Search

The accessibility of CAR-T cells in centralized production models faces significant challenges, primarily stemming from logistical complexities and prohibitive costs. However, European Regulation EC No. 1394/2007 introduced a pivotal provision known as the hospital exemption. This exemption enables academic institutions to produce ATMPs, including autologous CAR-T cells, under GMP conditions tailored to specific needs. In response to this regulatory framework, our work group has launched a guideline initiative. This endeavor aims to bolster academic CAR T-cell manufacturing by implementing strategic workshops that serve a dual purpose: standardizing production processes and ensuring both efficacy and safety standards are met. This inaugural focused on delineating criteria for the release of fresh CAR-T cell batches. Key emphases included thorough product characterization, stringent safety and potency evaluations. These criteria are essential for compliance with regulatory mandates and aligning with industry best practices. Notably, the release of initial CAR T-cell batches will be facilitated through provisional certification, with final certification contingent upon the acquisition of comprehensive analytical control results. This procedural framework adheres to methodologies endorsed by the SFGM-TC and the EBMT. Such adherence underscores a commitment to harmonizing practices across academic manufacturing facilities, thus fortifying the accessibility, efficacy, and safety of point-of-care units., Competing Interests: Competing interests: OB received research funding and/or honoraria from Argenx, BMS, CSL Behring, Egle Tx, OGD2 and UCB. DB: Declares no conflict of interest in the field of CAR T cells. HB: Licensing fees and royalties from Medac; research support from Erydel, Miltenyi, Sandoz-Hexal (a Novartis company); honoraria and speaker fees from Medac, Miltenyi, Novartis and Terumo BCT; consultancy and membership of advisory boards for Boehringer-Ingelheim, Celgene (a BMS company), Medac, Novartis and Sandoz-Hexal; stock ownership in Healthineers CC: received research funding and honoraria (institutional or personal) for participation in advisory boards and speakers bureau from BMS, Janssen Pharmaceuticals, Kite/Gilead, Miltenyi Biotec, Novartis. BC: Declares no conflict of interest in the field of CAR T cells. AC: Declares no conflict of interest. GD: Declares no conflict of interest in the field of CAR T cells. JSD: Declares no conflict of interest in the field of CAR T cells. SD: Declares no conflict of interest in the field of CAR T cells. JDV: Declares no conflict of interest in the field of CAR T cells. AD: Declares no conflict of interest in the field of CAR T cells. LD: Declares no conflict of interest in the field of CAR T cells. CF: shareholder and employee Advesya. EF: received honoraria for participation in advisory boards and speaker’s bureau from Kite/Gilead, Novartis, Alexion, Astellas, GSK. JG: Declares no conflict of interest in the field of CAR T cells. AG: Declares no conflict of interest in the field of CAR T cells. CG: Declares no conflict of interest in the field of CAR T cells. JM: Declares no conflict of interest in the field of CAR T cells. CM: Declares no conflict of interest. JL: received honoraria from Novartis, Kite/Gilead, BMS, Janssen, Miltenyi Biotec. LR: Declares no conflict of interest in the field of CAR T cells. SV: Declares no conflict of interest. IYA: received honorarium from Novartis, BMS, KITE and Milteny Biomedecine. MD: shareholder and employee Advesya., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

While CAR-T and tgTCR-T therapies have exhibited noteworthy and promising outcomes in hematologic and solid tumors respectively, a set of distinct challenges remains. Consequently, the quest for novel strategies has become imperative to safeguard and more effectively release the full functions of engineered T cells. These factors are intricately linked to the success of adoptive cell therapy. Recently, CRISPR-based technologies have emerged as a major breakthrough for maintaining T cell functions. These technologies have allowed the discovery of T cells' negative regulators such as specific cell-surface receptors, cell-signaling proteins, and transcription factors that are involved in the development or maintenance of T cell dysfunction. By employing a CRISPR-genic invalidation approach to target these negative regulators, it has become possible to prevent the emergence of hypofunctional T cells. This review revisits the establishment of the dysfunctional profile of T cells before delving into a comprehensive summary of recent CRISPR-gene invalidations, with each invalidation contributing to the enhancement of engineered T cells' antitumor capacities. The narrative unfolds as we explore how these advancements were discovered and identified, marking a significant advancement in the pursuit of superior adoptive cell therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Engineered T-cell therapies have proven to be successful in cancer and their clinical effectiveness is directly correlated with the infused T-cell differentiation profile. Indeed, stem cell memory and central memory T cells proliferate and persist longer in vivo compared with more-differentiated T cells, while conferring enhanced antitumor activity. Here, we propose an optimized process using cord blood (CB) to generate minimally differentiated T-cell products in terms of phenotype, function, gene expression, and metabolism, using peripheral blood (PB)-derived T cells cultured with IL-2 as a standard. Phenotypically, CB-derived T cells, particularly CD4 T cells, are less differentiated than their PB counterparts when cultured with IL-2 or with IL-7 and IL-15. Furthermore, culture with IL-7 and IL-15 enables better preservation of less-differentiated CB-derived T cells compared with IL-2. In addition, transcriptomic and metabolic assessments of CB-derived transgenic T cells cultured with IL-7 and IL-15 point out their naivety and stemness signature. These relatively quiescent transgenic T cells are nevertheless primed for secondary stimulation and cytokine production. In conclusion, our study indicates that CB may be used as a source of early differentiated T cells to develop more effective adoptive cancer immunotherapy., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)