Chimeric antigen receptor T cell therapy and nephrotoxicity: From diagnosis to treatment strategies

Chimeric antigen receptor T (CAR-T) cell therapy is a breakthrough in cancer treatment. With the widespread use of this therapy, increasing evidence is available that CAR-T cell therapy is associated with acute kidney injury (AKI). Nephrologists need to understand the potential nephrotoxicity arising from CAR-T cell therapy. Determining the cause of AKI is a key factor of clinical management. This review focuses on the clinical use of CAR-T cell therapy and the cause and outcomes of nephrotoxicity with its use. We also provide clinical suggestions for clinicians towards both better diagnosis and management of AKI in those receiving CAR-T cell therapy.     

多靶点CAR-T细胞治疗肿瘤的研究进展

嵌合抗原受体T细胞（CAR-T）是一种过继细胞免疫疗法,其通过基因手段改造T细胞,从而发挥肿瘤靶向杀伤作用。CAR-T细胞疗法在治疗肿瘤,特别是血液系统恶性肿瘤方面具有显著的作用,但在实体肿瘤中作用不佳。单靶点的CAR-T在应用的过程中容易出现脱靶效应,存在复发或更加难治的风险。双靶点或多靶点CAR-T的开发有望扩大靶细胞抗原覆盖率,有效避免抗原逃逸和防止肿瘤复发,延长患者的生存时间。本文综述了目前多靶点嵌合抗原受体T细胞的研究进展,并探讨了其发展的前景。     

Characteristics and Clinical Outcomes of Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma Who Received At Least 3 Lines of Therapies

IntroductionThe treatment landscape for diffuse large B-cell lymphoma (DLBCL) has recently changed. We examined characteristics and clinical outcomes of DLBCL patients who initiated a third (3L) and fourth (4L) line of therapy during a contemporary time frame.Materials and MethodsAdult patients diagnosed with DLBCL who received ≥ 3L after January 1, 2014 were selected from the COTA database. Patients were grouped into cohorts by 3L or 4L initiation and further stratified by type of treatment received: chemotherapy or chemoimmunotherapy (CT/CIT), targeted therapy (TT), chimeric antigen receptor T cells (CAR-T), or salvage therapy consolidated with hematopoietic cell transplant (HCT). Patient characteristics, response rates, and overall survival (OS) were examined.ResultsAmong adult patients with relapsed/refractory (r/r) DLBCL, 212 (mean age; 61.8 years; 59.0% male) received their 3L and 127 (mean age: 61.0 years; 61.4% male) their 4L. Among those treated with their 3L and 4L, 55.2% and 50.4%, respectively, received CT/CIT; 26.9% and 34.6% received TT. The complete response rate of 3L patients was 9.4% for CT/CIT, 10.5% for TT, and 60% for CAR-T. Similar findings were seen with 4L patients (CT/CIT: 6.3%; TT: 15.9%; CAR-T: 53.8%). For those who received pharmacological treatment in 3L and 4L, median OS times were 7.7 and 4.4 months, respectively. Median OS times of patients who received cell-based therapies (CAR-T/HCT) were not reached.ConclusionIn this study, a majority of r/r DLBCL patients were treated with CT/CIT or TT in 3L and 4L settings and had poor clinical outcomes, underscoring the need for more effective treatments.     

Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation

Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life-threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient- and disease-related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular features that may lead to phenotypic changes that induce procoagulant, pro-inflammatory and pro-apoptotic mediators leading to EC dysfunction and damage. Elevated levels of coagulation factors, cytokines and adhesion molecules are indicative of endothelial dysfunction, and endothelial damage may lead to clinical signs and symptoms of pathological post-HCT conditions, including veno-occlusive disease/sinusoidal obstruction syndrome, graft-versus-host disease, transplant-associated thrombotic microangiopathy and idiopathic pneumonia syndrome/diffuse alveolar haemorrhage. The endothelium represents a rational target for preventing and treating HCT complications arising from EC dysfunction and damage. Additionally, markers of endothelial damage may be useful in improving diagnosis of HCT-related complications and monitoring treatment effect. Continued research to effectively manage EC activation, injury and dysfunction may be important in improving patient outcomes after HCT.     

CAR-T细胞治疗淋巴瘤的进展

CD19 CAR-T细胞治疗复发/难治性B细胞淋巴瘤取得了前所未有的应答率和持久的缓解。CAR-T细胞治疗在国内外迅速获批用于治疗二线以上复发/难治性大B细胞淋巴瘤,随后其套细胞淋巴瘤和滤泡性淋巴瘤的适应证也相继获批。CAR-T细胞治疗改变了B细胞淋巴瘤治疗的格局。随着CAR-T细胞在真实世界的广泛应用和早期治疗病例随访时间的延长,有部分患者可通过CAR-T细胞治疗获得临床治愈,这进一步肯定了CAR-T细胞在治疗高危淋巴瘤中的作用和地位。然而,CAR-T细胞治疗也还存在着许多问题,如患者的选择和治疗的时机、与现有治疗方式的优劣对比;同时也面临着很多的挑战,如通过桥接治疗以及联合治疗进一步提高安全性和有效性,进一步确认对霍奇金淋巴瘤、T细胞淋巴瘤等疾病的治疗作用等。本文将概述CAR-T细胞治疗淋巴瘤的相关进展,并浅要讨论CAR-T细胞治疗的相关问题及解决方法。     

GD2-directed CAR-T cells in combination with HGF-targeted neutralizing antibody (AMG102) prevent primary tumor growth and metastasis in Ewing sarcoma

Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2-specific, CAR-reengineered T-cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR-T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway.