Subsequently, various clinical trials expanding CAR-T indications to other hematological malignancies were carried out

Subsequently, various clinical trials expanding CAR-T indications to other hematological malignancies were carried out. as approaches to reverse CAR-T cell exhaustion in hematological malignancies, providing novel strategies for immunotherapies. 1. Introduction Based on the safety and effectiveness in clinical treatment, a CD19-targeting CAR-T cell therapy for treating relapsed or refractory B cell acute lymphoblastic leukemia (ALL) in both children and young adults has been approved by the U.S. Food and Drug Administration (FDA) in 2017 [1, 2]. This landmark development of CAR-T therapy for B cell malignancies benefitted from the phase 2 global ELIANA trial involved in 75 patients with refractory ALL. Olaquindox Notably, the overall remission rate in patients who received CAR-T cell infusion reached to 81%, with 59% 12-month relapse-free survival (RFS) and 76% overall survival (OS), respectively [3, 4]. Furthermore, in one of our clinical Rabbit Polyclonal to Histone H2A (phospho-Thr121) trials to investigate the safety and efficacy of CD19 CAR-T cell therapy in relapsed and refractory B cell lymphoma, the complete remission was observed in 6/14 patients at 3 months with 77% overall response rate [5]. Subsequently, various clinical trials expanding CAR-T indications to other hematological malignancies were carried out. However, disease relapses following CAR-T therapy becomes a severe problem limiting clinical curative effect which cannot be ignored. On the one hand, antigen-positive or negative relapses occur in patients which leads to resistance to CAR-T cell therapy [6, 7]. On the other hand, poor persistence and restricted function resulted from T cell exhaustion is also a common cause of relapse [8]. In this review, we discuss the characteristics of exhausted CAR-T cells in hematological malignancies, as well as the strategies to restore Olaquindox the function and prolong the survival of exhausted CAR-T cells. 2. Molecular and Functional Characteristics of CAR-T Cell Exhaustion T cell exhaustion was firstly described in mice during Olaquindox lymphocytic choriomeningitis virus (LCMV) infection [9, 10]. Subsequently, similar findings were defined in human with chronic viral infection, as well as in cancers [11, 12]. Tex cells were characterized as a distinct population with loss of proliferation potential and effector function, multiple immune inhibitory receptors upregulation [13]. These features are used together for Tex cells definition. 2.1. Loss of Effector Function It is clear that Tex cells are always lack of additional proliferation ability upon restimulation from Tregs that inhibit CAR-T cell activity and proliferation. Alteration of metabolic environment, including increase of adenosine by CD39 and CD73 in MDSCs, accumulation of kynurenine by IDO from tumor, limitation of arginine, and high level of glutamine, results in tumor cell survival and CAR-T cell dysfunction. 3.1. Inhibitory Receptors in Tex Cells Sustained expression of multiple inhibitory receptors is a key characteristic of Tex. It was established that tumor cells can escape through immune checkpoint pathways including CTLA-4 and PD-1 in hematological malignancies [21]. The PD-1 expression in CD19 CAR-T cells has already been described in clinical trials [22]. PD-1 limits CAR-T cell function when engagement with its ligand programmed death-ligand 1 (PD-L1) [23, 24]. Aberrant PD-L1 expression is not only observed in solid tumors but also Olaquindox detected in hematological malignancies including DLBCL, CLL, and AML [18, 25, 26], which creates opportunities for engagement of PD-1 and PD-L1. The PD-1 expression can be regulated by transcriptional factors (TF) and epigenetic modification. There is an additional enhancer in Tex cells which promotes the PD-1 expression [27, 28]. Upregulation of T-bet is consistent with PD-1intEomeslo Tex formation, while Eomes is elevated in the more terminal Tex subset [29]. NFAT is a transcription factor family with a clear effect in T cell exhaustion, which binds to PD-1 promoter to induce inhibitory receptor expression [30]. Recently, it has been demonstrated that relative deficiency in c-JunCc-Fos AP-1 heterodimers related to T cell exhaustion. Overexpression c-Jun in CAR-T cells reduced Olaquindox the PD-1 expression, restored effector function, reversed exhaustion, and improved cytotoxicity against tumor cells in different leukemia models [31, 32]. Furthermore, in a murine model with AML, B7-1, the specific ligand of CTLA-4, is increased in tumor cells, which mediated the resistance to immune response and poor survival [33]. In addition, the CAR-T cells from murine model involved in AML showed a significant upregulation of the Tim-3.

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