Improving CAR T-Cell Persistence

Abstract

Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

Co-Expression of miR155 or LSD1 shRNA Increases the Anti-Tumor Functions of CD19 CAR-T Cells

“…Besides, it is increasingly clear that less differentiated naive and memory T cells are superior to effector T cells in CAR-T cell therapy, and one of the recent strategies to improve CAR-T cell persistence is focusing on memory cell formation ( 38 ). In this study, increased level of T CM cells in miR155 co-expressing anti-CD19 CAR T cells might be associated with the long-term T cell persistence, consistent with the discovery that miR155 regulated the transcription factor T-bet to promote the differentiation of CD8+ T cells into memory T cells by targeting to SHIP-1, thus improving the proliferation and long-term persistence of CD8+ T cells ( 37 , 39 , 40 ).…”

Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

“…The poor persistence of CAR T cells is the most important reason for antigen-positive relapse. The fitness of T cells collected from patients is likely to be devastated by tumour and frontline treatments, resulting in insufficient CAR T cell quantity and poor quality (21). In addition, sustained antigenic stimulation in vivo tends to cause exhaustion of CAR T cells by transcriptomic and epigenetic modulation, whose features include impaired persistence and cytotoxicity, upregulation of inhibitory receptors, metabolic changes and increased apoptosis.…”

CAR-T Immunotherapy to Beat Solid Tumors: From Challenges to Improvements

“…In contrast, effector T cells have limited persistence and poor expansion capacity and are prone to depletion. Stem memory T cells are perfect candidates due to their long lifespan, high self-renewal capacity and differentiation ability among a variety of T cell populations [29].…”