Committed to the precise manufacturing of immunogenic T cell therapy
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Committed to the precise manufacturing of immunogenic T cell therapy
Committed to the precise manufacturing of immunogenic T cell therapy. In this article, we reviewed the current CAR-T unit production process, discussed the main challenges and commented on the latest developments in related manufacturing platforms. Finally, we will describe process improvement strategies for treating a large number of patients.
Standard and replicable autologous T cell manufacturing process
The current CART cell manufacturing process begins with the collection of peripheral blood leukocytes through hematology (Figure 1). Then use commercially available devices (for example, Haemonetics Cell Saver 5+ and Terumo COBE 2991) to wash and concentrate the cells. According to our experience, the effective separation of lymphocytes and bone marrow cells can be achieved by size-based centrifugation systems (for example, TerumoBCT Elutra) [10]. Using immunomagnetic beads coated with anti-CD3 and -CD28 monoclonal antibodies (for example, ThermoFisher Scientific CTS DynaBeads), T lymphocytes can be further enriched by positive selection [11,12].
Alternatively, Ficoll density centrifugation or an automatic closed cell processing system (such as GE Biosafe Sepax II) can be used to separate peripheral blood mononuclear cells (PBMC) [13]. In this method, purified lymphocytes are subsequently stimulated with soluble anti-CD3 antibodies [8,14]. In addition, before in vitro stimulation, magnetic activated cell sorting (MACS) can be used for further T cell enrichment or to determine the separation of subpopulations [15-17].
Efficient delivery of CAR transgenes to T lymphocytes is essential for the successful production of effective cell products. Lentiviruses, retroviruses, and transposon/transposase systems are common methods of transgene delivery in clinical settings. In some cases, transfection of in vitro transcribed messenger RNA mediates sufficient levels of CAR expression in T cells and has the additional benefit of preventing long-term transgene expression [18].
Continuous production of the best viral vector is a key step to ensure effective genetic modification of therapeutic T cells. According to our experience, it is possible to use the third-generation high-titer lentiviral vector for gene redirection of T cells. Levine et al. recently reviewed the process of producing these lentiviral vectors [19].
In short, HEK293T cells were transfected with packaging and transfer plasmids required for the production of replication-defective viral vectors [20]. The packaging system uses plasmids encoding Gag-Pol, Rev, and envelope genes (for example, usually encoding vesicular stomatitis virus glycoproteins) to generate a pseudotype.
The transfer plasmid contains the CAR transgene and cis-acting sequences required for effective reverse transcription, packaging and integration. Compared with retroviral vectors, the main advantage of using lentiviral vectors is that they tend to integrate in regions of the genome that are not close to the promoter, resulting in a relatively low risk of insertional mutagenesis [21].
Figure 1. Standardized production of CAR T cells.
Cytokines further promote expansion and in vitro culture. For example, using antibody-coated magnetic beads and interleukin (IL)-2[11,12], the combination of IL-7/IL-15[22] has successfully achieved the successful production of CD19-specific CAR T cell products or with Soluble anti-CD3 antibody bound by IL-2 [8,14].
Cell lines expressing tumor-associated antigens (eg, CD19) and IL-2/IL-21 [23, 24] have also previously been used to produce CD19-specific CAR-T cell products for clinical trials. After expansion for a certain period of time, the T cells are harvested, washed and stored frozen in an insoluble medium. Finally, after in-process testing and release standards are met, the cryopreserved cell product can be shipped to the clinic to treat the patient (Figure 1).
Autologous T cell manufacturing process needs to be optimized
In the case of B-cell malignancies, CD19 is an antigen widely used in immunotherapy. CD19 is expressed in all pre-B cell and mature B cell populations, and B cell hypoplasia can be controlled in people receiving immunoglobulin therapy [25]. Therefore, the production of CD19-specific CARs that bind to the costimulatory domain of 4-1BB[6] or CD28[8,26] has achieved great success in clinical settings [2,12,14,15,25,27-29] .
In particular, 4-1BB CAR-modified T cell products have shown long-term persistence and sustained anti-tumor activity in most patients with relapsed/refractory ALL [2]. However, in the more immunosuppressive B-cell chronic lymphocytic leukemia (CLL), the overall clinical response rate of clinical trials is 57%. However, some patients show long-term persistence to these adoptively transferred CAR-T cells [29]. Unlike ALL, the poor quality of T cells in CLL may be attributed to their pseudo-failing state and the inability to form functional immune synapses with tumor cells, resulting in poor proliferation [30,31].
The best “seed” population for the production of effective T cell products
The heterogeneity of cells isolated from the product of leukocyte separation may be attributed to donor-specific and disease-related variables, including age, race and gender, and disease type/burden. Therefore, the presence of non-T cell components, such as myeloid cells [35-37], and the difference in T cell composition (for example, the increase in the number of regulatory T cells [38]) or the intrinsic quality (that is, the increase in the number) of false fatigue /The number of tired T cells [30] may hinder the stimulation and subsequent expansion steps in the cell manufacturing process.
Although methods such as gold panning and magnetic bead-based selection methods can be used to enrich T cells before activation and transgene delivery, the final cell product may still contain non-T cell components, thereby affecting the safety and efficacy of the treatment. For example, we recently reported the accidental transduction of leukemia cells and the reinfusion of CAR modified tumor cells and CAR T cells in ALL patients [39]. As a result, leukemia cells expressing CAR expanded in vivo and escaped the detection of CAR T cells by masking the CD19 epitope in cis [39]. This finding emphasizes the importance of improving the efficiency of T cell selection before genetic modification and expansion.
Depending on the overall differentiation state, the bulk human T cells that constitute the seed population for T cell production consist of several subsets. These populations include naive (Tn), stem cell memory (Tscm), central memory (Tcm), effector memory (Tem) and terminally differentiated effector cells (Teff) [40]. These different subsets can be characterized by the differential expression of specific surface markers (such as CCR7, CD62L, CD45RO, CD45RA and CD95) [41].
It is speculated that the adoptive transfer of poorly differentiated or early memory T cells into cancer patients may improve anti-tumor immunity [42]. The reason is that the Tscm and Tcm lineages with a lower degree of differentiation show superior proliferation capacity and self-renewal potential. Fully differentiated Teff [40,43,44]. In fact, compared with other traditional memory and effector T cell populations, the CD8+ Tscm subpopulation has these characteristics and mediates deep and continuous tumor regression [40]. Subsequent studies evaluated the less differentiated T cell subpopulation as the starting population for CART cell production.
In a study, CD8+ Tn cells were enriched from healthy donors to produce CAR T cell products [16]. These Tn cells are then stimulated with Dynabeads (ThermoFisher Scientific) in a specific medium that is conducive to Tscm production. Compared with the products produced by a large number of CD8+ T cells, the metastasis of these modified T cells leads to prolonged tumor control time in the ALL xenograft model [16].
Another study focused on evaluating CD19-specific CART cells generated from enriched CD8+ Tcm subpopulations to treat non-Hodgkin’s lymphoma [45,46]. We recently reported that the frequency of CD27+ CD45RO- subpopulations in prefabricated CD8+ T cells is predictive. Studies on the response and resistance of CAR T cell therapy to CLL indicate that this population may be the target of enrichment at the beginning of the manufacturing process. Enhance the in vivo efficacy of anti-CD19 CAR T cells [47].
Previous studies have shown that the persistence of CAR T cells in neuroblastoma patients depends on the absolute number of CD4+ T cells in the cell infusion product [33], and both CD4+ and CD8+ T cell subsets mediate synergistic anti-tumor activity. This setting is in [48]. Therefore, the most recent attempt is to study the effect of combining CAR T cells derived from CD4+ T cells with CD8+ T cell subsets in a fixed ratio to produce uniform cell products [15,17]. In these studies, CD4+ T cells were enriched by positive selection, CD8+ T cells were selected by consuming CD4+, CD14+ and CD45RA+ cells, and then CD62L+ cells were further purified [15]. The resulting CAR-T cell product is an expanded mixture. A fixed ratio of 1:1 CD4+ and CD8+ T cell subsets is very effective, and 93% of adult ALL patients have remission in the bone marrow [15]. These findings emphasize the feasibility, safety and practicality of choosing fixed CD4+ and CD8+ T components to produce CART cell products for the treatment of patients [15].
All in all, these studies show that choosing a less differentiated T cell subpopulation with self-renewal ability and strong anti-tumor activity may be the best choice to improve the uniformity, long-term durability and anti-tumor activity of CAR T cell products. However, it should be noted that the low frequency of early memory cells in the peripheral blood of patients may limit their use in this area. In addition, selecting a certain subpopulation of T cells from patients before T cell stimulation will add a certain degree of complexity and may increase the length and cost of the manufacturing process. Clinical-grade reagents and equipment may also be limited. In particular, the best cell surface markers for defining these subgroups are still being studied.
T cell activation, expansion and in vitro culture
Enriched T cells must be optimally activated to achieve effective transduction of lentiviral and retroviral vectors, and then expanded to meet the total infusion dose. Current challenges at this stage of the process include, if needed, generating sufficient numbers of T cells to treat patients with multiple doses, while minimizing differentiation and maintaining consistent proliferation potential. Here, we review the current strategies and latest developments of these steps in the honeycomb manufacturing process.
Anti-CD3 and CD28 magnetic beads
Our group is the first method to immobilize monoclonal antibodies against CD3 and CD28 on magnetic beads [49]. This improvement greatly enhances the activation and activation of human T cells by providing TCR stimulation and co-stimulation through CD28 linkage. Amplification. Monoclonal antibodies are reported that anti-CD3 (OKT3) with IL-2 can activate and amplify PBMC to generate sufficient number of CART cells to treat patients [50]. Subsequent studies have shown that magnetic beads have selective growth of Tcm cell expansion for T cells coated with anti-CD3 and CD28 antibodies compared with cultures using soluble anti-CD3 antibodies and large doses of IL-2 [51]. This method has been widely used for large-scale production of T cells for adoptive T cell therapy [12,25,27].
Although anti-CD3/CD28 beads effectively induce the activation and proliferation of CD4+ T cells [49], CD8+ T cells generally do not expand this stimulation method like CD4+ T cells. This may be due to the lack of additional costimulatory molecules and adhesion. Molecule [56,57]. Further understanding of the particle size and shape of magnetic beads and optimal immune synapse formation should help develop T cell stimulators based on next-generation magnetic beads.
Although the magnetic beads are uniformly manufactured, they can only remain stable for a limited time. In addition, the manufacture of magnetic beads coated with other antibodies requires complicated protein purification and coating processes. This poses a challenge for adding other molecules that may be beneficial for T cell activation (Table I).
Cell-based artificial antigen presenting cells
Many groups, including ourselves, have tried to use the cell-based artificial antigen presenting cell (aAPC) platform as an alternative to ex vivo T cell-based stimulation to expand human T cells in vitro. Currently, Drosophila cells [58], NIH-3T3 murine fibroblasts [59] and the human erythrocyte-like cell line K562 have been used as aAPC [60] (Table II).
K562 cells
K562 is the most widely used cell-based aAPC. This cell line lacks the surface expression of human leukocyte antigen (HLA) class I and II molecules. Unlike magnetic beads, K562 can easily express other costimulatory molecules through viral transduction [60,61]. We originally designed K562 cells to express low-affinity Fc receptor CD32 and 4-1BB ligand (4-1BBL) [60]. However, in this system, aAPC and T cells must be co-cultured in the presence of soluble anti-CD3 and -CD28 antibodies. These antibodies can provide TCR and costimulatory signals to activate T cells. Compared with the bead-based culture system, this platform has the advantage of more powerfully stimulating CD8+ T cells [60].
Compared with the original anti-CD3 and -CD28 antibody-coated versions, it was found that K562 cells expressing other costimulatory molecules (such as CD83, CD86, CD80, 4-1BBL and OX40) can enhance the proliferation of CD8+ T cells [61]. The K562-based aAPC expressed by 4-1BBL enables the expansion and survival of CD28-negative CD8+ T cells. CD28-negative CD8+ T cells are the main T cell subset that increases in aging humans [60,62-64]. Compared with anti-CD3/CD28 magnetic beads and anti-CD3/CD28 aAPC, repeated stimulation of CD8 + T cells with aAPC expressing 4-1BBL can rapidly and increase the expansion of CD8 + T cells [60].
K562 cells can be further modified to express CD19 together with membrane-bound cytokines (such as IL-15) to spread clinical grade CD19-specific CART cells [13,68]. Recently, K562 cells engineered to express membrane-bound forms of anti-CD3 monoclonal antibodies (mAb) (mOKT3) and other costimulatory molecules (CD80 and CD83) can induce durable T cell activation [69,70]. In a comparative analysis with anti-CD3/CD28 Dynabeads, mOKT3 (K562/mOKT3) expressing K562 provided relatively short-term T cell stimulation and produced excellent proliferation signals of CD8+ T cells, accompanied by enrichment of Tscm subtypes [69]. This leads to the persistence of these adoptively transferred T cells in vivo and the prolonged anti-tumor efficacy [69].
In addition, the feasibility and safety of administering a leukemia cell vaccine composed of radioautologous tumor cells and bystander K562 cells engineered to produce GM-CSF in patients with advanced CLL has been demonstrated [74]. These findings provide other reasons for using K562-based aAPC as an alternative and safe platform for large-scale cell manufacturing.
NIH3T3 fibroblasts
Adherent mouse embryonic fibroblasts (NIH3T3) can be used to expand T cells in vitro [59]. Similar to K562 cells, they are engineered to stably express human CD80, intercellular adhesion molecule 1 (ICAM-1 or CD54), LFA-3 (CD58) and MHC class I peptide complexes for effective antigen specificity Expansion of cytotoxic T lymphocytes (CTL) [59,75]. However, the safety of NIH3T3 cells in the clinical production of human T cells has yet to be determined.
Alternative cell manufacturing technology
Several companies and academic centers have designed stimulatory reagents for CAR T cell manufacturing. Examples include MACS GMP TransAct CD3/CD28 magnetic beads (Miltenyi Biotec Inc) [78], Expamer platform (Juno Therapeutics) [79], phase change hydrogel matrix and agonist antibody (Quad Technologies) and other new technologies (Table I) ).
TransAct CD3/CD28 magnetic beads are a polymeric nano-matrix, composed of nanoscale iron oxide crystals conjugated with anti-CD3 (clone: OKT3) and CD28 mAb (clone: 15E8). It is a biodegradable soluble reagent that can be passed through Centrifugation easily removes from the cells (Table I). It has been proven that this stimulating reagent can provide an effective and easy-to-use method by which T cells can be expanded under GMP conditions [80].
Optimizing strategies for in vitro T cell culture
In the presence of the above-mentioned T cell stimulators, T cells are expanded in a cytokine-containing medium on a large scale to meet the clinical dose for adoptive transfer. According to our experience, after 9-11 days of culture with IL-2 and anti-CD3/CD28 antibody-coated beads, T cells can grow to a sufficient number [12]. However, manufacturing difficulties and even failures have occurred using this method, which highlights the need to improve the current T cell expansion system.
Regarding the instruments used to optimize these processes, Wang et al. recently reviewed Wave bioreactors (GE Healthcare Life Sciences), G-Rex bioreactors (Wilson Wolf Corporation), and CliniMACS prodigy systems (Miltenyi Biotec Inc.) [84] Several devices and platforms for T cell expansion. In the following sections, we will focus on improving T cell expansion protocols that can improve the quality and yield of CAR T cells during large-scale in vitro expansion.
Optimizing cultured cytokines
Adding exogenous cytokines to large-scale cell cultures can provide growth and homeostasis signals for T cells. Historically, IL-2 has been used in adoptive treatment methods to enhance the proliferation of transferred T cells (especially CD8+ T cells). However, IL-2 may be harmful to the persistence of memory T cells with high differentiation potential, and due to its high level of IL-2 receptor alpha chain, it also increases the number of immunosuppressive T cells (Treg) ( CD25) [85,86].
In contrast, IL-7 and IL-15 are important mediators of T cell expansion, which can promote the persistence of Memory T lymphocytes without selectively driving Treg expansion [87]. Compared with CD4+ T lymphocytes, the expression of IL-7 greatly increases the size of the T cell pool and slightly facilitates the expansion of CD8+ T cells [88]. In vitro, the addition of IL-7 can enhance the ability of CD3/CD28 activated T cells to produce IL-2 [88].
Similarly, IL-15 is a key CD8+ T cell survival factor. Recent studies have shown that in vitro culture of murine T cells in IL-15 will lead to CTL populations, which are actually more effective when transferred to tumor-bearing mice [89]. When the anti-tumor efficacy of redirected human T cells was tested after culturing in IL-15, another group of people obtained similar results [90].
It has also been suggested that the combination of IL-7 and IL-15 drive the expansion of human CD8 + Tscm cells [91]. A recent study emphasized that IL-7 and IL-15 are better than IL-2 in the enrichment and expansion of early memory T cell subsets from B-cell ALL patients [22]. In addition, compared with soluble IL-15, NIH3T3-based aAPCs expressing IL-15/IL-15R can expand virus-specific T cells with a Tcm-enriched phenotype [92], indicating that the IL-15/15R complex may It is a substitute for soluble IL-15.
IL-21 is another cultured cytokine under study for improving the expansion of T cells in vitro. In combination with IL-2, IL-21 supports the digital expansion of CAR T cells, which is characterized by an increased frequency of Tn and Tcm cells [93].
Therefore, it is conceivable that optimizing the combination of cytokines will be an effective and simple T cell expansion strategy to improve the quality and yield of CAR T cells.
Limit the duration of T cell manufacturing
The cost of dynamic culture systems, reagents, and labor have a significant impact on the scalability of the cell manufacturing process. Therefore, researchers are already designing strategies to reduce manufacturing time and reduce costs without sacrificing the yield and quality of cell products. Indeed, we and others have recently conducted preclinical studies to shorten the production time as a strategy to support the generation of rapidly differentiated CART cells [95,96]. Using this method, we proved that effective CART cells can be produced, characterized by their strong proliferation and cytolytic activity [96]. After conducting these feasibility studies, a rapid CART cell expansion process based on a closed manufacturing system and serum-free medium was recently reported [97]. Therefore, limiting the manufacturing time is a feasible method for process and product improvement.
Reproducibility and scalability of T cell manufacturing
Most CAR T cell manufacturing facilities are located in academic institutions, including the University of Pennsylvania, Memorial Sloan Kettering Cancer Center, and the National Cancer Institute. Many of these academic centers have established strategic partnerships with small or large pharmaceutical companies with the goal of commercializing cell therapies. These manufacturing plants are involved in the production of patient-specific cell products for phase 1 and 2 clinical trials. Currently, the manufacturing process relies on skilled cell manufacturing experts and many open processing steps. When performing these open processing steps, even small changes can affect the quality of the final cell product. It is necessary to consider the production of a stable and robust transgene delivery platform for predictable cytogenetic engineering, understand the long-term safety of gene therapy and anticipate global regulatory limitations.
Improve cell manufacturing efficiency
As mentioned above, the rapid growth of knowledge surrounding CAR T treatments has led to a deeper understanding of how to improve individual CAR T manufacturing steps. In addition, for clinical T cell production, the following basic requirements must be considered. First, the manufacturing process must be optimized to provide patients with safe and robust cellular products. The best selection and expansion/culture of the best functional T cells from patients (including the use of T cell stimulators, media, cytokines, and the incorporation of pharmacological modulators into the culture system) remains a major challenge. Secondly, improving the robustness of the manufacturing process and reducing the manual workload, while minimizing the risk of contamination and increased production capacity, together promote the need for standardization of T cell manufacturing.
Automated cellular manufacturing
Considering that the production of autologous T cells requires a large amount of labor and each step requires the use of multiple instruments, expensive reagents and several open operating procedures, it is crucial to minimize the variation that may affect reproducibility, efficacy and safety. important. In this regard, the recently developed automation system seems promising. Many semi-automatic or fully automatic devices are being developed to perform individual processing steps (for example, Biosafe Sepax and Elutra for cell separation; Cell Saver and COBE cell processor for cell washing and concentration). Currently, the only system that can automate the steps of T cell isolation, activation, transduction and expansion is CliniMACSTM Prodigy (Miltenyi Biotec Inc.) [109]. The device can generate honeycomb products in a completely closed system, thereby effectively simplifying the manufacturing process of T cells.
Gene editing technology for T cell manufacturing
Another way to simplify T cell manufacturing is to produce generic “off-the-shelf” T cell products for adoptive cell therapies that serve more patients. The emergence of new gene editing technologies, including zinc finger nucleases (ZFN), transcriptional activator-like effector nucleases (TALENs), and recently clustered regularly spaced short palindrome repeats (CRISPR/CRISPR-related 9 (CRISPR/ Cas9), paving the way for the commercialization of allogeneic generic “off-the-shelf” production.
Large-scale cell therapy (Figure 2). Using “off-the-shelf” generic T cell products, we can overcome due to quality, yield and/or disease status Poor and unable to produce T cell products from the patient’s body. This will reduce manufacturing costs and time, resulting in replicable and effective T cell products. Importantly, by targeting endogenous αβTCR and MHC class I molecules HLA, It can minimize the risk of graft-versus-host disease (GVHD) mediated by alloreactive αβT cells and improve the ability of T cells to be transplanted into the recipient.
In addition to allogeneic T cells, the destruction of endogenous TCR through gene editing technology may be beneficial to the production of autologous TCR T cell products to reduce the TCR mismatch between endogenous TCR and recombinant TCR.
In 2016, the Recombinant DNA Advisory Committee of the National Institutes of Health approved a proposal by our research team at the University of Pennsylvania to use CRISPR/Cas9 to knock out endogenous TCRα/β chains and programmed cell death 1 (PD1, The T cell failure marker in NY-ESO-1 redirects autologous human T cells. Based on the use and optimization of CRISPR/Cas9 and the use of similar gene editing technology in large-scale T cell production, it is expected to be in the near future General T cell products are used in clinical practice.
Costs associated with cell manufacturing
Cell products for human therapeutic use must be produced under GMP conditions that comply with the guidelines of regulatory agencies. The cost of extensive testing of such cell products is often staggering, which presents another challenge to commercialization. In addition to the evaluation of identity, purity and efficacy, if the culture is harvested within 96 hours after transduction, according to the FDA guidelines, the cell product modified by the integrated virus must also undergo retroviral and lentiviral vector replication capabilities (RCR/RCL) )filter.
The current standard method for RCR/RCL testing in infusion products is a cell culture-based method, in which the test sample is co-cultured with a highly permissible cell line (for example, lentiviral C8166 cells) for at least 3 weeks or more to reach the virus Amplify, and then end-point detection of RCR/RCL ability. However, these rigorous co-cultivation assays are time-consuming, laborious and very expensive. If RCR/RCL testing can be avoided by shortening the merging time, but an effective T cell manufacturing process (eg, harvesting the culture within 96 hours after transduction) can be used, production costs can be significantly reduced.
Alternatively, quantitative polymerase chain reaction (qPCR)-based detection of viral components or transgene expression is a rapid and cost-effective initial screening for RCR/RCL capabilities. Both qPCR and biological RCR/RCL tests are widely used to screen clinical viral vector batches and artificial T cell products.
However, to date, there is no evidence that clinical trials using third-generation lentiviral vectors [111] and retroviral vectors [112] have reported positive RCR/RCL results in cell products, which indicates the development of RCR in infusion products The possibility of /RCL is very small. We recently reported additional evidence supporting this safety profile [113]. Therefore, further efforts are needed to re-evaluate the FDA guidelines to screen RCR/RCL in lentiviral/retroviral modified T cell products.
Another major cost of the cell manufacturing process is human serum (HS), which is an important factor in enhancing the survival and growth of T cells. Commercially available HS is expensive and limited in quantity. In addition, the differences between batches must be evaluated to meet regulatory and performance requirements. The presence of serum in the cell product before infusion may also induce adverse patient events.
Therefore, HS alternatives of non-animal origin may be alternatives in the field of cell manufacturing and are currently being explored. In this regard, recent studies have shown that compared with traditional HS-containing expansion media, immune cell serum replacement (ThermoFisher Scientific) can at least promote T cell proliferation with the same efficiency.
For economic purposes, it is expected that the serum replacement will be integrated into the current T cell production with the goal of maintaining or improving the quality of T cell products.
Global regulatory expectations
Although the FDA has been regulating cell and gene therapy for many years and has developed guidance documents for product testing and release, these regulations are not consistent with other countries and regions. Therefore, depending on the focus of a particular regulatory agency, the cost of testing and releasing genetically modified cell products for clinical applications may vary greatly.
The work of harmonizing regulatory requirements on a global scale with the goal of standardizing best practices based on cell/gene therapy will greatly facilitate the creation of a safe, effective and cost-effective platform. In this regard, members of the global regulatory community have been actively trying to form a unified group to unify regulatory compliance standards [19].
Many challenges need to be considered when trying to provide safe, reliable and consistent cellular products in a complex manufacturing process. For this reason, close cooperation must be established between academic centers, industry and regulatory agencies to carefully evaluate products and processes , While paying attention to continuous improvement and promotion of optimization.
Predicting manufacturing problems before they arise, and working to standardize the production of immune gene T cell therapies through precision manufacturing will accelerate the process of bringing this promising treatment platform to the global patient population.
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