The magic of small-molecule drugs during ex vivo expansion in adoptive cell therapy

Abstract

In the past decades, advances in the use of adoptive cellular therapy to treat cancer have led to unprecedented responses in patients with relapsed/refractory or late-stage malignancies. However, cellular exhaustion and senescence limit the efficacy of FDA-approved T-cell therapies in patients with hematologic malignancies and the widespread application of this approach in treating patients with solid tumors. Investigators are addressing the current obstacles by focusing on the manufacturing process of effector T cells, including engineering approaches and ex vivo expansion strategies to regulate T-cell differentiation. Here we reviewed the current small-molecule strategies to enhance T-cell expansion, persistence, and functionality during ex vivo manufacturing. We further discussed the synergistic benefits of the dual-targeting approaches and proposed novel vasoactive intestinal peptide receptor antagonists (VIPR-ANT) peptides as emerging candidates to enhance cell-based immunotherapy.

Keywords: PI3K; adoptive cell therapy (ACT); chimeric antigen receptors (CAR); ex vivo manufacturing; peptide-based drugs; protein kinase inhibitor; small-molecule drugs; vasoactive intestinal peptide (VIP).

Figure 1

Pharmacological blockade of PI3K and VIPR signaling improves T-cell expansion and function in vivo ((A) adoptive antigen-specific T cells in metastatic colon cancer PDX model) and in vitro ((B–D), human T cells). (A) Left: Increased IFN-γ secreting CD8+ T cells using decorated TMV with VIPhyb and idelalisib (CRCLM-02, n=1); Right: Decreased tumor growth in PDX (CRCLM-02 and CRCLM-04) mice receiving T cells expanded with beads+TMV+drugs. ANOVA was used to determine significance. The standard error (SE) was shown. (B) Total CD3+ T cells, the actively proliferating Ki67+CD3+ subset, CD4+CD3+ T cells, and CD8+CD3+ T cells are synergistically expanded in vitro by the combination of ANT308 and duvelisib. The mean +/- SD fold increase in cell expansion over control cultures containing neither added ANT308 nor duvelisib is shown (n=4), with color shading according to the relative increase. The pair of concentrations yielded the maximal increase in mean fold expansion is shown with a yellow border around the cell. (C) Frequencies of CD27+CD28+ T cells in cultures with duvelisib and ANT308 led to the highest average expansion for that subset of T cells (n=4). An example of gating is on the left. (D) ANT308 and duvelisib demonstrated synergy in decreasing PD1+, Lag3+, Tim3+, and PD1+Lag3+Tim3+ cells (n=4). Figures were plotted with Microsoft Excel and Prism 9. Paired two-sided student t-test was used to determine significance. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.