Adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer

• Main Author: Qiao Li, Takekazu Iuchi, Maria N. Jure-Kunkel, Alfred E. Chang
• Format: Article
• Language: English
• Published: Ivyspring International Publisher 2007-01-01
• Series: International Journal of Biological Sciences
• Online Access: http://www.biolsci.org/v03p0455.htm

<p>Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other therapeutic approaches, e.g. chemotherapy, cytokine therapies, anti-OX40 therapy, and peptide or DC vaccines. However, the adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer has not been fully evaluated. In this report, effector T cells were generated <i>in vitro </i>by anti-CD3/anti-CD28 activation of tumor-draining lymph node (TDLN) cells and used in an adoptive immunotherapy model. While T cells or anti-4-1BB alone showed no therapeutic efficacy in mice bearing macroscopic 10-day pulmonary metastases, T cells plus anti-4-1BB mediated significant tumor regression in an anti-4-1BB dose dependent manner. Mice bearing microscopic 3-day lung metastases treated with T cells alone demonstrated tumor regression which was significantly enhanced by anti-4-1BB administration. NK cell depletion abrogated the augmented therapeutic efficacy rendered by anti-4-1BB. Cell transfer between congenic hosts demonstrated that anti-4-1BB administration increased the survival of adoptively transferred TDLN cells. Using STAT4^-/- mice, we found that modulated IFN&#947; secretion in wt TDLN cells after anti-CD3/CD28/4-1BB activation <i>in vitro </i>was lost in similarly stimulated STAT4^-/- TDLN cells<i>.</i> Additionally, anti-4-1BB administration failed to augment the therapeutic efficacy of T cell therapy in STAT4^-/- mice. Together, these results indicate that administered anti-4-1BB mAb can serve as an effective adjuvant to augment the antitumor reactivity of adoptively transferred T cells by recruiting the host NK cells; increasing the persistence of infused effector T cells, and modulating the STAT4 molecular signaling pathway.</p>