Combining metabolic intervention with T-cell immunotherapy is safe and resulted in improved efficacy in two mouse models of solid tumors, providing an alternative combination strategy for boosting solid tumor immunotherapy, according to a new study by scientists at China Pharmaceutical University (CPU).
The study proves the concept of cell-surface anchor-bioengineering, which can be readily adapted to other combinations of cell therapy and metabolic drugs and/or antibodies, the authors reported in the November 25, 2020, edition of Science Translational Medicine.
"We have constructed a cell-surface anchor-bioengineered T cell combining metabolic and T-cell therapy, then shown this strategy be safe and effective against solid tumors in mice," said lead researcher Can Zhang, a professor in the Center of Advanced Pharmaceuticals and Biomaterials at CPU in Nanjing.
T-cell therapy has achieved considerable clinical and preclinical success in treating hematologic malignancies, but has had limited therapeutic effects in solid tumors.
Most studies have focused on combining proinflammatory cytokines or immune checkpoint inhibitors with T cells to improve efficacy, but that approach is effective only in a fraction of patients, and has toxicity risks.
The oxygen- and nutrient-deprived tumor microenvironment has been shown to impede T-cell infiltration, survival, and function, limiting the benefit of solid tumor T-cell therapy.
T-cell metabolic pathways offer potential intervention targets. For example, T-cell function requires cell membrane cholesterol to cluster T-cell receptors (TCRs) and form an immune synapse. Cholesterol metabolic modulation plus T-cell therapy may thus improve solid tumor immunotherapy.
Avasimibe is an effective cholesterol acetyl-CoA acetyltransferase 1 (ACAT1) inhibitor, which increases plasma membrane cholesterol, thereby promoting TCR clustering and improving T-cell effector function.
"ACAT1 is the major enzyme of cholesterol esterification in CD8+ T cells, and it has recently been shown that inhibiting ACAT1 activity via avasimibe can significantly potentiate the effector function of these T cells," said Zhang.
Moreover, "avasimide has previously progressed to phase III trials in atherosclerosis patients, in whom it showed a good safety profile," she told BioWorld Science.
This established safety and efficacy led to the hypothesis that combining avasimide with T-cell therapy might boost solid tumor immunotherapy, but it has been challenging to optimize the two modalities as a combination therapy.
Thus it is necessary to develop combinatorial technologies that maximize both treatments, whereby genetically engineered T cells can be used to produce designed protein drugs.
Unfortunately, heterogeneous expression of engineered proteins and toxicity potential reduces this strategy's efficacy and small molecule drugs cannot be genetically manipulated.
An alternative to genetic engineering involves 'backpacking' nanoparticle drugs onto the T-cell surface via chemical conjugation or ligand-receptor interaction to augment T-cell function and increase the therapeutic efficacy of combinations.
However, previous studies have shown that backpacking may impair T-cell physiological functions, due to long-term occupation of T-cell membrane biomolecules or altered T-cell glycometabolism.
Thus, technology involving backpacking nanoparticle drugs onto the T-cell surface needs to be further improved to reduce the impact of backpacking on T-cell function.
In their new Science Translational Medicine study, Zhang and her team attached liposomal avasimide onto the T-cell surface by lipid insertion and a click molecular insertion technique, without disturbing T-cell physiological function.
They demonstrated that avasimide could be retained on the T-cell surface during circulation and extravasation then locally diffused to increase the T-cell membrane cholesterol concentration, inducing rapid TCR clustering and sustained T-cell activation.
Treatment with cell-surface anchor-engineered T cells, including mouse TCR transgenic CD8+ T cells or human chimeric antigen receptor T (CAR T) cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma.
Moreover, glioblastoma was completely eradicated in 3 of 5 mice receiving surface anchor-engineered CAR T cells, whereas saline-treated control mice survived no more than 64 days. Regarding safety, the administration of bioengineered T cells showed no apparent systemic side effects in these mouse tumor models.
"Although safety findings made with engineered T cells in mice can reflect safety in humans to some extent, potential interspecies differences should also be considered," noted Zhang. These findings show that cell-surface anchor-engineered T cells hold translational potential, because of their simple generation and their good safety profile, but further developmental work is necessary.
"We need to optimize preparation techniques to improve the yield of bioengineered T cells and to develop integrated and automated production techniques, in order to realize large-scale production," said Zhang.
"It will also be necessary to establish quality standards and corresponding rapid detection methods during each production stage, all of which might take several years or more," said Zhang.
"This new therapeutic strategy of combining metabolic intervention and CAR T therapy, including the use of different CAR T cells, might also be effective in diverse solid tumors," she said.
"Our group will continue to investigate the safety and efficacy of cell-surface-modification technologies that can be deployed to various cell types, including neutrophils, natural killer cells and so forth."