Th1 cells would also play a critical role for tumor immunotherapy. Among the identified peptides, SU22 is capable of binding to HLA-DR53. The other peptide was presented to Th1 cells by HLA-DRB1*1501/1502. The Th1 cells induced by SU21 or SU22 produced IFN-\#947; against autologous dendritic cells pulsed with recombinant survivin protein, suggesting that both epitopes are functional antigens, which are naturally processed and presented. When PBMC were cultured with activated survivin-reactive Th1 cells in the presence of survivin peptide, most immunoregulatory cells including CD8-, CD19-, CD56- and CD11c-positive cells increased the expression levels of early activation maker, CD69. Moreover cytotoxic activity of NK cells and CD8+ T cells increased. It is suggesting that administration of activated Th1 cells would promote activity of immune cells in patients with cancer. Thus, our identified MAGE-A4 and survivin helper epitope peptides will become good tools for the propagation of tumor-specific Th1 cells applicable to adoptive immunotherapy of human cancer. We are planning a clinical trial of Th1 cell therapy combined with helper peptides after evaluating its rationality in hu-mouse therapy model. The new challenge to the adoptive immunotherapy is now started and we believed Th1 cell therapy using tumor-specific Th1 cells expanded with helper epitope peptide will become a promising strategy for the immunotherapy of human cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-154.