International Journal of Biological Sciences

Impact factor
3.873

ISSN 1449-2288

News feeds of IJBS published articles
My Manuscript
My Account

Journal of Biomedicinenew

Theranostics

International Journal of Medical Sciences

Journal of Cancer

Oncomedicine

Journal of Genomics

Journal of Bone and Joint Infection (JBJI)

Nanotheranostics

PubMed Central Indexed in Journal Impact Factor

Int J Biol Sci 2007; 3(7):455-462. doi:10.7150/ijbs.3.455

Research Paper

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

Qiao Li1,*, Takekazu Iuchi1,2,*, Maria N. Jure-Kunkel3, Alfred E. Chang1

1. Division of Surgical Oncology, University of Michigan, Ann Arbor, MI 48109-5932, USA.
2. Shiga University of Medical Science, Shiga, Japan.
3. Bristol-Myers Squibb Company, Princeton, NJ, USA.
* These two authors contributed equally to the work.

Abstract

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 in vitro 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 IFNγ secretion in wt TDLN cells after anti-CD3/CD28/4-1BB activation in vitro was lost in similarly stimulated STAT4-/- TDLN cells. 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.

Keywords: Anti-4-1BB, T cells, Cancer, Adoptive immunotherapy, NK cells, STAT4

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Li Q, Iuchi T, Jure-Kunkel MN, Chang AE. Adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer. Int J Biol Sci 2007; 3(7):455-462. doi:10.7150/ijbs.3.455. Available from http://www.ijbs.com/v03p0455.htm