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

Abstract

<div>AbstractPurpose:<p>Adoptive T-cell therapy (ACT) of cancer, which involves the infusion of <i>ex vivo</i>–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.</p>Experimental Design:<p>The role of PIM kinases in T cells was studied either by genetic ablation (PIM1<sup>−/−</sup>PIM2<sup>−/−</sup>PIM3<sup>−/−</sup>) or its pharmacologic inhibition (pan-PIM kinase inhibitor, PimKi). Murine melanoma B16 was established subcutaneously and treated by transferring tumor epitope gp100–reactive T cells along with treatment regimen that involved inhibiting PIM kinases, anti-PD1 or both.</p>Results:<p>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.</p>Conclusions:<p>This study highlights the potential therapeutic significance of combinatorial strategies where ACT and inhibition of signaling kinase with checkpoint blockade could improve tumor control.</p></div>