CAR-T Cell Performance: How to Improve Their Persistence?

Abstract

Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.

Fatty acid synthase (FASN) signalome: A molecular guide for precision oncology

“…Indeed, insufficient T-cell priming is now receiving increasing attention as a major cause of 'cold tumors' (lack of T-cell infiltration) and their unresponsiveness to checkpoint inhibitors. The limited therapeutic efficacy of ACIs, which is largely dependent on the survival and replicative capacity of the implanted immune cells, may be due to a similar failure to mount cytotoxic responses to cancer cell antigens [260][261][262]. Once reintroduced into patients, engineered T-, NK-, CAR-T-or CAR-NK immune cells experience physiological levels of nutrients (e.g.…”

Particle-Based Artificial Antigen-Presenting Cell Systems for T Cell Activation in Adoptive T Cell Therapy

“…Besides, T cells may experience rapid exhaustion due to excessive activation, leading to a decline in their function and efficacy . The differentiation and proliferation of certain T cell subgroups with specific phenotypes, such as memory-like characteristics and stemness, has proven critical to achieve a long-lasting remission in cancer treatment. ,, However, current aAPCs are unable to effectively control the desired bias in T cell differentiation and ratio of activated T cells. Hence, further investigation is necessary to better understand how the properties of aAPCs can be manipulated to control the differentiation of T cells upon stimulation.…”

“…Some aAPCs have already become commercially available as an off-the-shelf technology for FDA-approved ACTs . However, despite the great advancements, current engineering of aAPCs still faces challenges including limited specificity and effectiveness, overstimulation, rapid exhaustion, and a lack of sustained cytokines release . Developing more efficient and safer aAPCs remains crucial and urgent for improving the efficacy and accessibility of ACTs.…”

“…10 However, despite the great advancements, current engineering of aAPCs still faces challenges including limited specificity and effectiveness, overstimulation, rapid exhaustion, and a lack of sustained cytokines release. 11 Developing more efficient and safer aAPCs remains crucial and urgent for improving the efficacy and accessibility of ACTs. This article will review and discuss recent strategies for engineering nano-/microparticle-based aAPCs for T cell activation in current ACTs.…”

Label free metabolic imaging to enhance the efficacy of Chimeric Antigen Receptor T cell therapy

“…Third, media composition and cytokines used during expansion can impact CAR T cell phenotype, fitness and clinical outcomes (16). While several cytokine cocktails, including IL-7 and IL-15 have been studied to control CAR T cell differentiation and retain stem-like characteristics (e.g., expression of CCR7, CD62L, CR45RA) for enhanced in vivo potency and persistence (17,18,19), metabolites in culture media such as glucose and glutamine could similarly program CAR T cell metabolic states for enhanced in vivo potency and persistence (16,18). Metabolic fitness, such as high dependence on oxidative phosphorylation (OXPHOS) and fatty acid oxidation, low glycolytic activity, and high mitochondrial mass, has recently emerged as a key critical quality attribute for CAR T cells (20)(21)(22)(23) As metabolism plays an intricate role in T cell activation, cell cycle progression, gene transfer efficiency, and in vivo potency, metabolic monitoring of T cells at various stages during CAR T manufacturing could provide complementary measurements for dynamic fine-tuning of manufacturing conditions.…”