2021 The curret status of global CAR-T production and treatment

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2021 The curret status of global CAR-T production and treatment

2021 The curret status of global CAR-T production and treatment. Immunotherapy using chimeric antigen receptor-modified T cells has proven to have a high response rate in patients with B-cell malignancies, and chimeric antigen receptor T cell therapy is currently in several hematology and solid tumor types research.

Chimeric antigen receptor T cells are produced by removing T cells from the blood of a patient and engineering the cells to express chimeric antigen receptors that reprogram the T cells to target tumor cells. As chimeric antigen receptor T cell therapy enters late-stage clinical trials and becomes the choice of more patients, the manufacturing process of chimeric antigen receptor T cell compliance with global regulatory requirements has become the subject of widespread discussion.

In addition, the challenge of transferring the chimeric antigen receptor T cell manufacturing process from a single facility to a large multi-site manufacturing center must be resolved. We have foreseen these problems in our experience with CD19 chimeric antigen receptor T cell therapy CTL019.

In this review, we discussed the steps involved in the cell processing of this technology, including consistent cell processing using the best carrier, and addressing the challenge of expanding chimeric antigen receptor T cell therapy to the global patient population.

Chimeric Antigen Receptor (CAR) T cell therapy is a type of cell therapy that redirects the patient’s T cells to specifically target and destroy tumor cells. CAR is a genetically engineered fusion protein consisting of (1) antigen recognition domain from monoclonal antibodies and (2) intracellular T cell signaling and costimulatory domains [1-5]. The use of CAR T cells as a cancer treatment has been most extensively studied in patients with B-cell malignancies, and early results are encouraging. For example, CAR T cell therapy has confirmed that the complete remission rate of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) in phase 1 clinical trials is 69%-90% [6-10]. T

he development of CAR T cell therapy has now expanded to the first phase of trials and entered the second phase of multi-site trials (NCT02435849 and NCT02228096). A major consideration for academic institutions and industry is how to expand CAR T cells in an efficient and effective manner. produce. Here, we describe the process of making CAR T cells and discuss the regulatory issues that must be resolved to successfully produce CAR T cells for a large number of patients.

Production of CAR T cells

The production of CART cells requires several carefully executed steps and quality control testing throughout the protocol [11]. First, the process involves the use of leukopenia to remove blood from the patient, separate the white blood cells, and return the remaining blood to the circulation [12]. After harvesting a sufficient number of white blood cells, the white blood cell separation products are rich in T cells (Figure 1).

This process involves washing the cells from a leukocyte separation buffer containing anticoagulant [13]. Subsequently, the enrichment of lymphocytes is completed by countercurrent centrifugal elutriation, which separates cells by size and density and maintains cell viability [14]. The expression of CD4/CD8 compositions using specific antibody bead conjugates or markers to isolate T cell subpopulations at this level is an additional step that can be performed.

2021 The curret status of global CAR-T production and treatment

Purification of autologous antigen presenting cells (APC) from patients for T cell activation will require several additional steps, making it labor intensive and difficult to obtain effective CAR T cell products [11]. To this end, a method was developed to activate T cells in a more standardized and effective way using, for example, beads coated with anti-CD3/anti-CD28 monoclonal antibodies (Life Technologies).

Compared with beads coated with anti-CD3/anti-CD28 monoclonal antibodies or cells, it has become common practice for many years to use anti-CD3 antibodies alone or in combination with feeder cells and growth factors (such as IL-2). Based on artificial APC (aAPC), activation and ex vivo amplification are sub-optimal [16,17]. Beads or aAPC can be easily removed from the culture by magnetic separation [18]. In the presence of interleukin-2 and aAPC, T cells can grow logarithmically in a perfusion bioreactor for several weeks [11,16,18].

The use of aAPC derived from the chronic myeloid leukemia cell line K562 can be used to express the required costimulatory ligands, and has also been studied as a method for in vitro expansion of T cells [17,21]. The culture conditions can be further refined to polarize T cells to a specific phenotype (ie Th2 or Th17) during expansion. In fact, CAR T cells polarized to the Th17 phenotype have shown efficacy in preclinical models, indicating that T cell polarization is a strategy that may enter the clinic in the future [22].

During the activation process, the T cells are incubated with the viral vector encoding the CAR, and a few days later, the vector is washed out of the culture by dilution and/or medium exchange. Viral vectors use viral mechanisms to attach to patient cells, and after entering the cells, the vector introduces genetic material in the form of RNA [23]. In the case of CAR T cell therapy, this genetic material encodes CAR. RNA is reverse transcribed into DNA and permanently integrated into the genome of the patient’s cells; therefore, CAR expression is maintained during cell division and grows to large amounts in the bioreactor.

The CAR is then transcribed and translated by the patient’s cells, and the CAR is expressed on the cell surface. Lentiviral vectors have safer integration sites than gamma retroviral vectors [24,25], and are often used in clinical trials of CAR T cell therapy, including CTL019. Other gene transfer methods have been studied, including Sleeping Beauty transposon system or mRNA transfection, as an alternative method of expressing CAR in T cells [26,27].

CAR T cells produced by transient mRNA transfection have been used clinically; however, this method requires several rounds of CAR T cell infusion [28]. In addition, although the Sleeping Beauty transposon system is considered cheap and has been tested in early clinical trials, there are still some problems, including efficiency relative to lentiviral vectors, unknown potential for insertional mutations, and transposons Reactivate.

The bioreactor culture system is designed to provide optimal gas exchange requirements and culture mixing to cultivate a large number of clinical cells (Figure 2). The WAVE bioreactor (now called Xuri; GE Healthcare Life Sciences), using a rocking platform, has been used to expand CD19-targeted CAR T cell therapy CTL019 [11,20,30]. Another culture system that can be used is G-Rex (Wilson Wolf), which can expand cells from low seeding densities [31,32].

G-Rex uses a gas-permeable membrane to put the flask directly into the cell culture incubator. However, one disadvantage of this system is that the flask must be opened during cell seeding. CliniMACS Prodigy (Miltenyi Biotec) is a single device that can complete cell preparation, enrichment, activation, transduction, expansion, final preparation and sampling [33].

This is in contrast to other methods, which use separate machines for cell culture, cell washing and other steps in preparation. Recently, it has been shown that CliniMACs Prodigy can be used to generate CAR T cells, and it is expected that the device will soon be used to prepare CAR T cells for clinical trials [34].

When the cell expansion process is over, the volume of the cell culture can reach 5L, and it must be concentrated to a volume that can be injected into the patient [11,18]. The washed and concentrated cells are frozen and stored in an insoluble medium, and, after the product is released, the frozen cells are transported to the center where the patient will be treated and thawed therein. Although the aspects of cell washing, isolation and culture are semi-automated, improving the throughput of the current manual processing part is essential for developing CAR T cell therapies that can be used for a wider range of indications and a larger population.

Challenges of introducing CAR T cell therapy to the global patient population

Although a program for the production of clinical-grade CAR T cells has been established, CAR T cell therapy has only been used to treat a few hundred patients so far. When expanding this complex manufacturing process to treat more patients in larger trials in more clinical centers, the process should be carefully evaluated to ensure production efficiency without compromising the integrity and effectiveness of the final product.

Because CAR T cells can be used to target several types of cancer, the production scale of vectors and CAR T cells will also depend on the incidence of each indication. Other considerations include generating consistently high-quality vectors for predictable genetic modification of cells, understanding the long-term safety of gene therapy, and anticipating global regulatory issues.

Towards consistent cell processing: using the best carrier

In the United States, the viral vector used to transfer CAR into T cells is considered to be the key raw material for the manufacturing process of CART cells, and the modified T cells are considered to be research end products, also known as research drug products. European Union. In contrast to the final CAR T cell product that must be generated separately for each patient, viral vectors encoding CAR can be prepared in large quantities and stored at 80°C for 4 years in our experience. Other reports indicate that frozen viral vectors can be stable for up to 9 years at this temperature [35,36].

As with the CAR T cell manufacturing process, the production of carrier raw materials must be carried out in a Good Manufacturing Practice (GMP) facility. The sterility of the carrier is very important, because the final CAR T cell product cannot be sterilized by filtration; the carrier is manufactured under controlled clean room conditions, and minimal open processing and sterile filtration are performed in the final aseptic production stage. All of these are supported and verified through a series of safety tests to ensure sterility and no packaging cells in the final carrier product. In addition, the use of the third-generation minimal lentiviral vector, combined with key safety functions, enhances safety [37,38].

According to our experience, it takes at least 2 weeks to mass produce viral vectors for cell therapy. Most of the time is spent on culturing a sufficient number of cells, such as HEK293T cells, to produce a large number of replication-defective virus vectors [39]. Starting with cryopreserved aliquots of an appropriate working cell bank, the cells are expanded in the culture medium for several days to an appropriate production number, allowing a substantial expansion from the original seed cell number.

The cells are then transfected with plasmids, which together result in the production of minimal lentiviral vectors. These plasmids are usually (1) Gag/Pol packaging constructs, which encode viral structural proteins (Gag) and enzymes (Pol); (2) constructs encoding suitable envelope glycoproteins from heterologous sources, leading to pseudotyped vector particles (For example, VSV-G); (3) the expression construct of the viral accessory protein Rev; and (4) the vector plasmid encoding the CAR construct and other sequences required for effective reverse transcription, RNA packaging and integration [40].

The vector system should adopt many key safety features to jointly prevent the regaining of replication ability (for example, codon optimized Gag/Pol, which minimizes the homology between vector components to prevent recombination, and self-inactivates long terminal repeats. , And remove all unnecessary sequences and auxiliary genes) [41-43]. Within 48 hours of transfection, the producer cells begin to release the CAR-expressing lentiviral vector that can be collected from the culture medium.

Over the course of a few days, the medium exchange allows multiple batches of vector-containing medium to be harvested, usually two harvests. After the production cells and debris are removed by filtration, the viral vector is purified by downstream processing to enrich the viral vector, while removing impurities and formulating the vector into a suitable storage buffer.

According to our experience, the carrier can be frozen at this time to allow the production of multiple sub-batches to produce a larger amount of the final carrier product to improve economic efficiency. Once the target amount of carrier is available, additional GMP processes are performed, including filtration and sterilization of vials under aseptic conditions. After the production is completed, the carrier is frozen and stored until later use.

It is very important to establish quality control tests for safety, sterility, purity, potency, characteristics, and titer, so that the manufacturing center can ensure that each batch of vectors meets the required standards before being used to transduce T cells [44]. These quality control tests are described in guidance documents prepared by the U.S. Food and Drug Administration (FDA) and are briefly summarized here. Safety testing may involve preclinical experiments or toxicity studies on animals, with the aim of determining that the product is safe for humans when properly administered.

Test the sterility of the product to ensure that it does not contain contaminating microorganisms; in the case of γ retroviral vector and lentiviral vector, the determination of replication competent retrovirus/lentivirus (RCRs / RCLs) and the used in the process Mycoplasma testing of cells and culture media helps to determine that the final CAR T cell product does not contain foreign factors and is safe. Enter patients and extensively test the impurities in the vector product to (1) verify the consistent purification provided by the vector manufacturing process, and (2) thus ensure that the quality of the vector is consistent before it is used in the T cell manufacturing process.

Impurity testing includes testing for process-related impurities, such as Benzonase (Merck KGaA; used to degrade and promote DNA removal) and bovine serum albumin (derived from fetal bovine serum), as well as characterization of residual host cell DNA and residual plasmid DNA . In addition, test for bacterial and fungal contamination during the cell culture of T cells.

The effectiveness of the carrier product is tested to assess whether it works as expected, and its properties are proven through relevant physical, chemical or biological tests. For example, the titer of a viral vector can be measured by analyzing the percentage of healthy donor cells transduced by a predefined MOI, which can verify whether a particular batch of vector is expected to best transduce patient cells.

In early clinical trials conducted by the University of Pennsylvania, multiple vector suppliers were used in the production of CD19-targeted therapy CTL019. The use of carriers from different suppliers as starting materials raises other issues regarding carrier purity, stability, and comparability of functions. Therefore, it is expected to use a single vector source to generate CTL019 cells in current and future clinical trials.

In addition, vector suppliers should be able to meet GMP compliance and other requirements, and meet mass production needs. Therefore, our approach is to use a lentiviral vector manufacturing process that can meet the requirements of global health authorities and has appropriate supporting process verification (Figure 3).

Based on our experience using lentiviral vectors produced by Oxford BioMedica (OXB), we have found that consistent vector quality can minimize the site-to-site variation in the subsequent CAR T cell manufacturing process. In order to provide large enough batches to support clinical and commercial needs, the process has been designed and optimized to manufacture vectors in a series of multiple sub-batches in a given manufacturing activity spanning several weeks.

This method relies on purification and preparation steps prior to cryopreservation and subsequent retention periods. Once the sub-batch is proven to meet the key sub-specifications of the manufacturing stage, a specific sub-batch is selected for filling, and the final processing is completed within one day.

Choose the intermediate container closure system (and related filling volume), GMP processing parameters (freezing/thawing conditions, further aseptic processing conditions, final container, etc.) and formulation buffers to ensure that any loss of titer is minimized. Therefore, the resulting Of filling products meet the target specifications,And consistently and robustly in the T cell manufacturing process. In addition, the holding phase is supported by a stability test program, which shows that the carrier titer is stable during long-term storage.

The transduction efficiency of the OXBCTL019 vector was examined in a two-site study, and consistent dose-dependent transduction efficiency was observed at both sites (unpublished data). The study also provides an understanding of the variability of transduction efficiency between healthy donors, which provides a meaningful baseline for us to compare patient data. The data shows that the OXB vector can use the same performance in the donor and production sites. When selecting a carrier that can be produced and used on a large scale, these qualities are both desirable and necessary, and they reduce the risk of process validation.

Optimizing the vector for CART cell transduction before starting large-scale manufacturing can reduce variability and maximize efficiency. The scale of carrier production ultimately needs to consider the potential scale of the patient population on the basis of instructions. On this basis, our strategy is to concentrate the current clinical supply and initial commercial supply on the current and complete production platform, while investing in the development of next-generation production processes to provide functional vectors of the same quality.

The scale is significantly larger. The most common vectors used for CAR T cell manufacturing are replication-defective vector systems based on two types of retroviruses: gamma-retrovirus and lentivirus. Both γ retrovirus and lentivirus can provide RNA that is reverse transcribed into DNA in target cells; this DNA encoding the CAR construct is then integrated into the host genome through a process catalyzed by the vector integrase and several key sequences in the vector construct Zhong[23].

Another advantage of lentivirus-derived vectors is that they retain the ability of lentivirus. Infect non-dividing cells, thereby increasing their ability to transduce a variety of cells, including quiescent and difficult-to-transduce cells [45]. However, as mentioned earlier, the introduction of T cell activation during cell activation is necessary to improve transduction efficiency and lentiviral vectors.

Insertion mutagenesis caused by the integration of vector DNA into host cells near the oncogene is a potential problem for all integrated vectors [46,47]. However, the lentiviral integration mode is conducive to sites far away from the cell promoter, and gamma transcriptional viral integration more often occurs near the transcription start site, indicating that lentiviral vectors may have a lower risk of mutagenesis.

The risk of insertional mutagenesis also seems to depend on factors outside the vector system, such as the encoded transgene, promoter, and targeted cell type or disease. In our experience and decades of research, the carcinogenicity mediated by CAR T cell viral vectors has not been observed in patients treated with CAR T cells [48]. If RCRs / RCLs are present in the carrier product, it may increase the carcinogenic potential.

However, the current vector design makes the generation of RCRs / RCLs extremely unlikely. 49 The FDA 2006 guidelines believe that lentiviral and retroviral vectors may be carcinogenic; therefore, the clinically used CAR T cell therapy vectors are carefully tested RCR / RCL.

In addition to testing RCR throughout the vector manufacturing process and multiple stages of vector-modified cell products, the FDA also recommends that patients should follow RCRs/RCLs for up to 15 years to monitor any potential delayed adverse events associated with these vectors.

Investigating the long-term safety of viral vectors requires patient follow-up

Evaluating the long-term safety of using viral vectors for cell and gene therapy requires extensive follow-up. As mentioned above, the health authority guidelines also require the use of viral vectors for long-term follow-up of studies; however, the requirements may vary depending on the individual countries involved. For example, the United States (USA) trial has been developed to monitor patients who have received CD19 CAR T cell therapy CTL019 for 15 years after treatment (NCT02445222). The study will include patients of any age who have received CTL019 to treat any B-cell malignancies.

The main purpose of this follow-up study is to describe delayed adverse events that are suspected to be related to CD19 CAR T cell therapy, such as the development of new malignant tumors, the onset or worsening of pre-existing neurological diseases or autoimmune diseases, or new incidence. Blood disease. The secondary goal of the study is to monitor the persistence of CTL019 cells in peripheral blood and the long-term efficacy of treatment. The persistence of CTL019 cells was checked by using qPCR to detect the CD19 CAR transgene at specific time points.

In addition, the proportion of patients who relapse or experience disease progression will be monitored, as well as the incidence of patient deaths from any cause. Since the effect of persistent CAR T cells on pregnancy is still unclear, reproductive health and pregnancy outcomes will also be followed in female patients receiving CAR T cell therapy. Therefore, carefully designing and manufacturing viral vectors for CAR T cell therapy to maximize safety, as well as quality and safety testing and long-term patient follow-up, ensuring patient safety is the top priority.

Ensure product quality from a single organization to a multi-site large-scale manufacturing process

A major challenge in expanding the production of CAR T cell therapy is the transition from a flexible process at a single academic institution to a highly controlled process that can be implemented in many collection, manufacturing, and treatment sites (Figure 4). Therefore, effective coordination between the collection, manufacturing, and treatment sites involved is essential to ensure that the materials are handled correctly and that the patient is properly arranged throughout the treatment process.

The global manufacturing process for successfully developing CAR T cells will be promoted by a deep understanding of products and processes to determine the target product profile and key quality attributes. For CTL019, the target product profile includes those qualities that have already been discussed: targeting specificity, high-efficiency T cells, which are capable of powerful expansion and long-term persistence in the body.

Using this product profile, key quality attributes were explored. Cell number, transduction efficiency, growth rate, cell phenotype and functional analysis are all key quality attributes of CTL019, and these attributes are well understood and controlled. Cell phenotypes include measurements such as the distribution of T cell subsets (helper or cytotoxicity, effector or memory, etc.) and functionality (cell killing, cytokine release, proliferation capacity, failure, apoptosis, etc.).

These key quality attributes will be coordinated with process understanding to formulate consistent manufacturing processes and control strategies to ensure product uniformity. Examples include the percentage of CD3 + T cells in the product and the measurement of potency. However, it should be noted that the values of CAR positivity, vitality, phenotype and potency will vary from product to product. As more experience is gained and these data begin to be published, a fair comparison of utilities and appropriate scope can be assessed [51,52].

Supplier agreements (such as our previous agreement with OXB) are critical to maintaining a controlled manufacturing process. In the case of CAR T cell therapy, product comparability poses an additional challenge, that is, the variability between the starting materials of the patient’s plasma composition may produce greater differences than factors related to the manufacturing site. Therefore, we controlled the processes of CTL019 manufacturing and vector production in order to minimize the variability associated with the manufacturing process.

Meet global regulatory expectations and successfully implement CAR T cell therapy

Early results of CAR T cell therapy indicate that patients have significant benefits, and therefore, the treatment has the potential for clinical success, which may lead to greater global regulatory collaboration and coordination. The patient benefits provided by CAR T cell therapy provide a promising opportunity for establishing common ground between different regulatory agencies and improving international cooperation. Ensuring compliance is a key factor in the successful development of this new treatment method, which will be an interesting challenge in a global environment. For many years, the FDA has been monitoring cell and gene therapy and has developed many guidance documents on these products.

However, these guidance documents are inconsistent with other countries or regions. In addition, each major country has slightly different priorities when reviewing clinical trial applications. For example, the European Union (EU) countries require qualified personnel to determine cGMP compliance, while the United States uses paper reviews to assess cGMP compliance.

Therefore, the more countries participating in clinical trials, the more the manufacturing process needs to meet all issues and regulatory requirements. In order to achieve coordination in the emerging field of cell and gene therapy, on October 11, 2012, nine members of global regulatory agencies, including Brazil ANVISA; European Medicines Agency (EMA); Health Canada, India National Institute of Biological Products (NIB) ); Japan’s Ministry of Health, Welfare and Labor/Medical and Medical Devices Agency; Korea’s Ministry of Food and Drug Safety (formerly known as the Food and Drug Administration [KFDA]); Singapore Health Sciences Agency (HSA); Swiss Medicine Administration; The Food and Drug Administration convened a meeting to form a comprehensive group to discuss best practices in cell/gene-based therapy regulation and support coordination (https://www.iprf.org/en/working-groups/gene- therapy-workinggroup/).

CAR T cell developers should have a thorough understanding of this diverse regulatory environment. Before the formulation of uniform regulations and common experience between regions, we can expect significant uncertainties in product development and rely more on the subjective judgment of regulatory agencies.

An example of this challenge is the different manufacturing-related requirements that exist between regions. For example, donor screening and testing, traceability and labeling, patient confidentiality, and apheresis blood composition requirements may vary greatly from country to country. This is especially challenging if the donor raw materials and final products are transported across international borders.

Another example is the definition of the materials used (ie starting materials or raw materials) and the quality control requirements for these materials vary from region to region. Balancing the requirements of different countries and the quality of starting materials can be challenging, but it is essential for cross-border trials.

Therefore, the source, traceability, composition and certification of each reagent must be easily obtained. Finally, since each region has unique literature and recommendations related to the materials used in the manufacture of cells and gene therapy, human or animal serum used for cell culture has different requirements for global regions.

Therefore, in order to solve some of these regulatory issues, we are using reagents that meet the quality requirements of major regions around the world (for example, using the same international suppliers in all regions of the world) to establish CAR T cell manufacturing agreements.

Other active investigation areas in the development and manufacturing of CAR T cell therapy

There are several areas of preclinical research aimed at improving CAR T cell therapy and providing benefits to a larger patient population. One aspect of the research is the T cell subtypes used for CAR T cell therapy. The starting cell population for many CAR T cell therapies is composed of CD4 + and CD8 + T cells, the proportion of which is present in the patient’s peripheral blood.

However, the use of a fixed 1:1 ratio of CD4+:CD8+ CAR T cells in patients with ALL and non-Hodgkin’s lymphoma has been studied [53]. If the proportion of T cell subpopulations becomes an important factor in CAR T cell therapy, manufacturing may require changes to the protocol to include the additional purification steps necessary to administer CAR T cells at a fixed subset ratio.

Other considerations for the future of making CAR T cell therapy include reducing possible short-term and long-term adverse events. For example, one side effect associated with CAR T cell therapy is severe cytokine release syndrome (CRS), which occurs in a small number of patients. CRS is caused by the release of pro-inflammatory cytokines directly from CAR T cells and dying tumor cells. Although most CRS cases can be managed by established treatment algorithms, it is speculated that the mechanism of inactivating CAR T cells in patients experiencing adverse reactions may help improve the safety of CAR T cell therapy.

The use of suicide switches incorporated into CAR constructs is a strategy currently under investigation as a potential way to specifically deplete CAR T cells in a controlled manner, and as CAR T cell therapies are studied in the growing clinical population, it may Becomes important [55,56]. For example, the iCasp9 safety switch has been effectively used to reduce graft-versus-host disease (GVHD) in patients receiving allogeneic stem cell transplantation [57]. However, depletion of CAR T cells may also eliminate long-term potential benefits. The term CAR T cell-mediated tumor monitoring.

Another approach to potentially increase the safety of CAR T cell therapy involves improving the specificity of modified T cells. This approach may be particularly important for CAR T cells targeting solid tumors, which usually do not have antigens that are uniquely expressed on the tumor. Preclinical studies have shown that CAR T cells can be used to target tumors that express two antigens, PSCA and PSMA; therefore, CAR T cells cannot kill tumor cells that express only one of these antigens. Therefore, combining antigen recognition strategies may be important when designing CARs for the treatment of solid tumors. According to our experience, CRS has not been observed in clinical trials using CAR T cells to target solid tumors, possibly because fewer tumor cells are killed immediately and quickly due to the mass of solid tumors.

Another strategy under investigation is to use CAR T cells of allogeneic manifestations. This platform uses genome editing to inactivate the endogenous TCRa gene, which limits the ability of allogeneic cells to cause GVHD [59]. Existing CAR T cells have shown efficacy in lymphoma xenograft models. However, although there is a report of sympathetic use by patients, the results are controlled and the use of clinical trials has not been reported [59,61]. How to better study how the quality of patient cells used for CAR transduction affects the efficacy of the final CAR T cell product. It has recently been shown that a reduction in the phenotype of depleted T cells is associated with improved CAR T cell efficacy [62]. Therefore, select CAR signal domains, select cell subpopulations, and adjust cell culture conditions to reduce its percentage. Cells that become depleted during transduction and expansion may be critical to producing the highest quality CAR T cell product.

Conclusion

In view of the success of CAR T cells in patients with B cell malignancies in the United States, expanding CAR T cell production capacity will allow testing the safety and effectiveness of CAR T cell therapy in a large number of patients worldwide. However, when trying to introduce cell therapies with complex manufacturing processes to a larger international patient population, many manufacturing and regulatory challenges need to be considered.

We are currently manufacturing CD19 CAR T cell therapy CTL019 to simplify the process of using this therapy worldwide. To achieve this goal, we have established strong partnerships with academic institutions and suppliers to thoroughly investigate products and processes to ensure that our materials are controlled to maintain high quality.

Pre-determining regulatory and manufacturing issues and proactively addressing them can help speed up the process of bringing this promising treatment to more patients.

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