Targeting PIM Kinase with PD1 Inhibition Improves Immunotherapeutic Antitumor T-cell Response

Abstract

Purpose: Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of ex vivo-engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable antitumor response following ACT is hampered either by loss of effector function or survival of the antitumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the antitumor T cells are of immense importance. Given the role of metabolism in determining the therapeutic efficacy of T cells, we hypothesize that inhibition of PIM kinases, a family of serine/threonine kinase that promote cell-cycle transition, cell growth, and regulate mTORC1 activity, can improve the potency of T cells in controlling tumor.Experimental Design: The role of PIM kinases in T cells was studied either by genetic ablation (PIM1 À/À PIM2 À/À PIM3 À/À ) or its pharmacologic inhibition (pan-PIM kinase inhibitor, PimKi). Murine melanoma B16 was established subcutane-ously and treated by transferring tumor epitope gp100-reactive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both.Results: With inhibition of PIM kinases, T cells had significant reduction in their uptake of glucose, and upregulated expression of memory-associated genes that inversely correlate with glycolysis. In addition, the expression of CD38, which negatively regulates the metabolic fitness of the T cells, was also reduced in PimKi-treated cells. Importantly, the efficacy of antitumor T-cell therapy was markedly improved by inhibiting PIM kinases in tumor-bearing mice receiving ACT, and further enhanced by adding anti-PD1 antibody to this combination.Conclusions: This study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhibition of signaling kinase with checkpoint blockade could improve tumor control.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…The inhibition of PIM can increase the tolerance and persistence of T cells in the tumor microenvironment, and the combined effect with blocking PD-1 can significantly improve efficacy (Fig. 7) [170].…”

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

“…These effects were potentiated by the use of an anti-PD1 antibody (triple combination therapy), prolonging mouse survival, decreasing tumor growth and improving T-cell migration. 140 Multiple studies have suggested the use of immunotherapeutics, perhaps alongside PIM inhibitors, to overcome the mechanisms of resistance to treatment and improve the functional outcomes. 27,133 CONCLUDING REMARKS Inhibition of PIM in PCa has attracted much attention as a potential monotherapeutic over the last decade, with growing in vitro, in vivo and early clinical trial data supporting this approach to varying degrees.…”

Obesity and CD8 T cell metabolism: Implications for anti‐tumor immunity and cancer immunotherapy outcomes

“…Data from Sabatino, et al demonstrate that activating naive (CD8+CD62L+CD45RA+) T cells engineered to express a CD19‐specific CAR with CD3/CD28 in the presence of IL‐7, IL‐21, and the glycogen‐synthase‐3b inhibitor TWS119, enhances metabolic fitness and mediates a robust, long‐lasting anti‐tumor response against systemic acute lymphoblastic leukemia xenografts compared to current CAR T cell expansion protocols. Interestingly, inhibition of proviral integration site for Moloney murine leukemia virus (PIM) kinases, a family of serine/threonine kinases that participate in T cell glucose metabolism, during CD8 T cell expansion can enhance mTORC1, improve the uptake of glucose by CD8 T cells, and increase anti‐tumor effector function . Data from Klebanoff, et al demonstrate that Akt signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells and promotes a CD62L‐expressing central memory phenotype.…”