Review Article2024-05-01 Transfusion and Cell Therapy

Current Challenges in Chimeric Antigen Receptor T-cell Therapy in Patients With B-cell Lymphoid Malignancies

Seok Jin Kim , M.D., Ph.D., Sang Eun Yoon , M.D., Ph.D., and Won Seog Kim , M.D., Ph.D.

Ann Lab Med 2024; 44(3): 210-221

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Abstract : Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy based on genetically engineered T cells derived from patients. The introduction of CAR T-cell therapy has changed the treatment paradigm of patients with B-cell lymphoid malignancies. However, challenging issues including managing life-threatening toxicities related to CAR T-cell infusion and resistance to CAR T-cell therapy, leading to progression or relapse, remain. This review summarizes the issues with currently approved CAR T-cell therapies for patients with relapsed or refractory B-cell lymphoid malignancies, including lymphoma and myeloma. We focus on unique toxicities after CAR T-cell therapy, such as cytokine-related events and hematological toxicities, and the mechanisms underlying post-CAR T-cell failure.

Review Article2024-07-01 Transfusion and Cell Therapy

Manufacturing Cell and Gene Therapies: Challenges in Clinical Translation

Na Kyung Lee , Ph.D. and Jong Wook Chang , Ph.D.

Ann Lab Med 2024; 44(4): 314-323

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Abstract : The safety and efficacy of both cell and gene therapies have been demonstrated in numerous preclinical and clinical trials. Chimeric antigen receptor T (CAR-T) cell therapy, which leverages the technologies of both cell and gene therapies, has also shown great promise for treating various cancers. Advancements in pertinent fields have also highlighted challenges faced while manufacturing cell and gene therapy products. Potential problems and obstacles must be addressed to ease the clinical translation of individual therapies. Literature reviews of representative cell-based, gene-based, and cell-based gene therapies with regard to their general manufacturing processes, the challenges faced during manufacturing, and QC specifications are limited. We review the general manufacturing processes of cell and gene therapies, including those involving mesenchymal stem cells, viral vectors, and CAR-T cells. The complexities associated with the manufacturing processes and subsequent QC/validation processes may present challenges that could impede the clinical progression of the products. This article addresses these potential challenges. Further, we discuss the use of the manufacturing model and its impact on cell and gene therapy.

Review Article2024-07-01 Transfusion and Cell Therapy

Guide to Rho(D) Immune Globulin in Women With Molecularly Defined Asian-type DEL (c.1227G>A)

In Hwa Jeong , M.D., SooHo Yu , M.D., Tae Yeul Kim , M.D., Soo-Young Oh , M.D., and Duck Cho , M.D.

Ann Lab Med 2024; 44(4): 307-313

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Abstract : Rh hemolytic disease of the fetus and newborn is a potential risk for D-negative mothers who produce anti-D during pregnancy, which can lead to morbidity and mortality in subsequent pregnancies. To prevent this hemolytic disease, Rho(D) immune globulin (RhIG) is generally administered to D-negative mothers without anti-D at 28 weeks of gestation and shortly after delivery. However, current guidelines suggest that pregnant mothers with molecularly defined weak D types 1, 2, 3, 4.0, and 4.1 do not need RhIG as they are unlikely to produce alloanti-D when exposed to fetuses with D-positive red cells. This issue and the necessity of RHD genotyping have been extensively discussed in Western countries, where these variants are relatively common. Recent evidence indicates that women with Asian-type DEL (c.1227G>A) also do not form alloanti-D when exposed to D-positive red cells. We report that mothers with molecularly defined Asian-type DEL, similar to those with weak D types 1, 2, 3, 4.0, and 4.1, do not require RhIG before and after delivery. Collectively, this review could pave the way for the revision of international guidelines to include the selective use of RhIG based on specific genotypes, particularly in women with the Asian-type DEL.

Original Article2023-09-01 Transfusion and Cell Therapy

Pre-transfusion Testing Using Crossmatching Agglutination Reaction Grades Combined With Rh Subgroup Phenotyping in Patients With Autoantibodies: A Three-year Experience at a Tertiary Hospital

Jongmin Kim , M.D., Kyung-Hwa Shin , M.D., Ph.D., Hyerim Kim , M.D., Ph.D., Hyung-Hoi Kim , M.D., Ph.D., and Hyun-Ji Lee , M.D., Ph.D.

Ann Lab Med 2023; 43(5): 470-476

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Abstract : Background: The currently recommended pre-transfusion testing techniques for patients with autoantibodies are complex, time-consuming, and labor-intensive. Therefore, although the red blood cell (RBC) selection method using crossmatched RBC agglutination reaction grades (i.e., the “least incompatible” transfusion) is discouraged, many institutions still use it. We aimed to evaluate the effectiveness of this method combined with Rh subgroup phenotyping. Methods: We retrospectively investigated RBC transfusions from January 2019 to December 2021 in patients presenting as auto-control-positive via antibody identification (auto-control (+) group), where Rh subgroup phenotype-matched RBCs were selected based on the agglutination reaction grades of crossmatched units. For each study patient, an auto-control-negative patient was matched based on age, sex, department, and pre-transfusion Hb levels (auto-control (−) group). The mean Hb change per unit, transfusion-associated symptom/sign reports, and agglutination reaction grades upon crossmatching were analyzed. Results: In the auto-control (+) group, the Hb change per unit among different agglutination reaction grades of transfused RBCs and among different relative grades of transfused RBCs and crossmatching auto-controls was not significantly different (P=0.392 and P= 0.132, respectively). No significant difference was observed in Hb changes and transfusion-associated symptom/sign occurrence between the auto-control (+) and auto-control (−) groups (P=0.121 and P=0.822, respectively). In addition, no definite evidence of hemolysis in the auto-control (+) group was observed in the medical record review. Conclusions: Together with Rh subgroup phenotyping, selecting the RBC unit with the lowest agglutination reaction grade upon crossmatching does not adversely affect transfusion efficiency.

Original Article2024-09-01 Transfusion and Cell Therapy

Metformin Suppresses Both PD-L1 Expression in Cancer Cells and Cancer-Induced PD-1 Expression in Immune Cells to Promote Antitumor Immunity

Su Hwan Park , M.S., Juheon Lee , M.S., Hye Jin Yun , B.S., Seok-Ho Kim , Ph.D., and Jong-Ho Lee , Ph.D.

Ann Lab Med 2024; 44(5): 426-436

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Abstract : Background: Metformin, a drug prescribed for patients with type 2 diabetes, has potential efficacy in enhancing antitumor immunity; however, the detailed underlying mechanisms remain to be elucidated. Therefore, we aimed to identify the inhibitory molecular mechanisms of metformin on programmed death ligand 1 (PD-L1) expression in cancer cells and programmed death 1 (PD-1) expression in immune cells. Methods: We employed a luciferase reporter assay, quantitative real-time PCR, immunoblotting analysis, immunoprecipitation and ubiquitylation assays, and a natural killer (NK) cell-mediated tumor cell cytotoxicity assay. A mouse xenograft tumor model was used to evaluate the effect of metformin on tumor growth, followed by flow-cytometric analysis using tumor-derived single-cell suspensions. Results: Metformin decreased AKT-mediated β-catenin S552 phosphorylation and subsequent β-catenin transactivation in an adenosine monophosphate-activated protein kinase (AMPK) activation-dependent manner, resulting in reduced CD274 (encoding PD-L1) transcription in cancer cells. Tumor-derived soluble factors enhanced PD-1 protein stability in NK and T cells via dissociation of PD-1 from ubiquitin E3 ligases and reducing PD-1 polyubiquitylation. Metformin inhibited the tumor-derived soluble factor-reduced binding of PD-1 to E3 ligases and PD-1 polyubiquitylation, resulting in PD-1 protein downregulation in an AMPK activation-dependent manner. These inhibitory effects of metformin on both PD-L1 and PD-1 expression ameliorated cancer-reduced cytotoxic activity of immune cells in vitro and decreased tumor immune evasion and growth in vivo. Conclusions: Metformin blocks both PD-L1 and PD-1 within the tumor microenvironment. This study provided a mechanistic insight into the efficacy of metformin in improving immunotherapy in human cancer.

Original Article2023-09-01 Transfusion and Cell Therapy

Reducing Microbial Contamination in Hematopoietic Stem Cell Products and Quality Improvement Strategy: Retrospective Analysis of 1996-2021 Data

You Keun Ko , M.D., Jong Kwon Lee , M.D., Hye Kyung Park , M.T., Ae Kyung Han , M.T., Sun Kyoung Mun , M.T., Hye Jeong Park , M.T., Hae Kyoung Choung , R.N., Se Mi Kim , R.N., Kwang Mo Choi , M.T., Nam Yong Lee , M.D., Ph.D., Duck Cho , M.D., Ph.D., Dae Won Kim , M.D., Ph.D., and Eun-Suk Kang , M.D., Ph.D.

Ann Lab Med 2023; 43(5): 477-484

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Abstract : Background: Sterility and safety assurance of hematopoietic stem cell (HSC) products is critical in transplantation. Microbial contamination can lead to product disposal and increases the risk of unsuccessful clinical outcomes. Therefore, it is important to implement and maintain good practice guidelines and regulations for the HSC collection and processing unit in each hospital. We aimed to share our experiences and suggest strategies to improve the quality assurance of HSC processing. Methods: We retrospectively analyzed microbial culture results of 11,743 HSC products processed over a 25-year period (January 1996 to May 2021). Because of reorganization of the HSC management system in 2008, the 25-year period was divided into periods 1 (January 1996 to December 2007) and 2 (January 2008 to May 2021). We reviewed all culture results of the HSC products and stored aliquot samples and collected culture results for peripheral blood and catheter samples. Results: Of the 11,743 products in total, 35 (0.3%) were contaminated by microorganisms, including 19 (0.5%) of 3,861 products during period 1 and 16 (0.2%) of 7,882 products during period 2. Penicillium was the most commonly identified microorganism (15.8%) during period 1 and coagulase-negative Staphylococcus was the most commonly identified (31.3%) during period 2. HSC product contamination occurred most often during HSC collection and processing. Conclusions: The contamination rate decreased significantly during period 2, when the HSC management system was reorganized. Our results imply that handling HSC products by trained personnel and adopting established protocols, including quality assurance programs, aid in decreasing the contamination risk.

Original Article2023-09-01 Transfusion and Cell Therapy

Performance Validation of Three Scoring Systems for the Prediction of Thrombotic Microangiopathy Due to Severe ADAMTS13 Deficiency and the Response to Therapeutic Plasma Exchange: First Study in Korea

Sang Hyuk Park , M.D., Ph.D., Hyun-Ki Kim , M.D., Joseph Jeong , M.D., Ph.D., Seon-Ho Lee , M.D., Ph.D., Yoo Jin Lee , M.D., Ph.D., Yoo Jin Kim , M.D., Ph.D., Jae-Cheol Jo , M.D., Ph.D., and Ji-Hun Lim , M.D., Ph.D.

Ann Lab Med 2023; 43(5): 485-492

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Abstract : Background: The BENTLEY score (B-S), French thrombotic microangiopathy (TMA) Reference Center score (FTMA-S), and PLASMIC score (PLASMIC-S) have been developed for TMA diagnostic prediction. We retrospectively validated their predictive performances in patients with severe (

Original Article2024-01-01 Transfusion and Cell Therapy

Prediction of Mid-term Platelet Transfusion in Stable Trauma Patients Using Rotational Thromboelastometry

Ha Jin Lim , M.D., Hyunseok Jang , M.D., Ph.D., Naa Lee , M.D., Euisung Jeong , M.D., Yunchul Park , M.D., Younggoun Jo , M.D., Ph.D., Jungchul Kim , M.D., Ph.D., Young Eun Lee , Ph.D., Hyun-Jung Choi , M.D., Ph.D., Seung-Jung Kee , M.D., Ph.D., Jong Hee Shin , M.D., Ph.D., and Myung Geun Shin , M.D., Ph.D.

Ann Lab Med 2024; 44(1): 74-81

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Abstract : Background: Rotational thromboelastometry (ROTEM; TEM International GmbH, Munich, Germany) is a global coagulation test that guides evidence-based platelet transfusion in trauma patients. We evaluated ROTEM parameters for predicting mid-term (five days) platelet transfusion in trauma patients. Methods: Maximum clot firmness and clot amplitudes after 5, 10, and 15 mins (A5, A10, and A15, respectively) of fibrin-specific ROTEM (FIBTEM) and extrinsically activated ROTEM (EXTEM) were retrospectively collected from 82 hospitalized, stable, non-bleeding trauma patients after successful initial resuscitation. Platelet-specific ROTEM (PLTEM) was calculated by subtracting FIBTEM from EXTEM. Platelet transfusions were reviewed for five days after ROTEM. Results: The areas under the curve for FIBTEM, EXTEM, and PLTEM predicting platelet concentrate transfusion of >12 U at mid-term were 0.915–0.923, 0.878–0.896, and 0.551–0.735, respectively. FIBTEM and EXTEM parameters were comparable to those of fibrinogen, fibrin/fibrinogen degradation products, D-dimer, and antithrombin III. Strong correlations (r>0.7) were noted between platelet count and EXTEM (A5, A10, and A15) or PLTEM (A5), platelet function (per platelet count) and EXTEM (A10 and A15), and fibrinogen levels and all FIBTEM parameters. Conclusions: FIBTEM and EXTEM can reliably predict mid-term platelet transfusion in trauma patients. FIBTEM, EXTEM, and PLTEM parameters correlate with conventional coagulation tests (platelets and fibrinogen).

Letter to the Editor2023-11-01 Transfusion and Cell Therapy

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Review Article2025-03-01 Transfusion and Cell Therapy

Advancing Natural Killer Cell Therapy: Genetic Engineering Strategies for Enhanced Cancer Immunotherapy

Joo Dong Park , M.S., Ha Eun Shin , Ph.D., Yeon Su An , B.S., Hye Jung Jang , M.S., Juwon Park , Ph.D., Se-Na Kim , Ph.D., Chun Gwon Park , Ph.D., and Wooram Park , Ph.D.

Ann Lab Med 2025; 45(2): 146-159

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Abstract : Natural killer (NK) cells are pivotal innate immune system components that exhibit spontaneous cytolytic activity against abnormal cells, such as infected and tumor cells. NK cells have shown significant promise in adoptive cell therapy because of their favorable safety profiles and minimal toxicity in clinical settings. Despite their advantages, the therapeutic application of unmodified NK cells faces challenges, including limited in vivo persistence, particularly in the immunosuppressive tumor microenvironment. Recent advances in genetic engineering have enhanced the therapeutic potential of NK cells by addressing these limitations and improving their therapeutic efficacy. In this review, we have described various methodologies for the genetic modification of NK cells, including viral vectors, electroporation, and nanoparticle-based approaches. The ongoing research on nanomaterialbased approaches highlights their potential to overcome current limitations in NK cell therapy, paving the way for advanced cancer therapy and improved clinical outcomes. In this review, we also emphasize the potential of engineered NK cells in cancer immunotherapy and other clinical applications, highlighting the expanding scope of NK cell-based treatments and the critical role of innovative genetic engineering techniques.