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- W2809947929 abstract "There have been rapid advances in chimeric antigen receptor (CAR)-T cell technology in the past 8 years due to its potential for treating malignant diseases.1-3 Most of the chemotherapeutic agents used in the treatment of malignant disease carry significant acute and long-term toxicities with variable response rates. These chemotherapeutic agents are produced in large scale and can be given to many patients. CAR cells are not an exception to this rule for the acute toxicity. However, CAR cells are manufactured for a specific patient. Recently, two CAR-T products—Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel)—have received Food and Drug Administration approval for treatment of B-cell precursor acute lymphoblastic leukemia (ALL) and certain types of large B-cell lymphoma for patients with relapse or refractory disease, respectively. Clinical application of CAR-T cell technology is analogous to the functional role of donor lymphocyte infusions (DLIs). With CAR-T products, however, the immune cells are the recipient's own T cells that are targeted to a specific antigen using novel ex vivo techniques. Engineering CAR expression on T cells in a laboratory starts with T-cell collection and enrichment of the T cells from an apheresis product as the first step. While collection and processing of autologous or allogeneic stem cells for transplant and use of DLI to treat relapses have been extensively reported, data on feasibility concerns, logistics, and the regulatory aspects involved with apheresis collection for manufacturing proprietary CAR-T products are limited. With a burgeoning pipeline of pharmaceutical grade T-cell–based cellular products at various stages of clinical development, there is a need for developing standard operating procedures for apheresis collection tailored to disease and treatment subtype. The work published by Ceppi and colleagues4 in this issue of TRANSFUSION offers broad insights that could be utilized by many apheresis centers looking to partner with companies and hospitals involved in cellular-immunotherapeutic development that can substantially improve cancer patient outcomes. Ceppi and coworkers4 report on their experience with CAR-T cell collection and processing for heavily pretreated pediatric and young adults enrolled in two clinical trials (NCT02028455–ALL and NCT02311621–neuroblastoma). Study participants had demonstrated chemorefractoriness and, in some cases, had features of active disease (presence of circulating blasts in up to 33% of ALL patients) before CAR-T manufacturing. Understanding the consequences of prior therapy on collection yield, a relatively liberal inclusion criterion of an absolute lymphocyte count (ALC) of more than 100 × 106/L (22% had ALC < 500 × 106/L and 46% had CD3+ count < 500 × 106/L) was wisely set by the investigators. They chose to use the mononuclear cell (MNC) collection program with their COBE Spectra machines. Despite including patients with low lymphoid counts before apheresis, 100% of their patients met the target collection goal of MNCs (1 × 109 MNCs). The median MNC count was 8.8 × 109 (range, 1.2 × 109-2.98 × 1011) and median total lymphocyte count (TLC) was 3.2 × 109 (range, 0.32 × 109-6.22 × 1010) in the apheresis product. However, from what was thought to be a sufficient and viable T-cell number, six of 102 (5.9%) of the collections did not lead to a final acceptable CAR-T manufactured product. Of these products, one was unacceptable due to infection and two were inadequate due to lack of cell growth or expansion in the laboratory. However, upon repeat apheresis collections, these three patients were able to successfully achieve sufficient collections needed for CAR-T cell manufacture. One product was canceled due to patient death and two others who had neuroblastoma and had recently undergone metaiodobenzylguanidine (MIBG) therapy 8 weeks before apheresis, did not complete CAR-T therapy due to inadequate CD8 cell growth in vitro. This latter situation, however, led to protocol amendments to create a wash out period before apheresis. Finally, a retrospective review of the four apheresis products that showed insufficient expansion in the lab showed that median MNC (9.1 × 109 cells) and TLC count (1.84 × 109; range not specified) were neither significantly inferior to the whole cohort nor contaminated with circulating blasts. A main goal for effective CAR-T cell therapy is evidence of an increased level of in vivo proliferation as there is a strong correlation with a high success rate and long-term persistence of CAR-T cells, which allows for longer disease control. The exact length of in vivo persistence required for long-term remissions is yet unknown and it continues to be an area of debate. To achieve these goals for effective CAR-T cell manufacturing, it is very important to optimize T-cell collection so that anybody eligible for this therapy can be effectively treated. The main questions that remain in performing CAR-T cell studies are 1) is there an exact time window for the successful collection during patient's chemotherapy treatment plan, 2) are there tools to ensure or accurately predict an adequate CD3+ cell collection, and 3) are there effective techniques to isolate and expand sufficient T cells as well as to generate effective CAR-T cells from the collected apheresis product. The timing of T-cell collection is very important as one can encounter problems with a thin buffy coat layer in heavily pretreated patients, as this phenomenon impacts the red blood cell–white blood cell (WBC) interface in the apheresis machine. For autologous stem cell collections when treating patients with multiple myeloma or lymphoma, identifying a window period from the time of last chemotherapy until initiation of apheresis has resulted in better CD34+ cell yield.5 Drawing cues from this report, one CAR-T study by McGuirk and coworkers6 had set a certain washout period to facilitate better CD3+ yield with apheresis. However, as was learned in this study, not all drugs and conditions can be generalized. For example, the neuroblastoma patients receiving MIBG less than 8 weeks before apheresis had difficulty with CD8 cell expansion in vitro. At present, approved CAR-T cell protocols are used to treat relapsed and refractory diseases. Thus, timing of the collection should be determined as soon as possible based on patient disease progression, so that a chemotherapy plan can be tailored without compromising clinical efficacy. For nonapproved products that are currently under investigation, close discussion between research teams and apheresis centers can ensure selection of appropriate patients and provide attention to the pharmacodynamics of the drugs being used and the kinetics of cell recovery, early in the planning stages. For allo-hematopoietic stem cell transplantation (HSCT) or auto-HSCT preapheresis peripheral blood CD34+ count of 0.01 to 0.02 cells/mL has shown linear correlation with the desired product CD34+ count, while the precollection WBC count generally did not. In healthy adults, a single lymphocytapheresis session can result in collection of the required CD3+ dose (1 × 108/kg) needed for DLI (1 × 106/kg) infusions.7 Due to the paucity of data the quantity of CD3+ cells or its surrogate, ALC needed in peripheral blood to assure an adequate lymphocyte apheresis for DLI is still being evaluated. Similarly, at present we do not know the exact lower threshold of ALC needed to collect sufficient numbers of T cells for CAR-T manufacturing. In this regard, the work of Ceppi and colleagues4 is promising considering that 100% of their patients met their target collections despite starting with a lower ALC benchmark. As the field continues to evolve, further validation of these findings in other ongoing studies could direct future practice. Currently, based on pilot studies, only Kymriah manufacturers have provided guidance which recommends an ALC count of more than 500 × 106/L/L or CD3+ T cell count of more than 150 × 106/L/L before apheresis. To overcome this limitation, investigators at the National Institutes of Health have developed a collection efficiency formula that utilizes the preapheresis CD3+ count to predict the leukapheresis volume that needs to be processed to assure that an adequate amount of T cells needed for a successful manufacturing process can be obtained.8 While this approach is useful, some caveats remain: 1) mean CD3+ count was not used due to the lack of postapheresis counts and a fixed quantity of CD3+ cells was desired, not taking into account T-cell attrition and recruitment phenomenon during the apheresis process. Formula led to about 3% of collections failing to reach the minimum CD3+ dose and approximately 23% failing to reach the targeted dose. 2) A wide time range of preapheresis CD3+ counts (range, 0-11 days) was included in their calculation. In this study the median ALC was 944 × 106/L (range,142-6944 cells × 106/L) , the process was started with minimum criteria (ALC > 100 × 106/L) for reaching the desired MNC count. However, this led to a wide range (13.7%-6103.2%) of T-lymphocyte collection efficiency and lymphocyte count (range, 0.32 × 109-6.22 × 1010).4 While encouraging, these observations beg the question, can we afford to have any collection failures for these life-saving and expensive products in patients with a low preapheresis lymphoid yield. Thus, we believe it may be beneficial to look at the lymphocyte subsets (including absolute CD3+ count) before collection. This additional step would require ready availability of a flow cytometer laboratory that is able to provide timely support on all patients' samples that are proceeding to manufacture. In the study by Ceppi and coworkers4 the apheresis procedure was relatively well tolerated (adverse events, 9.8%). Apart from the study by Allen and colleagues8 (all grade 15.4%), there are no large studies to compare adverse events with lymphocytapheresis for CAR-T cell production. In both these studies, the sample size is small. To draw a narrative, we recommend examining adverse events reported from healthy donors registered with the National Marrow Donor Program (NMDP).9 In a recent NMDP report, 20% of the females and 7% of the men in good health experienced adverse events with apheresis for stem cell donation. While it would be unfair to make direct comparison between a large registry study of healthy donors, with data from specialized CAR-T processing centers treating patients, the safety profile of the at-risk population for apheresis is worth evaluating. This issue needs to be emphasized with staff caring for these patients. The medical team needs to address any concerns the patient may have in this area, during apheresis sessions. Also as more CAR-T trials are reported, it is likely that outcomes with newer apheresis platforms (Spectra Optia [TerumoBCT] and Amicus [Fresenius Kabi]) will soon be available. A detailed discussion on factors that lead to failed CAR-T cell manufacturing with adequate CD3+ cells is beyond the scope of this editorial. Better understanding of the role of cytokines (IL-2, IL-21) and signaling cascade activators (for example, OKT3) used in the medium to generate an activating signal for T-cell expansion might offer function insights. The ability to minimize the nondesirable cell fractions present during apheresis (monocytes, NK cells, blasts) that could contaminate and compete with T-cell growth in expansion chambers might be another important avenue for future research. As the transfusion community continues to provide the lymphocyte apheresis procedures for CAR-T cell manufacturing, there is an extensive list of other adoptive immunotherapeutics for which apheresis staff participation is essential. Viral-specific T lymphocytes, inducible Cas9 technology (CRISPR)-driven suicide switches for donor lymphocytes, and CAR-NK cells are a few illustrations for which apheresis will play a key role. The changing landscape of apheresis with the advent of cellular therapy has already prompted new accreditation requirements and new standards for new effector cell collection and processing techniques. Our knowledge of the limitations and benefits of cell processing needs further dissemination in the wider community, as the field of cellular therapy moves ever forward." @default.
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- W2809947929 date "2018-06-01" @default.
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- W2809947929 title "CAR-T cell manufacture: snatching victory when defeat is looming" @default.
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