Novelty in improvement of CAR T cell-based immunotherapy with the aid of CRISPR system

Abstract Introduction Chimeric Antigen Receptor (CAR) T cells have tremendous potentials for cancer treatment; however, various challenges impede their universal use. These restrictions include the poor function of T cells in tumor microenvironments, the shortage of tumor-specific antigens and, finally, the high cost and time-consuming process, as well as the poor scalability of the method. Creative gene-editing tools have addressed each of these limitations and introduced next generation products for cell therapy. The clustered regularly interspaced short palindromic repeats-associated endonuclease 9 (CRISPR/Cas9) system has triggered a revolution in biology fields, as it has a great capacity for genetic manipulation. Method In this review, we considered the latest development of CRISPR/Cas9 methods for the chimeric antigen receptor T cell (CAR T)-based immunotherapy. Results The ability of the CRISPR/Cas9 system to generate the universal CAR T cells and also potent T cells that are persistent against exhaustion and inhibition was explored. Conclusion: We explained CRISPR delivery methods, as well as addressing safety concerns related to the use of the CRISPR/Cas9 system and their potential solutions.

Use of CAR-T cells for the treatment of relapsed and refractory multiple myeloma: a systematic review / Uso de células CAR-T no tratamento de mieloma múltiplo recidivado e refratário: uma revisão sistemática

A systematic review of published articles based on randomized clinical trials was conducted to ascertain the efficacy or perspective of using CAR-T cell therapy for refractory multiple myeloma. The PubMed database was searched with the combination of terms "multiple myeloma", "refractory multiple myeloma", "CAR T-cell", and the PRISMA criteria were followed. Of the 78 articles found, only 5 were selected. The studies used different treatment protocols and four different types of CAR-T cells. All studies obtained interesting results in terms of increased progression-free survival and negative minimal residual disease responses. Some authors detected an expansion of CAR-T cells and noted dose-dependent relationship between treatment effectiveness and serum BCMA levels. Although the results were promising, a small number of patients still relapsed a few months after CAR-T cell infusion. Therefore, this new line of therapy should be further investigated, as it significantly increases progression-free survival and improves quality of life.

Uma revisão sistemática de artigos publicados com base em ensaios clínicos randomizados foi realizada para verificar a eficácia ou perspectiva do uso da terapia com células CAR-T para mieloma múltiplo refratário. Foi pesquisada a base de dados PubMed com a combinação dos termos "multiple myeloma", "refratory multiple myeloma", "CAR T-cell" e foram seguidos os critérios PRISMA. Dos 78 artigos encontrados, apenas 5 foram selecionados. Os estudos utilizaram diferentes protocolos de tratamento e quatro tipos diferentes de células CAR-T. Todos os estudos obtiveram resultados interessantes em termos de aumento da sobrevida livre de progressão e respostas negativas à doença residual mínima. Alguns autores detectaram uma expansão das células CAR-T e observaram uma relação dose-dependente entre a eficácia do tratamento e os níveis séricos de BCMA. Embora os resultados tenham sido promissores, um pequeno número de pacientes ainda apresentou recaída alguns meses após a infusão de células CAR-T. Portanto, esta nova linha de terapia deve ser mais investigada, pois aumenta significativamente a sobrevida livre de progressão e melhora a qualidade de vida.

Teorías subjetivas sobre el tiempo de espera y experiencias de la parentalidad adoptiva / Subjective theories about waiting time and experiences from adoptive parenting

Resumen El proceso de adopción comprende cambios importantes en las familias adoptivas, pues implica una reestructuración y adaptación a una nueva organización del sistema familiar. Durante este proceso los padres elaboran expectativas y creencias respecto a cómo comportarse frente a los cambios y adaptarse a sus hijos, desde donde dirigen sus prácticas de crianza. La percepción del tiempo que tenga cada persona posee un papel en cómo se desarrolla la identidad tanto individual como familiar, pues las experiencias pasadas, vivencias actuales y expectativas del futuro influyen en sus acciones. Por lo tanto, es posible decir que los padres adoptivos elaboran teorías subjetivas sobre este proceso y especialmente en relación con el tiempo de espera de la adopción, explicaciones que podrían incidir en la forma en que enfrentan este nuevo desafío y se preparan para la parentalidad. El presente estudio tuvo por objetivo comprender las teorías subjetivas sobre el tiempo de espera y las experiencias de la parentalidad adoptiva. Participaron diez madres y padres adoptivos mediante entrevistas episódicas individuales. Se analizaron los datos obtenidos utilizando técnicas de tres procedimientos de análisis: de contenido basado en la Teoría Fundamentada, específico para las teorías subjetivas y de la perspectiva temporal. De los hallazgos se destacan teorías subjetivas de contenido emocional ansioso durante el proceso de adopción. Además, contar con una red de apoyo, compartir experiencias con otros padres y el uso de estrategias personales son las principales estrategias de adaptación de los padres adoptivos que les permiten sobrellevar los sentimientos negativos durante el proceso.

Abstract The adoption process includes important changes in adoptive families, since it implies a restructuring and adaptation to a new organization of the family system. The path to parenthood entails changes at levels of mental, physical and social health, which in the case of adoptive parents, the challenges are greater or are altered in some way due to the unique characteristics of their experiences and the obstacles they face. To these challenges are added the usual stressors that parents face, such as changes in roles, increased stress, lack of sleep, alterations in the relationship and intimacy of the couple and difficulties that arise in raising their children. On the other hand, time is configured as a concrete dimension through which life develop. The relationship between objective time and subjective or psychological time will shape the perception of time that each person has, which has a role in how both individual and family identity develops. This is because people´s actions are influenced by past experiences, current experiences and future expectations. One of the areas of the adoption process that has not yet been deepened is the waiting time, the period of time between obtaining the suitability and assignment of the minor to the adoptive family, which can be considered important for the future family depending on how adoptive parents face it, this because the way in which the adoption process is experienced impacts both the path to parenthood and post-adoption adaptation. In fact, it confirms that waiting time influences the psychological well-being of adoptive parents. Therefore, it is possible to say that adoptive parents elaborate subjective theories about this process and especially in relation to the waiting time for adoption, explanations that could influence the way in which they face this new challenge and prepare for parenthood. The present study aimed to understand subjective theories about the waiting time and experiences of adoptive parenting. Ten adoptive mothers and fathers participated in this study through individual episodic interviews. The data obtained were analyzed using techniques of three analysis procedures: content based on Grounded Theory, specific for subjective theories and time perspective.

Family intervention in the initial adaptation of adoptive families: systematic review / Intervenção familiar na adaptação Inicial das famílias adotivas: revisão sistemática / Intervención familiar en la adaptación Inicial de las familias Adoptivas: revisión sistemática

Considering the importance of mapping family interventions practices aimed specifically to adoption, this study sought to identify through a systematic review, how family intervention models for adoptive families are structured in initial adaptation with children from 0 to 6 years old. Four databases were consulted, which led to 9.143 results: Google Scholar (n=8.056), Science Direct (n=814), SciELO (n=43) and PsycINFO (n=230). Seven articles considered pertinent to the proposal of this study were included. As a result, it was identified that most part of the interventions were not systematically described. Although promising results were indicated, replication would not be viable due to the lack of detailing of the performed practices. There was no hegemony in the choice of intervention models. Also, it was indicated that the specificity for adoption in the interventions analyzed is not clear. (AU)

Pensando na importância do mapeamento da prática de intervenção familiar voltada especificamente para a adoção, o presente estudo buscou identificar, por meio da revisão sistemática, como estão estruturados e aplicados os modelos de intervenção familiar para as famílias adotivas na adaptação inicial com as crianças de 0 a 6 anos. Para tanto, foram consultadas quatro bases de dados que levaram a 9.143 resultados: Google Scholar (n=8.056), Science Direct (n=814), SciELO (n=43), PsycINFO (n=230). Sete artigos foram considerados pertinentes à proposta deste estudo. Como resultado, identificou-se que as intervenções não estavam, em sua maioria, sistematicamente descritas. Apesar de resultados promissores serem indicados, a replicação não seria viável pela falta de detalhamentos das práticas realizadas. Ressalta-se que não houve homogeneidade na escolha dos modelos de intervenção. Por fim, destaca-se que não fica clara a especificidade voltada para adoção nas intervenções analisadas. (AU)

Pensando en la importancia de mapear la práctica de intervención familiar orientada específicamente a la adopción, el presente estudio buscó identificar, a través de una revisión sistemática, cómo se estructuran y aplican los modelos de intervención familiar para familias adoptivas en la adaptación inicial con niños de 0 a 6 años. Para ello, se consultaron cuatro bases de datos que arrojaron 9.143 resultados: Google Scholar (n=8.056), Science Direct (n=814), SciELO (n=43), PsycINFO (n=230). Siete artículos se consideraron relevantes para el propósito de este estudio. En su mayor parte, las intervenciones no se describían sistemáticamente. A pesar de los resultados prometedores, la replicación no sería factible debido a la falta de detalles de las prácticas realizadas. Cabe destacar que no hubo homogeneidad en la elección de los modelos de intervención. Por último, se señaló que no está clara la especificidad dirigida a la adopción en las intervenciones analizadas. (AU)

Clinical research advance in immunotherapy of pancreatic cancer / 中华消化外科杂志

Pancreatic cancer is one of the most common tumors in digestive system, which is characterized by insidious clinical symptoms, strong invasion, easy metastasis and high mortality. In recent years, immunotherapy is a new direction to the treatment of solid tumors, but its applica-tion in pancreatic cancer is limited by tumor microenvironment of pancreatic cancer. The authors systematically analyze the tumor microenvironment of pancreatic cancer, summarize the clinical researches related to pancreatic cancer immunotherapy, and discuss the prospect of pancreatic cancer immunotherapy.

Gut microbiome and tumor immunotherapy / 国际肿瘤学杂志

Neoplasms immunotherapy has made a major breakthrough in the clinical practice of refractory tumor. However, there are still individual differences in treatment results and drug resistance in clinical application. Gastrointestinal microbiome is gradually recognized as an immunoregulatory factor in recent years, and more and more studies have focused on its influences on the efficacy of tumor immunotherapy. Targeting gastrointestinal microbiota to improve the response of tumor patients to immunotherapy has potential clinical application value.

Clinical research progress of immunotherapy for nasopharyngeal carcinoma / 国际肿瘤学杂志

Immunotherapy mainly uses the effector units of the body's immune system to overcome the immune escape or adaptive immune resistance of tumors, accurately identify and remove tumor cells, and normalize or enhance the function of the immune system, which mainly includes cytokine therapy, immune checkpoint inhibition therapy, adoptive cell immunotherapy, tumor vaccine and antibody targeted therapy. The immune characteristics of nasopharyngeal carcinoma make the patients potentially suitable for immunotherapy or combined therapy with radiotherapy and chemotherapy. In recent years, PD-1 inhibitors alone and in combination with chemotherapy have shown good anti-tumor activity and safety in the treatment of recurrent/metastatic nasopharyngeal carcinoma. The incorporation of immune checkpoint inhibitors into the treatment paradigms of nasopharyngeal carcinoma has become a clinical research hot spot.

Progress of companion diagnostics in chimeric antigen receptor T-cell therapy / 白血病·淋巴瘤

Chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved good efficacy in treatment of hematological malignancies. As a precise and individualized treatment method, CAR-T is gradually moving towards commercialization. In addition to the introduction of corresponding policies and guiding principles, the related detection protocols should also be updated and improved to maximize its effect and achieve precise individualization. This article introduces and expands the concept of "companion diagnostics" that first appeared in targeted drugs, and introduces the significances of various detection technologies and biomarkers for patient screening, safety monitoring and evaluation of efficacy and CAR-T function in the whole process of CAR-T treatment.

Application and prospect of cell therapy in clinical treatment of liver diseases / 临床肝胆病杂志

Cell therapy is an emerging therapy different from traditional drug therapy, among which immune cells and mesenchymal stem cells are the two types of most promising cells in the treatment of liver diseases at present, and preliminary results have been achieved for their therapeutic effects. This article summarizes the advances in cell therapy in the field of liver diseases, analyzes the challenges and coping strategies of different cell therapies, and discusses the application prospects of cell therapy in liver-related diseases.

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).

A história pregressa da criança e o processo de revelação da adoção, na perspectiva de pais adotivos / The child's history past and the adoption revelation process, from the perspective of adoptive parents / La historia pasada del niño y el proceso de revelación de la adopción, desde la perspectiva de los padres adoptivos

O presente artigo teve como objetivo compreender a história pregressa da criança e o processo de revelação da adoção na perspectiva de pais adotivos. Trata-se de uma pesquisa de campo, qualitativa, descritiva e exploratória, que utilizou como método o estudo de caso. Foram realizadas entrevistas semiestruturadas com duas mães e um pai adotivos. Os dados foram analisados por meio da análise do conteúdo de Minayo. Observou-se que as histórias das crianças e/ou o acesso dos pais a essas, mostraram-se com questões muito particulares, mediante a disponibilidade dos órgãos de proteção em passar informações sobre esse passado. A maioria dos pais demonstrou interesse em revelar a adoção, entretanto, a questão apareceu vinculada a insegurança, posto que, além de não terem tido acesso a informações sobre a história pregressa de seus filhos, os pais demonstraram dificuldades em lidar com o passado da criança, dados que revelam a importância do psicólogo para auxiliar adotantes na elaboração de conteúdos vinculados a experiência adotiva, dentre eles, suas próprias angustias vinculadas ao medo de perder seu filho, em virtude da camuflagem: família biológica x família adotiva.

This article aimed to understand the child's past history and the process of revelation of adoption from the perspective of adoptive parents. It is a research field qualitative, descriptive and exploratory, which used the case study as a method. Semi-structured interviews were conducted with two adoptive mothers and fathers. The results were analyzed through of the analysis of the content of Minayo. It was observed that the children's stories and/or the parents' access to them, showed themselves with very particular issues, due to the availability of the protection organs, associated with the cases, to pass on information about this past. Most parents showed interest in revealing the adoption, however, the issue was linked to insecurity, since, in addition to not having access to information about their children's previous story, parents showed difficulties in dealing with the child's past, data that reveal the importance of the psychologist to assist adopters in the elaboration of contents linked to the adoptive experience, among them, yours anxieties linked to the fear of losing their child, due to the camouflage: biological family x adoptive family.

Buscamos entender cómo los padres adoptivos significan la historia pasada de los niños y su revelación. Se trata de una investigación de campo cualitativa, descriptiva y exploratoria, que utilizó el estudio de caso como método. Se realizaron entrevistas semiestructuradas con dos madres y padres adoptivos. Los datos fueron analizados a la luz del análisis del contenido de Minayo. Se observó que las historias de los niños y/o el acceso de los padres a ellas, se mostraron con problemáticas muy particulares, debido a la disponibilidad de los órganos de protección, asociados a los casos, para transmitir información sobre este pasado. La mayoría de los padres mostraron interés en revelar la adopción, sin embargo, el problema parecía estar relacionado con la inseguridad, ya que, además de no tener acceso a información sobre la historia pasada de sus hijos, los padres demostraron dificultades para lidiar con el pasado del niño, datos que revelan la importancia del psicólogo para ayudar a los adoptantes en la elaboración de contenidos vinculados a la experiencia adoptiva, entre ellos, sus propias ansiedades ligadas al miedo a perder a su hijo, debido al camuflaje: familia biológica x familia adoptiva.

Aplicación de células madres autólogas en pacientes con aterosclerosis obliterante grado IV / Application of autologous stem cells in patients with grade IV atherosclerosis obliterans

RESUMEN Introducción: la enfermedad arterial periférica de los miembros inferiores afecta a un elevado porcentaje de la población mundial, con las células madres autólogas obtenidas de sangre periférica se logra una mayor síntesis de factores de crecimiento que inducen la angiogénesis. Objetivo: describir el autotrasplante de células madres autólogas obtenidas de sangre periférica en pacientes con aterosclerosis obliterante grado IV, de Pinar del Río, atendidos en el período de 2009-2019. Métodos: se realizó un estudio descriptivo, longitudinal, con 296 pacientes que presentaban aterosclerosis obliterante grado IV durante en el período de 2009-2019. Se obtuvo el concentrado de células madres autólogas de sangre periférica. Las células se analizaron por citometría de flujo, donde mostraron una viabilidad celular del 99,3 %. Se les inyectó por vía intramuscular un concentrado de células madres con un número de células inyectadas de ocho, seis, diez. Las variables estudiadas fueron: índice de presión tobillo-brazo en reposo, distancia de claudicación libre de dolor, evaluación de la escala del dolor y criterio de amputación. Resultado: se observó alivio del dolor a las cuatro semanas y aumento de la distancia de claudicación libre de dolor. La angiografía post tratamiento mostró formación de vasos colaterales. Presentaron criterio de amputación 95 casos (32 %) se logró salvar la extremidad en 201 pacientes (68 %). El proceder realizado no se asoció con ninguna complicación. Conclusión: la aplicación de células madres autólogas de sangre periférica es segura y eficaz para el tratamiento de la aterosclerosis obliterante grado IV.

ABSTRACT Introduction: peripheral arterial disease of the lower limbs affects a high percentage of the world population; with autologous stem cells obtained from peripheral blood a greater synthesis of growth factors that induce angiogenesis is achieved. Objective: to describe the auto-transplantation of autologous stem cells obtained from peripheral blood in patients with grade IV atherosclerosis obliterans in Pinar del Rio treated during period 2009-2019. Methods: a descriptive, longitudinal study was carried out with 296 patients with grade IV atherosclerosis obliterans during the period 2009-2019. Autologous peripheral blood stem cell concentrate was obtained. The cells were analyzed by flow cytometry, where they showed a cell viability of 99,3 %. Stem cell concentrate was injected intramuscularly with a number of cells injected of eight, six and ten. The variables studied were ankle-brachial pressure index at rest, pain-free claudication distance, pain scale assessment and amputation criteria. Result: pain relief was observed at four weeks and increase in pain-free claudication distance. Post-treatment angiography showed collateral vessel formation. Amputation criteria were met in 95 cases (32 %) and the limb was saved in 201 patients (68 %). The procedure carried out was not associated with complications. Conclusion: the application of autologous peripheral blood stem cells is safe and effective for the treatment of grade IV atherosclerosis obliterans.

Neurologic adverse events of cancer immunotherapy / Eventos adversos neurológicos da imunoterapia contra o câncer

ABSTRACT Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system and have revolutionized oncological treatment in recent years, with approval for its use in more and more cancers. However, it is not without side effects. Several neurological adverse events have been recognized associated with immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T-cell therapy, the two main classes of cancer immunotherapy. With the increase in the prevalence of oncological diseases and this type of therapy, it is improbable that neurologists, oncologists, hematologists, and other healthcare professionals who deal with cancer patients will not encounter this type of neurologic complication in their practice in the following years. This article aims to review the epidemiology, clinical manifestations, diagnosis, and management of neurological complications associated with ICI and CAR T-cell therapy.

RESUMO A imunoterapia contra o câncer engloba uma gama de modalidades de tratamento que aumentam os efeitos antitumorais do próprio sistema imunológico do paciente e revolucionaram o tratamento oncológico nos últimos anos, com aprovação para seu uso em cada vez mais neoplasias. No entanto, não é sem efeitos colaterais. Vários eventos adversos neurológicos foram reconhecidos associados aos inibidores de checkpoint imunológico (ICI) e à terapia de células T com receptor de antígeno quimérico (CAR-T), as duas principais classes de imunoterapia contra o câncer. Com o aumento da prevalência de doenças oncológicas e desse tipo de terapia, é improvável que neurologistas, oncologistas, hematologistas e demais profissionais de saúde que lidam com pacientes com câncer não encontrem esse tipo de complicação neurológica em sua prática nos próximos anos. Este artigo tem como objetivo revisar a epidemiologia, as manifestações clínicas, o diagnóstico e o manejo das complicações neurológicas associadas à terapia com ICI e células CAR-T

Chimeric antigen receptor T cell immunotherapy for refractory and relapsed acute lymphoblastic leukemia: Challenge and Countermeasures / 中华检验医学杂志

Chimeric antigen receptor(CAR)-T cell immunotherapy for refractory and relapsed acute lymphoblastic leukemia (R/R ALL) is one of the breakthroughs in the field of hematological malignant disease treatment. However, several challenges remain, such as immune rejection of allogeneic CAR-T cells, leukemia relapse, as well as could we apply CAR-T cell immunotherapy to ALL patients with positive measurable residual disease and those of newly diagnosed cases. The safety and efficiency of CAR-T therapy will be further improved for patients with ALL only by establishing appropriate strategies to address these challenges.

Progress of advanced hepatocellular carcinoma adoptive cell therapy based on tumor neoantigens / 中华肝胆外科杂志

Advanced hepatocellular carcinoma has a high degree of malignancy and poor prognosis. Studies showed that there is a close relationship between the progression of hepatocellular carcinoma and the immune status in tumor microenvironment. Adoptive cell therapy showed anti-tumor effects and improve immunosuppression by infusing patients with activated specific immune cells, which become a central issue in tumor therapy and shown promising effects in the treatment of various malignant tumors, indicating great application potential. Adoptive cell therapy based on neoantigen may become a new hot spot in the treatment of hepatocellular carcinoma, and their application, safety and effectiveness evaluation, efficacy prediction and assessment have become urgent issues to be solved. The purpose of this article is to introduce the progress related to adoptive cell therapy for advanced hepatocellular carcinoma and elaborate the problems that need to be solved in the future.

Current status and prospect of immunotherapy for cholangiocarcinoma / 中华消化外科杂志

Cholangiocarcinoma (CCA) is a category of highly heterogeneous and aggressive malignancy mainly originating from bile duct epithelial cells. The median survival time of untreated CCA patients is approximately 12?24 months, and the effectiveness and durability of surgical resection and neoadjuvant chemotherapy are limited. Results of the next-generation sequencing show that dysregulation of the immune system plays an important role in the pathogenesis of CCA. It has opened up new possibilities for the study of therapies targeting the natural course of aggressive CCA, such as immune checkpoint inhibitors, adoptive cell therapy, and tumor vaccines. Based on the current status of immunotherapy for CCA, the authors review the efficacy and dilemmas of current CCA immunotherapy strategies and look forward to the future treatment prospects of CCA.

CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success? / 医学前沿

Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.

Emerging role of natural products in cancer immunotherapy

Cancer immunotherapy has become a new generation of anti-tumor treatment, but its indications still focus on several types of tumors that are sensitive to the immune system. Therefore, effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy. Natural products are reported to have this effect on cancer immunotherapy, including cancer vaccines, immune-check points inhibitors, and adoptive immune-cells therapy. And the mechanism of that is mainly attributed to the remodeling of the tumor-immunosuppressive microenvironment, which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy. Therefore, this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism. And we found that saponins, polysaccharides, and flavonoids are mainly three categories of natural products, which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment. Besides, this review also collected the studies about nano-technology used to improve the disadvantages of natural products. All of these studies showed the great potential of natural products in cancer immunotherapy.

Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.

Células asesinas naturales con el receptor de antígeno quimérico (CAR-NK): terapia emergente contra el cáncer / Chimeric antigen receptor-natural killer cells: novel therapy against cancer

Resumen Una de las herramientas más novedosas en inmunoterapias adoptivas contra leucemias y tumores malignos es el uso del receptor de antígeno quimérico "CAR". El receptor CAR ha sido ampliamente utilizada en células T (células CAR-T) potenciando su eficacia en el reconocimiento y eliminación de tumores, obteniéndose a la fecha terapias basadas en esta tecnología. No obstante, las células CAR-T llegan a repercutir negativamente en la salud del paciente, presentando el síndrome neurológico de efecto inmune asociado a células (ICANS) y el síndrome de lanzamiento de citocinas (SLC). Como consecuencia, el paciente necesita ser hospitalizado durante la terapia. Además, el coste de manufactura y terapia es elevado, siendo una tecnología limitada a un sector muy bajo de la población. En este trabajo, mencionamos el empleo de una terapia emergente de células asesinas naturales (NK) con el receptor CAR (CAR-NK), que cuentan con muchas ventajas por encima de las células CAR-T. Las células CAR-NK conservan su capacidad citotóxica en contra de tumores gracias a su acción dependiente de receptores activadores e inhibidores, por lo que el receptor CAR, solo estimula sus habilidades y persistencia. Sumado a esto, el coste de una terapia de células CAR-NK podría resultar redituable debido a la capacidad de las células CAR-NK de eliminar múltiples células tumorales sin generar daño colateral en el paciente. Aquí analizamos las características de los múltiples receptores CAR y los fenotipos de células NK que han sido utilizados durante múltiples ensayos (NK-92, células NK de sangre cordal y periférica, y células NK iPSC).

Abstract One of the novel and effective devices against leukemia and solid tumors in adoptive immunotherapies is the use of the chimeric antigen receptor "CAR". CAR technology has been widely used in T-cells (CAR-T cells) empowering its efficacy on the identification and elimination of tumor cells, getting today certain drugs based on this technology. Nevertheless, CAR-T cells can have a negative impact on patient health, causing in many cases immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS). As a consequence, the patient will have to be hospitalized for the duration of therapy. Moreover, the cost of manufacture and therapy is quite expensive, limiting its use to a low range of people. On the other hand, we analyze the advantages of Natural Killer cells with the CAR receptor (CAR-NK), which have many plusses over CAR-T cells. CAR-NK cells retain their cytotoxic abilities against tumor cells due their activator/ inhibitor receptors balance. Thus, the CAR receptor technology just increases their skills and persistence. Furthermore, CAR-NK therapy could be more profitable since CAR-NK can eliminate multiple tumor cells without generating collateral damage on patient health. Here, we discuss the characteristics of the multiples CAR receptors in general and the NK types cells that have been used in trials demonstrating their viable emerging therapy (NK-92, cord and peripheral blood NK cells, and iPSC-derived NK cells).