Chimeric antigen receptor T (CAR T) cell therapy has demonstrated efficacy in the treatment of haematologic malignancies. However, the accompanying adverse events, the most common of which is cytokine release syndrome (CRS), substantially limit its wide application. Due to its unique physiological characteristics, CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma (B-NHL) may exhibit some special features. Although existing guidelines had greatly promoted the recognition and management of CRS, many recommendations are not fully applicable to B-NHL. Therefore, it is imperative to identify responses that are specific to CRS observed following CAR T treatment for B-NHL. Based on underlying biological processes and known pathophysiological mechanisms, we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in B-NHL. In this model, tumour burden and bone marrow suppression are considered determinants of CRS. Novel phenomena after CAR T-cell infusion (such as local inflammatory response) are further identified. The proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.
3D ordered structures beyond microscale with targeted modification are catching increasing attention due to its application as tissue scaffolds. Especially scaffolds with necessary growth factors at designated locations are meaningful for induced cell differentiation and tissue formation. However, few fabrication methods can address the challenge of introducing bioactive species to the interior targeted places during the preparation process. Herein, for the first time macroscopic supramolecular assembly is applied to obtain such 3D ordered structures and established a proof‐of‐concept idea of complex scaffold with targeted modification. Taking strip‐like polydimethylsilicon building block as a model system, microscaled multilayered structures have been fabricated with parallel aligned building blocks in each layer. The morphology can be adjusted in a flexible way by tuning the number of layer, the space between two adjacent building blocks, and the position and orientation of each PDMS. The as‐prepared 3D structures are demonstrated biocompatible and potential as scaffolds for 3D cell culture. Moreover, bioactive species can be in situ incorporated into designated locations within the 3D structure precisely. In this way, a novel strategy is provided to address the current challenges in fabricating complex 3D tissue scaffolds with localized protein for future induced cell differentiation.
Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24–36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23–37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy.
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