Targeting T cell negative pathway induces powerful and long-lasting antitumor effect in vivo
Presentation Start/End Time: Sunday, Apr 15, 2007, 1:00 PM - 5:00 PM
2007 AACR Annual Meeting
April 14-18, 2007
Los Angeles, CA
Abstract Number: 968
Location: Exhibit Hall, Los Angeles Convention Center
Poster Section: 8
Poster Board Number: 17
Author Block: Masayuki Sho, Takeo Nomi, Takahiro Akahori, Hiromichi Kanehiro, Miyuki Azuma, Hideo Yagita, Yoshiyuki Nakajima. Nara Medical University, Nara, Japan, Tokyo Medical and Dental University, Tokyo, Japan, Juntendo University School of Medicine, Tokyo, Japan
Recent studies have suggested that tumors might escape from host immunity through PD-L/PD-1 interaction that provides negative regulatory signal for T cell activation. We and others have recently found that PD-L/PD-1 pathway may play a pivotal role in some human malignancies including esophageal and pancreatic cancer. In this study, we extended our study to examine therapeutic efficacy of targeting T cell negative pathway toward clinical application. To this end, we utilized murine syngeneic tumor models.
In hepatic metastasis model, a murine colon cancer, CT26 was inoculated into the spleen in syngeneic BALB/c mice. We treated mice with anti-PD-1 (RMP1-14), anti-PD-L1 (MIH-5), anti-PD-L2 (TY25) mAb or control Ig starting on the day of tumor inoculation. Hepatic metastasis was significantly inhibited by either anti-PD-1 or PD-L2, but not PD-L1 mAb compared to controls. Interestingly, the coadministration of anti-CTLA-4 mAb (4F10) with PD-1 blockade further enhanced antitumor immunity and resulted in complete inhibition of liver metastasis, while CTLA-4 blockade alone was less effective. Thus, the combination of PD-1 and CTLA-4 blockade displayed significant synergistic effect on the inhibition of tumor metastasis.
Then, we applied this combined therapy of targeting PD-1 and CTLA-4 to the advanced tumor. CT26 was subcutaneously inoculated in the flank of mice. When tumor reached 8 mm in diameter around 10 days after inoculation, the treatment of both anti-PD-1 and anti-CTLA-4 mAbs was started. Compared to mice treated with control Ig, the simultaneous blockade of PD-1 and CTLA-4 induced substantial antitumor effect in vivo. Tumors were either completely rejected or significantly inhibited in all mice by 2 weeks after treatment. By histology, much more cell recruitments and necrosis in the established tumor in treated mice were observed during mAb treatment compared to controls.
Mechanistic analysis revealed that the treatment promoted the T cell infiltration, predominantly CD8+, into the tumor, thereby resulting in local immune activation as evidenced by the upregulation of IFN-gamma, Granzyme B, and Perforin.
Finally, in mice with complete response, CT26 or syngeneic another tumor (EMT-6) were rechallenged over 100 days after first tumor inoculation. As a result, rechallenged CT26 tumors did not grow or eventually regressed without further manipulation, while EMT-6 grew at the same tempo as controls. Data suggested that the treatment induced long-lasting and antigen-specific antitumor effect. There was no overt toxicity in mice during and after the treatment.
In conclusion, we have demonstrated for the first time that simultaneous blockade of differential T cell negative pathways of PD-L/PD-1 and B7/CTLA-4 evoked powerful as well as long-lasting tumor immunity in vivo. Thus, we suggest that this promising strategy is potentially effective in treatment of tumor metastasis and advanced tumors in humans. |
