Abstract 3520: Targeting spatiotemporal expression of CD137 on tumor-specific cytotoxic T lymphocytes as a novel strategy for agonistic antibody therapy
Authors: Kakimi Kazuhiro , Hosoi Akihiro , Noji Shuichi , Matsushita Hirokazu , Takeda Kazuyoshi 
Published: August 2012

Abstract
CD137 (4-1BB) is an important costimulatory ligand and a potent stimulator of T-cell responses. It has been used therapeutically to stimulate immunity against several solid malignancies as well as modulate susceptibility to autoimmune disease and infection. However, the trial of anti-CD137 agonistic antibody was currently suspended because of the induction of severe hepatitis. In addition, the deleterious side effects associated with anti-CD28 superagonist Ab have questioned the use of reagents to costimulatory molecules in human therapy. To overcome this problem, we combined adoptive transfer of tumor-specific cytotoxic T lymphocytes (CTL) and anti-CD137 Ab. C57BL/6 mice were challenged with 1x10*6 of B16F10 melanoma cells. CTL were prepared from Pmel-1 TCR transgenic mice. On day 9, mice were left untreated or received CTL (1x10*7) injection. Three days later (on day 12) mice received control rat IgG or anti-CD137 Ab (100 μg): (A) rat IgG, (B) anti-CD137 Ab, (C) CTL+rat IgG, (D) CTL+ anti-CD137 Ab. Transferred CTL distributed all over the body and infiltrated in the tumor. CTL were detected in the tumor on day 1 after CTL transfer, peaked on day 3-5 and gradually decreased by day 10. The CD137 expression was upregulated on CTL infiltrating in the tumor, but not in other tissues. Eleven days after CTL transfer, the tumor volumes were (A) 5280±1450 mm3, (B) 5600±980 mm3, (C) 959±571 mm3, (D) 220±347 mm3, respectively. The intratumoral expressions of IFN-γ, perforin and FasL mRNA were increased by CTL transfer and further increased by combining anti-CD137 treatment. In the tumor, only transferred CTL, not host derived T cells produced IFN-γ. IFN-γ production per cell was augmented by andi-CD137 treatment. However, IFN-γ production was not detected on CTL distributed in other tissues. Consistently, no organ damage was observed by anti-CD137 treatment. CTL disappeared by day 9 in anti-CD137 Ab treated animals, suggesting that anti-CD137 Ab did not support the CTL survival in our adoptive transfer CTL model. Anti-CD137 Ab treatment augmented the anti-tumor activity of CTL. At the same time, we have successfully prevented the nonspecific T cell activation by anit-CD137 Ab and accompanying tissue damage because we could selectively activate tumor-specific CTL within the tumor. This strategy based on the spatiotemporal expression of CD137 on antigen-recognizing CTL. It is important to administer anti-CD137 Ab 3 days after CTL transfer when CTL accumulate in the tumor, recognize tumor antigens and upregulate CD137. The CD137 signaling on adoptively transferred CTL contribute to the acquisition of enhanced cytotoxic functions by CTL rather than the regulation of T cell expansion. The tumor-specific CTL can guide agonistic anti-CD137 Ab to the tumor and enhance thier activity. Therefore, the CD137 Ab therapy can be revived by the combination of tumor-specific CTL therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3520. doi:1538-7445.AM2012-3520