Anti-TIM3 Antibody Promotes T Cell IFN-g–Mediated Antitumor Immunity and Suppresses Established Tumors (1)
Stimulation of T cell immunoglobulin and mucin domain 3 (TIM3) by its ligand results in Th1 cell death, implicating a role for TIM3 in negatively regulating Th1 response. Consequently, blockade of TIM3 has been shown to increase IFN-γ-secreting cells in the microenvironment, mediating the pathophysiology of Th1-driven autoimmune diseases, whereas TIM3 expressed on macrophages and monocytes has also been implicated in phagocytosis of apoptotic cells and cross-presentation.
B16F10 melanoma, TRAMP-C1 prostate carcinoma, MC38 and CT26 colon adenocarcinomas (all from ATCC), WTMCA2, and WT3 sarcomas were maintained, injected, and monitored.
Transplant of WT3 resulted in robust tumor growth and early therapy (from day 3) with a high dose of anti-TIM3 (250 μg per injection × 4) significantly suppressed WT3 growth. A dose–response experiment, in the same tumor, showed that 250 μg anti-TIM3 was the minimal optimal dose with lower doses having reduced therapeutic effects. Delayed dosing of anti-TIM3 (from day 11) was considerably less effective at all doses.
Anti-TIM3 was largely ineffective in the absence of CD4+ or CD8+ T cells, but effective in the absence of mature B cells. Anti-TIM3 was ineffective in the absence of functional IFN-γ, but largely suppressive in perforin-deficient mice. Host IL-12p35 was partially important in the antitumor activity of anti-TIM3. However, anti-TIM3 was not optimal in mice that were conditionally depleted of CD11c+ DC.
Early treatment of subcutaneous WT3 fibrosarcoma produced a nearly identical therapeutic effect of anti-TIM3 compared with anti–CTLA-4 and anti–PD-1 . For the treatment of subcutaneous B16F10, the effect of each of the 3 mAbs was quite inferior. Delayed treatment of TRAMP-C1 prostate tumors (commencing on day 10) with anti–CTLA-4 was only weakly effective, but the same regimen of either anti–PD-1 or anti-TIM3 significantly slowed TRAMP-C1 tumor growth. Delayed anti–CTLA-4 treatment of subcutaneous MC38 adenocarcinomas was largely ineffective, whereas anti–PD-1 or anti-TIM3 had quite profound effects on tumor growth.
Each dual therapy was more effective than any monotherapy, whereas the 3 mAbs, anti–CTLA-4, anti–PD-1, and anti-TIM3, produced a further suppression of B16F10 tumor growth, significantly prolonging the survival of all mice in this group. Synergy between anti-TIM3 and anti–PD-1 was also noted against CT26 colon carcinomas, while anti–CTLA-4 and anti-TIM3 were less effective.
Prophylactic anti-TIM3 had a modest effect in delaying MCA-induced fibrosarcomas compared with cIg and previous approaches, including anti–PD-1. Together, anti-TIM3 combined with anti–PD-1 prevented the development of a significant proportion of tumors compared with either anti–PD-1 or anti-TIM3 alone. The combination of anti–PD-1 and anti-TIM3 eradicated 1 of 15 established tumors and significantly suppressed the tumor growth of 3 of 15 other tumors for between 35 and 100 days.
The anti-TIM3 mAb (RMT3-23) does not deplete TIM3 cells in vivo and the same mAb has been shown to upregulate IFN-γ production by ConA-stimulated splenic T cells, but it is not clear whether proliferation may be enhanced by this mAb.