Data from The TOPK Inhibitor HI-TOPK-032 Enhances CAR T-cell Therapy of Hepatocellular Carcinoma by Upregulating Memory T Cells

Abstract

<div>Abstract<p>Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited because of their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naïve/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could further enhance their antitumoral effects. HI-TOPK-032 is a T-LAK cell–originated protein kinase (TOPK)-specific inhibitor that moderately represses some types of tumors. However, it is unknown whether HI-TOPK-032 works on hepatocellular carcinoma (HCC) and whether it impacts antitumoral immunity. Using both subcutaneous and orthotopic xenograft tumor models of two human HCC cell lines, Huh-7 and HepG2, we found that HI-TOPK-032 significantly improved proliferation/persistence of CD8<sup>+</sup> CAR T cells, as evidenced by an increase in CAR T-cell counts or frequency of Ki-67<sup>+</sup>CD8<sup>+</sup> cells and a decrease in PD-1<sup>+</sup>LAG-3<sup>+</sup>TIM-3<sup>+</sup>CD8<sup>+</sup> CAR T cells <i>in vivo</i>. Although HI-TOPK-032 did not significantly suppress HCC growth, it enhanced the capacity of CAR T cells to inhibit tumor growth. Moreover, HI-TOPK-032 augmented central memory CD8<sup>+</sup> T cell (T<sub>CM</sub>) frequency while increasing eomesodermin expression in CD8<sup>+</sup> CAR T cells in tumor-bearing mice. Moreover, it augmented CD8<sup>+</sup> CAR T<sub>CM</sub> cells <i>in vitro</i> and reduced their expression of immune checkpoint molecules. Finally, HI-TOPK-032 inhibited mTOR activation in CAR T cells <i>in vitro</i> and in tumors, whereas overactivation of mTOR reversed the effects of HI-TOPK-032 on CD8<sup>+</sup> T<sub>CM</sub> cells and tumor growth. Thus, our studies have revealed mechanisms underlying the antitumoral effects of HI-TOPK-032 while advancing CAR T-cell immunotherapy.</p></div>