The focus of two main areas of optimizing T-cell therapies are designing optimal genetic modifications of T cells and engineering improved cell activation and culture processes during ex vivo T-cell expansion ( 14). Manufacturing of modified T cells is a multi-step process ( 13). Namely, the expression of TCF1/7, a transcription factor critical to maintaining immunological memory, decreases during the transition from the plastic to the irreversible and fixed dysfunctional chromatin state ( 11, 12). T cell exhaustion comprises a differentiative process of several stages, accompanied by significant epigenetic reorganization and distinct transcriptional signatures ( 9, 10). However, expression of these molecules is also upregulated during early T cell activation, presumably as a homeostatic mechanism that modulates activation downstream of co-stimulatory signaling ( 8). Generally, exhausted T (Tex) cells have decreased expression of effector cytokines and increased expression of inhibitory immune checkpoint receptors such as PD-1, TIM-3, LAG-3, TIGHT, and CTLA-4 ( 7). T cell exhaustion is a homeostatic mechanism that protects the organism against severe immunopathology from overwhelming CD8 T cell responses ( 6). Hence, developing methods to counteract T-cell exhaustion and improve functionality is essential to improving ACT efficacy. However, many patients fail to achieve long-lasting remission due to loss of CAR T cell persistence and functionality ( 5). CAR T cell therapy, which involves the transfer of allogeneic or autologous T cells modified to express a chimeric antigen receptor (CAR), has gained FDA approval with studies documenting durable remissions in patients with relapsed/refractory (R/R) hematologic malignancies ( 2– 4). In the past few decades, cell-based therapies with chimeric antigen receptor (CAR) T cells, engineered T cell receptor (eTCR) T cells, tumor-infiltrating lymphocytes (TILs), and other antigen-specific T cells have rapidly developed and shown enormous clinical potential. Barnes and Loutit initially proposed the ACT concept in 1956, describing the graft-versus-leukemia (GvL) effect of allogeneic hematopoietic stem cell transplantation (HSCT), which represents the earliest clinical example of the adoptive transfer of T cells with anti-cancer activity ( 1). We further discussed the synergistic benefits of the dual-targeting approaches and proposed novel vasoactive intestinal peptide receptor antagonists (VIPR-ANT) peptides as emerging candidates to enhance cell-based immunotherapy.Īdoptive T-cell therapy (ACT) is a form of cellular immunotherapy in which tumor-reactive T cells recognize and eliminate malignant cells after infusion into patients. Here we reviewed the current small-molecule strategies to enhance T-cell expansion, persistence, and functionality during ex vivo manufacturing. Investigators are addressing the current obstacles by focusing on the manufacturing process of effector T cells, including engineering approaches and ex vivo expansion strategies to regulate T-cell differentiation. However, cellular exhaustion and senescence limit the efficacy of FDA-approved T-cell therapies in patients with hematologic malignancies and the widespread application of this approach in treating patients with solid tumors. In the past decades, advances in the use of adoptive cellular therapy to treat cancer have led to unprecedented responses in patients with relapsed/refractory or late-stage malignancies. 6Department of Microbiology and Immunology, Emory University of School of Medicine, Atlanta, GA, United States.5Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States.4Departmert of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, United States. ![]() 3Winship Cancer Institute, Emory University, Atlanta, GA, United States.2Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United States.1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, United States.Hanwen Zhang 1*, Tenzin Passang 1, Sruthi Ravindranathan 1, Ramireddy Bommireddy 2,3, Mohammad Raheel Jajja 4, Lily Yang 3,5, Periasamy Selvaraj 2,3, Chrystal M.
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