ABSTRACT
Introduction: Acute Lymphoblastic Leukemia (ALL) is the most prevalent malignancy in children; however, when the neoplasm becomes refractory/relapses (R/R) the cure possibilities are practically null. Objectives: To analyze the Anti-CD19 Chimeric Antigen Receptors (CAR) T-Cells immunotherapy efficacy in the treatment of R/R ALL, providing evidence about the efficacy and safety of the therapy for the analyzed group. Methods: The study consisted of a systematic review and meta-analysis based on the analysis of indexed articles. The searches were carried out with the terms: "acute lymphoblastic leukemia", "CAR T", and "CD19-specific chimeric antigen receptor". Results: Only 18 of the 94 articles obtained initially met the inclusion criteria and were selected for review, totaling 637 patients. Thus, it was observed in the responses that approximately 81% of the patients achieved a Complete Response; 7% did not respond; the neoplasm relapsed in 17% of the cases; and 6.1% of the patients died. The main side effects found were Cytokine Release Syndrome (CRS), Severe Cytokine Release Syndrome, and Neurotoxicity, present in 36.3%, 29%, and 24% of patients, respectively. Conclusion: Anti-CD19 CAR T-Cells immunotherapy is an effective therapy, capable of producing high rates of complete remission in R/R ALL treatment. [au]
Introdução: A Leucemia Linfoblástica Aguda (LLA) é a neoplasia maligna mais prevalente em crianças; entretanto, quando se torna refratária/recidivante (R/R) as possibilidades de cura são praticamente nulas. Objetivos: Analisar a eficácia da imunoterapia de Receptores de Antígenos Quiméricos anti-CD19 no tratamento da LLA R/R, fornecendo evidências sobre a efetividade e segurança da terapia para o grupo analisado. Métodos: O estudo consistiu em uma revisão sistemática e metanálise baseada em artigos indexados. As pesquisas foram realizadas com os termos: "acute lymphoblastic leukemia", "CAR T", and "CD19-specific chimeric antigen receptor". Resultados: Dos 94 artigos obtidos, apenas 18 atenderam inicialmente aos critérios de inclusão e foram selecionados para revisão, totalizando 637 pacientes. Assim, observou-se nas respostas que aproximadamente 81% dos pacientes obtiveram resposta completa; 7% não responderam; a neoplasia recidivou em 17% dos casos; e 6,1% dos pacientes morreram. Os principais efeitos colaterais encontrados foram síndrome de liberação de citocinas, síndrome de liberação grave de citocinas e neurotoxicidade, presentes em 36,3%, 29% e 24% dos pacientes, respectivamente. Conclusão: A imunoterapia com células CAR T anti-CD19 é uma terapia eficaz, sendo capaz de produzir altas taxas de remissão completa no tratamento de LLA R / R. [au]
ABSTRACT
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).
Subject(s)
Humans , Leukemia , Therapeutics , Immunotherapy, Adoptive , Cytokine Release SyndromeABSTRACT
Recent understanding of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.
Subject(s)
Immunotherapy/trends , Neoplasms/therapy , Antibodies, Monoclonal/immunology , CTLA-4 Antigen , Humans , Immunotherapy/methods , Neoplasms/immunology , T-Lymphocytes/immunology , Tumor Microenvironment/immunologyABSTRACT
La activación del sistema inmunológico en pacientes con cáncer ha sido un objetivo histórico en el campo de la oncología. En las últimas décadas, nuestro entendimiento de la respuesta inmunológica antitumoral ha promovido el desarrollo de novedosas estrategias terapéuticas dando como resultado un cambio de paradigma en el tratamiento del cáncer. La utilización de agentes bloqueantes de puntos de chequeo del sistema inmunológico como PD-1/PD-L1 y CTLA-4, de agonistas de moléculas co-estimuladoras como CD137 y OX-40 y la transferencia adoptiva de células T antitumorales modificadas genéticamente han generado importantes beneficios clínicos, reflejados en respuestas objetivas y durader as, en enfermos sin tratamientos convencionales disponibles. Sin embargo, un gran número de pacientes no responde a dichas terapias generando resistencia o sufriendo recaídas de la enfermedad debido a la aparición de circuitos inhibitorios o compensatorios. La combinación racional de estrategias terapéuticas permite eliminar mecanismos de resistencia, mientras que la identificación de biomarcadores predictivos facilita la selección de pacientes respondedores a dichos tratamientos. Recientes ensayos clínicos y estudios pre-clínicos permiten vislumbrar un escenario optimista con importantes desafíos en la implementación de estrategias de inmunoterapia en cáncer.
Recent under-standing of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.