Progress in Research and Application of CAR-T Cell Therapy in T-Lymphocyte Tumors --Review / 中国实验血液学杂志

T-lymphocyte tumors are a group of diseases containing various types of lymphatic system tumors, with strong heterogeneity and poor clinical outcomes. Chimeric antigen receptor T (CAR-T) cell therapy, as a new immune cell therapy, has made a breakthrough in the field of B-lymphocyte tumors. People are interested in the application prospect of this technique in the field of T-lymphocyte tumors. Some studies have shown that CAR-T cell therapy has made some progress in the treatment of T-lymphocyte tumors, and CAR-T for some targets has entered the stage of clinical trials. However, due to the characteristics of T cells, there are also many challenges. This article reviews the research and application of CAR-T cell therapy in T-lymphocyte tumors.

Generating universal chimeric antigen receptor expressing cell products from induced pluripotent stem cells: beyond the autologous CAR-T cells / 中华医学杂志(英文版)

Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achieved in intractable lymphoma treatments. Currently, well-explored approaches focus on autologous cells due to their low immunogenicity, but they are highly restricted by the high costs, time consumption of processing, and the insufficiency of primary cells in some patients. Induced pluripotent stem cells (iPSCs) are cell sources that can theoretically produce indefinite well-differentiated immune cells. Based on the above facts, it may be reasonable to combine the iPSC technology and the CAR design to produce a series of highly controllable and economical "live" drugs. Manufacturing hypoimmunogenic iPSCs by inactivation or over-expression at the genetic level and then arming the derived cells with CAR have emerged as a form of "off-the-shelf" strategy to eliminate tumor cells efficiently and safely in a broader range of patients. This review describes the reasonability, feasibility, superiority, and drawbacks of such approaches, summarizes the current practices and relevant research progress, and provides insights into the possible new paths for personalized cell-based therapies.

Alteration and significance of serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma: a retrospective study based on LEGEND-2 / 中华血液学杂志

Objective: To explore the dynamic changes in serum lipid levels and nutritional status during BCMA-CAR-T-cell therapy in patients with refractory or relapsed multiple myeloma (R/R MM) based on LEGEND-2. Methods: The data of patients with R/R MM who underwent BCMA-CAR-T therapy at our hospital between March 30, 2016, and February 6, 2018, were retrospectively collected. Serum lipid levels, controlled nutritional status (CONUT) score, and other clinical indicators at different time points before and after CAR-T-cell infusion were compared and analyzed. The best cut-off value was determined by using the receiver operator characteristic (ROC) curve. The patients were divided into high-CONUT score (>6.5 points, malnutrition group) and low-CONUT score groups (≤6.5 points, good nutrition group), comparing the progression-free survival (PFS) and total survival (OS) of the two groups using Kaplan-Meier survival analysis. Results: Before the infusion of CAR-T-cells, excluding triglycerides (TG), patients' serum lipid levels were lower than normal on average. At 8-14 d after CAR-T-cell infusion, serum albumin (ALB), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and apolipoprotein A1 (Apo A1) levels dropped to the minimum, whereas CONUT scores reached the maximum. In addition to TG, apolipoprotein B (Apo B) levels increased compared with baseline. After CAR-T-cell therapy, the patients' serum lipid levels significantly increased with well-improved nutritional status. Spearman's related analysis showed that TC, HDL, and ApoA1 levels after CAR-T-cell injection were significantly negatively correlated with the grade of cytokine-release syndrome (CRS) (r=-0.548, P=0.003; r=-0.444, P=0.020; r=-0.589, P=0.001). Furthermore, survival analysis indicated that the CONUT score was unrelated to PFS, and the median OS of patients with R/R MM in the high-CONUT score group was shorter than that in the low-CONUT score group (P=0.046) . Conclusions: During CAR-T-cell therapy, hypolipidemia and poor nutritional status were aggravated, which is possibly related to CRS. The patients' serum lipid levels and nutritional status were significantly improved after CAR-T-cell treatment. The CONUT score affected the median OS in patients treated with CAR-T-cells. Therefore, specific screening and intervention for nutritional status in patients receiving CAR-T-cell therapy are required.

Characteristics and impact factors of SARS-CoV-2 infection in adult patients with relapsed/refractory B-cell non-Hodgkin lymphoma receiving chimeric antigen receptor T-cell therapy / 中华血液学杂志

Objective: To explore the clinical characteristics and treatment of COVID-19 infection in patients with relapsed/refractory B-cell non-Hodgkin lymphoma before and after receiving chimeric antigen receptor T-cell therapy, and study the influencing factors of severe COVID-19 infection in these patients. Methods: The data of 59 patients with relapsed/refractory B-cell non-Hodgkin lymphoma who received chimeric antigen receptor T-cell therapy at the Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology and Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University between December 2017 and February 2023, and who were infected with novel coronavirus between December 2022 and February 2023 were retrospectively studied. Patients were divided into light, medium, severe, and critical groups, and the differences between the groups were analyzed using the chi-square test. A univariate logistic regression model was used to evaluate the contribution of each variable and its relationship with severe infection. The chi-square and Fisher's exact tests were used to analyze the differences between the B-cell aplasia and B-cell recovery (BCR) groups. Results: Of the 59 pre- and post-infusion infections, 39 (66.1%) led to mild COVID-19, 9 (15.3%) resulted in moderate COVID-19, 10 (16.9%) resulted in severe COVID-19, and 1 (1.7%) led to critical COVID-19. Moroever, age greater than 55 years, having received autologous hematopoietic stem cell transplantation, progressive disease status, and B-cell aplasia at the time of diagnosis of COVID-19 infection are factors affecting severe infection. Patients with B-cell aplasia had a more severe infection with COVID-19 (P<0.001), a longer duration (P=0.015), a longer antiviral therapy course (P<0.001), and a higher hospitalization rate (P<0.001) than the BCR group. Conclusion: Active prevention and treatment of COVID-19 infection remains a crucial issue requiring urgent attention in managing patients with relapsed/refractory B-cell non-Hodgkin lymphoma treated with chimeric antigen receptor T-cell therapy.

Efficacy and safety analysis of the zanubrutinib-based bridging regimen in chimeric antigen receptor T-cell therapy for relapsed/refractory diffuse large B-cell lymphoma / 中华血液学杂志

Objective: To further elucidate the clinical efficacy and safety of a combination regimen based on the BTK inhibitor zebutanil bridging CD19 Chimeric antigen receptor T cells (CAR-T cells) in the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) . Methods: Twenty-one patients with high-risk r/r DLBCL were treated with a zanubrutinib-based regimen bridging CAR-T between June 2020 and June 2023 at the Department of Hematology, Tongji Hospital, Tongji University and the Second Affiliated Hospital of Zhejiang University, and the efficacy and safety were retrospectively analyzed. Results: All 21 patients were enrolled, and the median age was 57 years (range: 38-76). Fourteen patients (66.7%) had an eastern cooperative oncology group performance status score (ECOG score) of ≥2. Eighteen patients (85.7%) had an international prognostic index (IPI) score of ≥3. Three patients (14.3%) had an IPI score of 2 but had extranodal infiltration. Fourteen patients (66.7%) had double-expression of DLBCL and seven (33.3%) had TP53 mutations. With a median follow-up of 24.8 (95% CI 17.0-31.6) months, the objective response rate was 81.0%, and 11 patients (52.4%) achieved complete remission. The median progression-free survival (PFS) was 12.8 months, and the median overall survival (OS) was not reached. The 1-year PFS rate was 52.4% (95% CI 29.8% -74.3%), and the 1-year OS rate was 80.1% (95% CI 58.1% -94.6%). Moreover, 18 patients (85.7%) had grade 1-2 cytokine-release syndrome, and two patients (9.5%) had grade 1 immune effector cell-associated neurotoxicity syndrome. Conclusion: Zanubrutinib-based combination bridging regimen of CAR-T therapy for r/r DLBCL has high efficacy and demonstrated a good safety profile.

Analysis of the feasibility and prognostic value of circulating tumor DNA monitoring in detecting gene mutations in patients with diffuse large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy / 中华血液学杂志

Objective: To explore the prognostic value of circulating tumor DNA (ctDNA) testing in patients with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) undergoing chimeric antigen receptor T-cell (CAR-T) therapy, and to guide the prevention and subsequent treatment of CAR-T-cell therapy failure. Methods: In this study, 48 patients with R/R DLBCL who received CAR-T-cell therapy at the First Affiliated Hospital of Zhejiang University School of Medicine between December 2017 and March 2022 were included. Furthermore, ctDNA testing of 187 lymphoma-related gene sets was performed on peripheral blood samples obtained before treatment. The patients were divided into complete remission and noncomplete remission groups. The chi-square test and t-test were used to compare group differences, and the Log-rank test was used to compare the differences in survival. Results: Among the patients who did not achieve complete remission after CAR-T-cell therapy for R/R DLBCL, the top ten genes with the highest mutation frequencies were TP53 (41%), TTN (36%), BCR (27%), KMT2D (27%), IGLL5 (23%), KMT2C (23%), MYD88 (23%), BTG2 (18%), MUC16 (18%), and SGK1 (18%). Kaplan-Meier survival analysis revealed that patients with ctDNA mutation genes >10 had poorer overall survival (OS) rate (1-year OS rate: 0 vs 73.8%, P<0.001) and progression-free survival (PFS) rate (1-year PFS rate: 0 vs 51.8%, P=0.011) compared with patients with ctDNA mutation genes ≤10. Moreover, patients with MUC16 mutation positivity before treatment had better OS (2-year OS rate: 56.8% vs 26.7%, P=0.046), whereas patients with BTG2 mutation positivity had poorer OS (1-year OS rate: 0 vs 72.5%, P=0.005) . Conclusion: ctDNA detection can serve as a tool for evaluating the efficacy of CAR-T-cell therapy in patients with R/R DLBCL. The pretreatment gene mutation burden, mutations in MUC16 and BTG2 have potential prognostic value.

Clinical analysis of long-term survival and influencing factors of chimeric antigen receptor T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia / 中华血液学杂志

Objective: To analyze the survival and influencing factors of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) . Methods: Clinical information of patients who received CAR-T-cell therapy and achieved complete remission of R/R B-ALL between May 2015 and June 2018 at the Shaanxi Provincial People's Hospital was obtained. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and leukemia-free survival (LFS) times of patients, and Cox regression analysis was performed to analyze the prognostic factors that affect patient survival after CAR-T therapy. Results: Among the 38 patients with R/R B-ALL, 21 were men, with a median age of 25 (6-59) years and a median OS time of 18 (95% CI 3-33) months. Multivariate Cox regression analysis showed that positive MLL-AF4 fusion gene expression was an independent risk factor for OS and LFS (OS: HR=4.888, 95% CI 1.375-17.374, P=0.014; LFS: HR=6.683, 95% CI 1.815-24.608, P=0.004). Maintenance therapy was a protective factor for OS and LFS (OS: HR=0.153, 95% CI 0.054-0.432, P<0.001; LFS: HR=0.138, 95% CI 0.050-0.382, P<0.001). In patients with MRD negative conversion, LFS benefit (HR=0.209, 95% CI 0.055-0.797, P=0.022) and OS difference was statistically insignificant (P=0.111). Moreover, patients with high tumor burden were risk factors for OS and LFS at the level of 0.1 (OS: HR=2.662, 95% CI 0.987-7.184, P=0.053; LFS: HR=2.452, 95% CI 0.949-6.339, P=0.064) . Conclusion: High tumor burden and high-risk genetics may affect the long-term survival rate of patients with R/R B-ALL receiving CAR-T, and lenalidomide-based maintenance therapy may improve their prognosis.

Long-term follow-up of humanized and murine CD19 CAR-T-cell therapy for B-cell acute lymphoblastic leukemia / 中华血液学杂志

Objective: Murine CD19 chimeric antigen receptor T-cell (CAR-T) products have been approved for the treatment of refractory/relapsed (R/R) B-cell acute lymphocytic leukemia (B-ALL) ; moreover, humanized products are also undergoing clinical trials. This study aimed to explore the differences in safety and short- and long-term follow-up efficacy between humanized and murine CD19 CAR-T-cells for treating relapsed and refractory B-ALL. Methods: Clinical data of 80 patients with R/R B-ALL treated with CD19-targeted CAR-T-cells at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between May 2016 and March 2023 were analyzed, which included 31 patients with murine CAR-T and 49 with humanized products. Results: The proportion of patients with cytokine-release syndrome (CRS) in the murine and humanized groups was 63.1% and 65.3%, respectively. Moreover, a higher proportion of patients suffered from severe CRS in the murine group than in the humanized CAR-T group (19.4% vs 8.2%, P=0.174). Furthermore, one patient per group died of grade 5 CRS. The incidence of grade 1-2 immune effector cell-associated neurotoxicity syndrome (ICANS) was 12.9% and 6.1%, respectively; severe ICANS were not observed. Among patients receiving murine CAR-T-cells, an overall response (OR) was observed in 74.2%. Conversely, the OR rate of patients receiving humanized CAR-T-cells was 87.8%. During the median follow-up time of 10.5 months, the median recurrence-free survival (RFS) of patients with murine CAR-T-cells was 12 months, which was as long as that of patients with humanized CAR-T-cells. The median overall survival (OS) were not reached in both groups. Of the 45 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a significantly improved RFS (43.25% vs 33.33%, P=0.027). Bridging transplantation was an independent factor in prolonging OS (χ(2)=8.017, P=0.005) and PFS (χ(2)=6.584, P=0.010). Common risk factors, such as age, high proportion of bone marrow blasts, and BCR-ABL fusion gene expression, had no significant effect on patients' long-term follow-up outcomes. Three patients reached complete remission after reinfusion of humanized CAR-T-cells. However, one patient relapsed one month after his second infusion of murine CAR-T-cells. Conclusions: The results indicate that humanized CAR-T therapy showed durable efficacy in patients with a higher tumor burden in the bone marrow without any influence on safety. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients who were not treated successfully with CAR-T therapies.

Double-negative T cells: a promising avenue of adoptive cell therapy in transplant oncology / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer. In addition to the common mechanisms underlying tumor recurrence, another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis. Transplant oncology is an emerging field that addresses oncological challenges in transplantation. In this context, a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients. Double-negative T cells (DNTs) are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor (TCR) type. Among them, TCRαβ+ DNTs are considered to induce immune suppression in immune-mediated diseases, while TCRγδ+ DNTs are widely recognized as tumor killers. As a composite cell therapy, healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host. In this work, we summarized the biological characteristics and functions of DNTs in oncology, immunology, and transplantation. Based on the multiple roles of DNTs, we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy (ACT).

Clinical development of chimeric antigen receptor-T cell therapy for hematological malignancies / 中华医学杂志(英文版)

Cellular therapies have revolutionized the treatment of hematological malignancies since their conception and rapid development. Chimeric antigen receptor (CAR)-T cell therapy is the most widely applied cellular therapy. Since the Food and Drug Administration approved two CD19-CAR-T products for clinical treatment of relapsed/refractory acute lymphoblastic leukemia and diffuse large B cell lymphoma in 2017, five more CAR-T cell products were subsequently approved for treating multiple myeloma or B cell malignancies. Moreover, clinical trials of CAR-T cell therapy for treating other hematological malignancies are ongoing. Both China and the United States have contributed significantly to the development of clinical trials. However, CAR-T cell therapy has many limitations such as a high relapse rate, adverse side effects, and restricted availability. Various methods are being implemented in clinical trials to address these issues, some of which have demonstrated promising breakthroughs. This review summarizes developments in CAR-T cell trials and advances in CAR-T cell therapy.

Some thoughts on the research of mesenchymal stem cell exosomes and wound microenvironment / 中华烧伤杂志

Since researchers have found that the conditioned medium and exosomes of mesenchymal stem cells (MSCs) had the biological effects equivalent to those of MSCs, MSC exosomes (MSC-Exos), the representative product of MSCs' paracrine effect, have become the research focus of the "cell-free" therapy of MSCs. However, most researchers currently use conventional culture condition to culture MSCs and then isolate exosomes for the treatment of wound or other diseases. Theoretically, the paracrine effect of MSCs is directly associated with the pathological condition of the wound (disease) microenvironment or in vitro culture condition, and their paracrine components and biological effects may be altered with the changes of the wound (disease) microenvironment or in vitro culture condition. Thus, the feasibility of using traditional culture condition to culture MSCs for exosome extraction for the treatment of different diseases without considering the actual situation of the disease to be treated needs further discussion. Therefore, the author suggests that the research of MSC-Exos should consider the microenvironment of the wound (disease) to be treated. as much as possible, otherwise the extracted MSC-Exos may not be "accurate" or may not really achieve the treatment effect of MSCs. In this article, we summarized some thoughts of the author and problems related to the researches about MSC-Exos and wound microenvironment, and hoped to discuss with researchers.

Effects of lipografts in immune-driven lipoatrophies. Case studies

Lipodystrophy is a pathological condition associated with an abnormal body adipose tissue redistribution. Facial lipoatrophy can be a consequence of congenital, acquired, or involutional. The lipograft is an autologous fat transplant, which constitutes a treatment option that provides volume, tissue regeneration, and advantages in relation to other fillers in autoimmune diseases. The aim is to highlight the filling action and the metabolic effect of facial lipotransfer, due to the grafted adipocytes survival, and the adipose tissue derived stem cells regenerative activity obtained by nano-fat in patients with facial lipoatrophy. Lipoinjection improves the architecture of the new dermis and increases its functional capacity. It is a treatment with autologous tissue (fatty graft) with great efficacy in relation to other alloplastic filler materials capable of exacerbating an inflammatory response mediated by antibody production.

La lipodistrofia es una condición patológica asociada a una redistribución anómala del tejido adiposo en el cuerpo. La lipoatrofia facial puede ser consecuencia de defectos congénitos, adquiridos o involutivos. El lipoinjerto es el trasplante de grasa autógena y constituye una opción de tratamiento que aporta volumen, regeneración tisular y ventajas en relación con otros materiales de relleno en enfermedades autoinmunes. Se busca resaltar la acción de relleno y el efecto metabólico de la lipotransferencia facial, por la supervivencia de los adipocitos injertados y la actividad regenerativa de las células madre provenientes del tejido adiposo obtenidas por nanofat en pacientes con lipoatrofia facial. La lipoinyección mejora la arquitectura de la nueva dermis y aumenta su capacidad funcional, es un tratamiento con tejido autógeno (injerto graso) con gran eficacia en relación con otros materiales de relleno aloplásticos capaces de exacerbar una respuesta inflamatoria mediada por la producción de anticuerpos.

Research advances in the treatment of liver failure with mesenchymal stem cell-derived exosomes / 中华肝脏病杂志

Liver failure is a serious clinical syndrome in which multiple pathogenic factors exceed the liver's self-repair capability, resulting massive hepatocellular necrosis, rapid disease progression and high mortality. Liver transplantation is the most effective method for the treatment of liver failure, but it has disadvantages, such as insufficient liver donor and high cost. The clinical efficacy of mesenchymal stem cells in liver failure have been validated, but its application has been limited to certain extent. Cell-free-based therapies, especially mesenchymal stem cell-derived exosomes, has become a research hotspot in recent years. This paper reviews the research advances in the treatment of liver failure with the use of mesenchymal stem cell-derived exosomes.

Clinical research in cell therapy of liver diseases: progress and challenges / 中华肝脏病杂志

The high incidence of chronic liver disease is a serious threat to public health, and the current comprehensive internal medicine treatment is ineffective. Liver transplantation is limited by the shortage of liver source and post-transplant rejection, and thus unmet the clinical needs. More importantly, cell therapy shows great promise for the treatment of chronic liver disease. Over recent years, domestic and foreign scholars have carried out a variety of cell therapy preclinical and clinical trials for critical liver disease, and achieved certain results, providing new methods for the treatment of chronic liver diseases. This review discusses the cell therapy research status and application progress, various existing problems and challenges, and key issues of mesenchymal stem cells in the treatment of chronic liver diseases.

Current status, challenges and reflections on stem cell therapy for liver diseases / 中华肝脏病杂志

There are increasing number of clinical studies on the use of stem cells in the treatment of liver diseases. Most studies have shown that stem cells can significantly improve liver function and prolong survival in patients with decompensated cirrhosis and liver failure. However, the current study has high heterogeneity and few mechanistic research data, which cannot answer many key questions about stem cell therapy for liver diseases. This paper reviews the research status of stem cells, in order to clarify the existing problems and challenges, and puts forward some reflections and countermeasures, with hope to promote the clinical application of stem cells in the treatment of liver diseases.

Terapia com células CAR-T: reprogramação celular para o combate de neoplasias malignas / CAR-T cell therapy: cell reprogramming to combat malignant neoplasms

As células CAR-T são linfócitos geneticamente modificados para reconhecerem um espectro amplo de antígenos de superfície celulares. Além disso, atacam células tumorais malignas, que expressam esses antígenos, por meio da ativação da coestimulação citoplasmática, secreção de citocinas, citólise de células tumorais e proliferação de células T. O objetivo desse estudo é abordar a imunoterapia com células CAR-T, a fim de explicar seu conceito, processo de fabricação e papel no tratamento de neoplasias hematológicas e tumores sólidos. Foi realizada uma revisão através do portal PubMed, utilizando como descritores: "car-t cell therapy" e "neoplasms", determinados com base nos "Descritores em Ciências da Saúde". Foram obtidos, inicialmente, 10 artigos, os quais foram lidos integralmente para a confecção dessa revisão. Além disso, foram adicionados 3 ensaios clínicos atualizados sobre o tema. Na terapia com células CAR-T, as células T são coletadas do paciente, geneticamente modificadas para incluir receptores de antígeno específicos e, posteriormente, expandidas em laboratórios e transfundidas de volta para o paciente. Assim, esses receptores podem reconhecer células tumorais que expressam um antígeno associado a um tumor. A terapia com células CAR-T é mais conhecida por seu papel no tratamento de malignidades hematológicas de células B, sendo a proteína CD19 o alvo antigênico mais bem estudado até o momento. Entretanto, estudos estão sendo feitos para verificar a eficácia desse tratamento, também, em tumores sólidos. Portanto, apesar de inicialmente ser indicada apenas para um grupo seleto de pessoas, essa terapia tem demonstrado grande potencial para atuar em um espectro maior de pacientes.

The CAR-T cells are lymphocytes genetically modified to recognize a broader spectrum of cell surface antigens. In addition, they attack malignant tumor cells, which express these antigens, by activating cytoplasmic co-stimulation, cytokine secretion, tumor cell cytolysis and T cell proliferation. The aim of this study is to address immunotherapy with CAR-T cells, in order to explain its concept, manufacturing process and role in the treatment of hematological neoplasms and solid tumors. This is a literature review conducted through the PubMed portal, that uses the terms "car-t cell therapy" and "neoplasms" as descriptors, determined based on the DeCS (Descritores em Ciências da Saúde). To prepare this review, initially 10 articles were found and read in full. In addition, 3 updated clinical trials on the subject were added. For CAR-T cell therapy, T cells are collected from the patient, genetically modified to include specific antigen receptors, and later expanded in laboratories and transfused back to the patient. Thus, these receptors can recognize tumor cells that express a tumor-associated antigen. CAR-T cell therapy is best known for its role in the treatment of B cell hematological malignancies, with the CD19 protein being the most studied antigenic target to date. However, studies are being conducted to verify the effectiveness of this treatment, also, in solid tumors. Therefore, despite being formulated only for a selected group of patients, this therapy has great potential to act on a broader spectrum of patients.

Ética en el ámbito de la investigación en medicina regenerativa / Ethics in the field of regenerative medicine research

Introducción: La medicina regenerativa se basa en la sustitución o regeneración de células humanas, tejidos u órganos con la finalidad de restablecer una función normal. Es una terapia basada en el tratamiento con células madre. Las estrategias terapéuticas basadas en la terapia celular permiten su empleo en diferentes enfermedades que no resuelven o tardan más en resolver por tratamientos médicos convencionales. Objetivos: Analizar aspectos éticos de la investigación que contribuyen a la reflexión cognitiva y ética de la ciencia en el ámbito de la medicina regenerativa. Métodos: Se realizó una revisión que consideró artículos originales y de corte experimental publicados en la última década, en algunas bases de datos de la Biblioteca Virtual de Salud (BVS) de Cuba. Se emplearon los descriptores del Medical Subject Headings y de Ciencias de la Salud. Análisis y síntesis de la información: Se abordan las aplicaciones y generalidades relacionadas con las células madre y los avances en la medicina regenerativa, así como los procedimientos y tratamientos con células madre para diferentes enfermedades con la aplicación de los conocimientos destinados al beneficio social del ser humano. Conclusiones: Se señala la importancia de una postura ética en la medicina regenerativa para la valoración adecuada de los avances en el tratamiento de diversas enfermedades, el impacto de la adquisición de nuevos conocimientos, así como una actitud más responsable y el desarrollo de valores sociales que forman parte de la humanidad(AU)

Introduction: regenerative medicine is based on the replacement or regeneration of human cells, tissues or organs in order to restore normal function; it is a therapy based on stem cell treatment. Therapeutic strategies based on cell therapy allow their use in different diseases that do not resolve or take longer to resolve by conventional medical treatments. Objectives: to address ethical aspects of research those contribute to cognitive and ethical reflection of science in the field of regenerative medicine research. Methods: A review was carried out that considered original and experimental articles published in the last decade, in some databases of the Virtual Health Library (VHL) of Cuba. The descriptors of the Medical Subject Headings and Descriptors in Health Sciences were used. Analysis and synthesis of the information: Applications and generalities related to stem cells and advances in regenerative medicine are summarized, as well as procedures and treatments with stem cells for different diseases with the application of knowledge aimed at the social benefit of the human being. Conclusions: the importance of an ethical posture in regenerative medicine was pointed out for the adequate assessment of the advances in the treatment of various diseases, the impact of the acquisition of new knowledge, as well as a more responsible attitude and the development of social values that they are part of humanity(AU)

Coautorias nas publicações brasileiras sobre medicina regenerativa: assimetrias na colaboração científica internacional / Brazilian co-authorships in regenerative medicine publications: inequalities in emerging countries scientific collaboration / Coautorías en las publicaciones brasileñas acerca de la medicina regenerativa: asimetrías en la colaboración científica internacional

A cooperação científica internacional tornou-se um fator essencial para que os países emergentes alcancem novos patamares de pesquisa, publicações e financiamento. No contexto de uma discussão analítica sobre a cooperação científica global, foram analisadas as publicações brasileiras indexadas na Web of Science e a coautoria entre pesquisadores locais e estrangeiros, com o objetivo de ilustrar as mudanças ocorridas na medicina regenerativa nas duas últimas décadas. O artigo conclui que, na última década, expandiu-se a coautoria entre autores brasileiros e destes com autores de países desenvolvidos, especialmente com aqueles dos Estados Unidos, mas também, em menor grau, com os de outros países emergentes e da América Latina. Pesquisadores brasileiros também publicaram artigos de impacto global, indicando a qualidade atingida, no país, pela pesquisa científica na área. A análise mostra que a colaboração abriu portas, no âmbito global, para a pesquisa local, mas também que as assimetrias científicas se mantiveram ao longo do tempo.

International scientific cooperation has become a key factor for emerging countries to improve research advancement, publication and funding. An analysis of local publications indexed in the Web of Science and co-authored between Brazilian researchers and non-residents was carried out, in the context of an analytical discussion on global scientific cooperation and with the aim of illustrating changes in the last two decades in regenerative medicine regarding this topic. The article concluded that in the last decade Brazil increased scientific co-authorships significantly domestically and with advanced country authors, especially with American authors, but also to a lesser degree with those of other emerging economies in and beyond Latin American. Local researchers have also published on their own several articles of global impact, revealing the academic quality attained in local sciences related to the area. Collaboration has undoubtedly opened doors for Brazilian regenerative medicine globally, but historical scientific inequalities remain.

La cooperación científica internacional se ha transformado en un factor sustancial para que los países emergentes progresen en investigación, publicación y financiación. Se desarrolló un análisis de publicaciones locales indexadas en la Web of Science y coautorías entre investigadores brasileños y extranjeros en el contexto de una reflexión sobre cooperación científica global y con el fin de ilustrar las modificaciones producidas en la medicina molecular regenerativa durante los dos últimos decenios. El artículo concluye que, en el último decenio, Brasil aumentó significativamente las coautorías domésticas y con autores de países avanzados, especialmente de los Estados Unidos, y en menor medida con aquellos de otras economías emergentes dentro y fuera de América Latina. Los investigadores locales han publicado varios artículos propios de impacto global, lo cual revela la calidad académica lograda, en Brasil, en el área. La colaboración ha abierto puertas en el mundo para la medicina regenerativa brasileña, pero las asimetrías científicas históricas persisten.

Empleo de células madre mononucleares en el tratamiento de osteoartritis en rodilla: caso de estudio en Cuba / Using Mononuclear Stem Cells for Osteoarthritis-Knee Treatments: A Case Study in Cuba / Uso de células-tronco mononucleares no tratamento da osteoartrite de joelho: estudo de caso em Cuba

Resumen Introducción: el desarrollo alcanzado en la medicina regenerativa posibilita el tratamiento de enfer medades incurables o que tienen una respuesta reducida a las terapéuticas actuales, así como la dis minución del consumo de medicamentos, en algunos casos. En Cuba, las especialidades de angiología y de ortopedia y traumatología son las que más han aplicado esta terapia. En el artículo se interpretan estadísticamente los resultados de la comparación, mediante STATGRAPHICS® Centurion XVI, de las varia bles controladas en dos tratamientos de osteoartritis en rodilla, uno empleando células madre mononucleares obtenidas de la sangre periférica y otro con la terapia convencional, para fundamentar la superioridad del nuevo tratamiento. Presentación del caso: se trataron 100 pacientes adultos atendidos en el Departamento de Ortopedia del Instituto de Hematología e Inmunología por osteoartrosis de rodilla, divididos en dos grupos. El grupo A (control) recibió el tratamiento convencional de infiltración con acetato de triamcinolona en la articulación afectada. El grupo B (estudio) recibió la implantación del concentrado de células mononucleares adultas hematopoyéticas por vía percutánea. Conclusión: se analizaron cada una de sus variables y se pudo comprobar que la mayoría de los datos recopilados no cumplía con una distribución normal, por lo que las siguientes pruebas se ejecutaron tomando como referencia la mediana de cada muestra. Se comparó entre la evaluación del dolor a la actividad y el consumo de medicamentos de cada uno de los grupos de tratamiento. Se evidenció la mejor respuesta de los pacientes para el tratamiento con células madre y una disminución en el consumo de fármacos.

Abstract Introduction: The development achieved in regenerative medicine has allowed the treatment of incurable diseases or those with a reduced response to current therapies, as well as cases with decreased consump tion of medicines. In Cuba, angiology, orthopedic, and traumatology specialists use this therapy the most. In this paper, we have presented the statistical analysis using the STATGRAPHICS® Centurion XVI for controlled variables in two osteoarthritis-knee treatments, one using mononuclear stem cells obtained from the peripheral blood and the other with a conventional therapy so as to demonstrate the superiority of the new treatment regime. Case report: A total of 100 adult patients treated in the Orthopedic Department at the Hematology and Immunology Institute for osteoarthritis-knee pains were studied. Group A (control) received the conventional treatment with triamcinolone acetate infiltration in the affected knee. Group B received the percutaneous implantation of the hematopoietic adult mononuclear cell concentrate. Conclusion: The analysis of each of the variables was performed to verify that most of the collected data did not comply with a normal distribution; hence, the following tests were performed taking the median of each sample as a reference. Comparisons were made between the evaluation of pain to the activity, as well as the consumption of drugs from each of the treatment groups. The best response of the patients was indicated for treatments with stem cells and a decrease in the consumption of drugs.

Resumo Introdução: o desenvolvimento alcançado na medicina regenerativa possibilita o tratamento de doenças incuráveis ou que têm uma resposta reduzida frente às terapias atuais, bem como a redução do consumo de medicamentos, em alguns casos. Em Cuba, as especialidades de angiologia e ortopedia e traumato logia são as que mais têm aplicado esta terapia. O estudo interpreta estatisticamente os resultados da comparação, por meio do STATGRAPHICS® Centurion XVI, das variáveis controladas em dois tratamentos de osteoartrite de joelho, sendo um utilizando células-tronco mononucleares obtidas de sangue periférico e outro com terapia convencional, com o objetivo de comprovar a superioridade do novo tratamento. Apresentação do caso: foram tratados 100 pacientes adultos atendidos no Departamento de Ortopedia do Instituto de Hematologia e Imunologia para osteoartrite de joelho, divididos em dois grupos. O grupo A (controle) recebeu tratamento convencional de infiltração com acetato de triancinolona na articulação afetada. O grupo B (estudo) recebeu implantação percutânea de concentrado de células mononucleares hematopoiéticas adultas. Conclusão: a análise de cada uma de suas variáveis foi realizada e constatou-se que a maioria dos dados coletados não obedecia a uma distribuição normal, de modo que os seguintes testes foram realizados tomando-se como referência a mediana de cada amostra. Foram feitas compara ções entre a avaliação da dor à atividade, bem como o consumo de medicamentos em cada um dos grupos de tratamento. Evidenciou-se uma melhor resposta dos pacientes ao tratamento com células-tronco e diminuição do consumo de medicamentos.

Cell therapy in the treatment of intervertebral disc degeneration / Terapia celular no tratamento da degeneração de disco intervertebral / Terapia celular en el tratamiento de la degeneración de disco intervertebral

ABSTRACT Approximately 80% of the world population experiences some type of back pain at some point in their life, and in 10% of this population the pain causes chronic disability resulting in a high cost for the treatment of these patients, in addition to compromising their work and social interaction abilities. Current treatment strategies include the surgical procedure for degenerated intervertebral disc resection, the nerve root block and physiotherapy. However, such treatments only relieve symptoms and do not prevent the degeneration of intervertebral discs. Therefore, new therapeutic strategies have emerged and include manipulating cells to recover the degenerated disc. This article will discuss the possible cell therapy alternatives used in the disc regeneration process, featuring a descriptive study of translational medicine that involves clinical aspects of new treatment alternatives and knowledge of basic research areas, such as cellular and molecular biology. Level of evidence V; Expert Opinion.

RESUMO Aproximadamente 80% da população mundial sofre algum tipo de dor nas costas em alguma fase de vida, sendo que em 10% dessa população, as dores acarretam incapacidade crônica, deflagrando alto custo de tratamento desses pacientes, além de comprometer as habilidades de trabalho e convívio social desses indivíduos. As estratégias de tratamento atuais incluem o procedimento cirúrgico por ressecção do disco intervertebral degenerado, bloqueio de raízes nervosas e fisioterapia. Entretanto, tais tratamentos apenas aliviam os sintomas e não impedem que ocorra a degeneração de discos intervertebrais. Portanto, novas estratégias terapêuticas têm surgido e incluem a manipulação de células com o objetivo de recuperar o disco degenerado. No presente artigo, serão discutidas as diferentes possibilidades alternativas de terapias celulares no processo de regeneração discal, caracterizando um estudo descritivo da medicina translacional que envolve aspectos clínicos de novas alternativas de tratamento e o conhecimento de áreas básicas de pesquisa como biologia celular e molecular. Nível de evidência V; Opinião do Especialista.

RESUMEN Aproximadamente 80% de la población mundial sufre algún tipo de dolor de espalda en alguna etapa de la vida, y en 10% de esa población, los dolores causan incapacidad crónica, deflagrando alto costo de tratamiento de esos pacientes, además de comprometer las habilidades laborales y convivencia social de esos individuos. Las estrategias de tratamiento actuales incluyen el procedimiento quirúrgico para la resección del disco intervertebral degenerado, bloqueo de las raíces nerviosas y fisioterapia. Entretanto, tales tratamientos solo alivian los síntomas y no impiden que ocurra la degeneración de discos intervertebrales. Por lo tanto, han surgido nuevas estrategias terapéuticas e incluyen la manipulación de células con el objetivo de recuperar el disco degenerado. En el presente artículo se discutirán las diferentes posibilidades alternativas de las terapias celulares en el proceso de regeneración discal, caracterizando un estudio descriptivo de la medicina traslacional que involucra aspectos clínicos de nuevas alternativas de tratamiento y conocimiento de áreas básicas de investigación como biología celular y molecular. Nivel de evidencia V; Opinión del especialista.