Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy

Abstract

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.

Pharmacologic and genetic inhibition of cholesterol esterification reduces tumour burden: a pan-cancer systematic review and meta-analysis of preclinical models

“…SOAT1 was genetically knocked out of the T-cells of mice rather than in the implanted B16F10 cells and interestingly produced a similar standardised mean difference in tumour volume to systemic avasimibe treatment [62]. Furthermore, the introduction of T-cells and avasimibe to lymphodepleted mice led to significantly smaller tumours than treatment with avasimibe alone [61]. Interestingly, animals from this study were treated with just 2 mg/kg avasimibe, considerably lower than the doses we found reported in other studies of skin, or any other cancer type.…”

“…Skin cancers (melanoma and non-melanoma) are the third most prevalent cancer type in the world [49]. Tumour burden was significantly lower in models of skin cancer that had been treated with SOAT1 inhibitors across all four studies relevant for quantitative analysis [53,[60][61][62] (SMD = -3.61; 95% CI: -4.55 to -2.67; I 2 = 25%; p < 0.00001; Fig4E). SOAT1 was genetically knocked out of the T-cells of mice rather than in the implanted B16F10 cells and interestingly produced a similar standardised mean difference in tumour volume to systemic avasimibe treatment [62].…”

“…We utilised these data to calculate a novel hazard ratio function that describes the risk of the animal being euthanised based on local ethical requirements related to tumour burden. Thirteen experiments from seven studies [12,39,53,54,[60][61][62]75] provided data suitable for this analysis. Animals in intervention groups where SOAT1 function or expression was inhibited had an 85% reduction in risk of being euthanised earlier than the planned end of experimental period (HR = 0.15; 95% CI: 0.08 to 0.28; I 2 = 63%; p < 0.00001; Fig7B).…”

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

“…It increases the plasma membrane cholesterol content, thereby promoting TCR aggregation and improving the T cell function [151]. Hao et al used click chemistry to attach Ava-containing nanoliposomes to the surface of engineered T cells without interfering with their physiological functions [26]. Finally, studies have shown that TCR transgenic CD8 + T cells and chimeric antigen receptor T cells carrying liposomal AVA have good antitumor effects in mouse models of melanoma and glioblastoma [152].…”

“…Drug resistance is an important characteristic of melanoma, resulting in the lack of effectiveness of current drug treatments [17][18][19][20][21]. Surgery [22,23], chemotherapy [24,25], and immunotherapy [26,27] are the most commonly approaches. However, these treatments are largely limited by an advanced cancer diagnosis, off-target drug delivery and concentration, systemic toxicity, and drug-induced undesirable side effects.…”