Ex Vivo Interleukin-12-Priming During CD8+ T Cell Activation Dramatically Improves Adoptive T Cell Transfer Antitumor Efficacy in a Lymphodepleted Host

Abstract

Background Clinical application of adoptive T cell therapy (ACT) has been hindered by an inability to generate adequate numbers of non-tolerized, functionally active tumor-specific T cells which can persist in vivo. In order to address this, we evaluated the impact of IL-12 signaling during tumor-specific CD8+ T cell priming in terms of persistence and anti-tumor efficacy using an established B16 melanoma tumor adoptive therapy model. Study Design B6 mice were injected subcutaneously with B16 melanoma tumor cells. On day 12 of tumor growth, mice were preconditioned with cyclophosphamide (4mg dose, i.p.), and one day later, treated by adoptive transfer of tumor-specific pmel-1 CD8+ T cells primed ex vivo 3 days earlier with (i) both IL-12 and antigen (hGP10025–33 peptide) or (ii) antigen only. Tumors were measured biweekly and infused donor T cells were analyzed for persistence, localization to the tumor, phenotype, and effector function. Results Adoptive transfer of tumor-specific CD8+ T cells primed with IL-12 was significantly more effective in reducing tumor burden in mice preconditioned with cyclophosphamide compared with transfer of T cells primed without IL-12. This enhanced anti-tumor response was associated with increased frequencies of infused T cells in the periphery and tumor as well as elevated expression of effector molecules including granzyme B and interferon-γ (IFNγ). Conclusions Our findings demonstrate that ex vivo priming of tumor-specific CD8+ T cells with IL-12 dramatically improves their in vivo persistence and therapeutic ability upon transfer to tumor-bearing mice. These findings can be directly applied as novel clinical trial strategies.

Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling

“…To determine whether b -restricted gp10025-33 peptide) (29). We found that adoptive T cell therapy in the WT mice slowed tumor growth, but 100% of the WT mice relapsed and succumbed to the progressive diseases ( Figure 9B).…”

Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent

“…Priming activated T cells with the Th1/Tc1 polarizing cytokine IL-12 (15,16) dramatically improves the persistence and antitumor efficacy of CD8 + T cells after adoptive transfer (17–19). As IL-7 and IL-15 are elevated after lymphodepletion (20–22), this enhanced persistence may be due to an increase in the expression of IL-2Rβ and/or IL-7Rα induced by IL-12 (7,23).…”

“…We initially focused on CD8 + T cells conditioned with IL-12 because these cells expand robustly in a lymphodepleted host without a requirement for exogenous cytokines or vaccination (17). This strategy revealed that activated CD8 + T cells require host IL-7, but not IL-15, for maximal initial expansion in a lymphodepleted host.…”

Harnessing the IL-7/IL-7Rαaxis to improve tumor immunotherapy

“…[6][7][8] In this murine melanoma tumor model, activated tumor-reactive CD8 C T cells are derived from pmel-1 TCR transgenic mice. These pmel-1 CD8 C T cells recognize an H-2D b -restricted peptide from the endogenous gp100 tumor antigen that is expressed on the transplantable mouse B16 tumor cells.…”

“…Using this model, we have previously shown that IL-12 conditioning of the activated T cells prior to adoptive transfer significantly (10-100 fold) improved their ability to persist and mediate antitumor immunity. 6,7 Importantly, the IL-12-conditioned T cells (Tc1) depended on lymphodepletion for optimal antitumor immunity. 6,7 Therefore, this model represents a powerful system for assessing the role of host IL-7 and IL-15 on activated CD8…”