Abstract
Tumor-specific T cells are central mediators of the antitumor response but their low frequency is one major reason for failed immunotherapy. IL-2 is an agent that boosts tumor-reactive T cells but its benefit is limited due to its short half life which necessitates high dosing that contributes to toxicity and potential off-target effects. We developed a mouse (m)IL-2/CD25 fusion protein which exhibits more favorable pharmacokinetics and pharmacodynamics when compared to IL-2. A single administration of high dose mIL-2/CD25 following vaccination with cognate peptide and LPS amplified tumor-specific Pmel-1 CD8+ and TRP-1 CD4+ Teff cells and Pmel-1 memory cells while only transiently increasing Tregs. This approach effectively controlled pre-established B16.F10 melanoma in vivo. This scheme was modified to amplify endogenous polyclonal melanoma-reactive T cells, which is translationally more relevant. Development of tumor-specific T cells required priming and boosting with a mixture of B16.F10 neoantigens and poly (I:C) followed by application of IL-2/CD25 only after the boost. This resulted in largely a CD4+ anti-neoantigen specific T cell response. This immunization scheme delayed tumor growth in mice with pre-established B16.F10 tumors. The immune response within the tumor microenvironment was accompanied by increased frequencies of granzyme B-expressing CD4+ and CD8+ T cells. Together, our data show that limited application of high-dose IL-2/CD25 in the context of neoantigen vaccines promotes effective antitumor immunity and has potential clinical translation.