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.
Highlights
Adoptive cell therapy (ACT) is a type of immunotherapy in which patient-derived T-cells are genetically engineered ex vivo to target and kill cancer cells and are subsequently delivered back into the patient [1]
Several factors impact the persistence of Chimeric Antigen Receptors (CARs) T-cells in patients, including activationinduced cell death (AICD) and peripheral tolerance, which may be described as a state of antigen recognition but lack of reactivity toward cancer cells [34]
This study showed that CARs encoding a single immunoreceptor tyrosine-based activation motifs (ITAMs) resulted in T-cells with balanced effector and memory programs and enhanced therapeutic profiles
Summary
Adoptive cell therapy (ACT) is a type of immunotherapy in which patient-derived T-cells are genetically engineered ex vivo to target and kill cancer cells and are subsequently delivered back into the patient [1]. No positive result was observed [19] Another example is the clinical trial #NCT01865617, where repeated infusions of the same CD19 CAR-T product were performed in patients with chronic lymphocytic leukemia, NHL, or acute lymphoblastic leukemia that have come back or have not responded to previous treatment. Patients that respond to CAR T therapies remain at risk of relapse due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer [16,21,22]. This issue is even more dramatic in solid tumors, as the tumor microenvironment (TME) negatively influences the survival, infiltration, and activity of T-cells. We will highlight the molecular mechanisms underlying T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies by counteracting T-cell exhaustion
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