Chimeric antigen receptor redirected T cells (CAR-T cells) have achieved inspiring outcomes in patients with B cell malignancies, and are now being investigated in other hematologic malignancies and solid tumors. CAR-T cells are generated by the T cells from patients’ or donors’ blood. After the T cells are expanded and genetically modified, they are reinfused into the patients. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. In this review, we first discuss the structure and evolution of chimeric antigen receptors. We then report on the tools used for production of CAR-T cells. Finally, we address the challenges posed by CAR-T cells.

Chimeric antigen receptor T (CAR-T) cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. Although the initially approved anti-CD19 CAR-T therapy has produced impressive outcomes, setbacks such as high relapse rates and resistance were experienced, driving the need to discover engineered CAR-T cells that are more effective for therapeutic use. Innovations in the structure and manufacturing of CAR-T cells have resulted in significant improvements in efficacy and persistence, particularly with the development of fourth-generation CAR-T cells. Paired with an immune modifier, the use of fourth-generation and next-generation CAR-T cells will not be limited because of cytotoxic effects and will be an efficient tool for overcoming the tumor microenvironment. In this review, we summarize the recent transformations in the ectodomain, transmembrane domain, and endodomain of the CAR structure, which, together with innovative manufacturing technology and improved cell sources, improve the prospects for the future development of CAR-T cell therapy.

The consensus recommendations in 2018 from The Chinese Society of Hematology (CSH) on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation (allo-HSCT) facilitated the standardization of clinical practices of allo-HSCT in China and progressive integration with the world. There have been new developments since the initial publication. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the consensus recommendations, which are summarized as follows: (1) there is a new algorithm for selecting appropriate donors for allo-HSCT candidates. Haploidentical donors (HIDs) are the preferred donor choice over matched sibling donors (MSDs) for patients with high-risk leukemia or elderly patients with young offspring donors in experienced centers. This replaces the previous algorithm for donor selection, which favored MSDs over HIDs. (2) Patients with refractory/relapsed lymphoblastic malignancies are now encouraged to undergo salvage treatment with novel immunotherapies prior to HSCT. (3) The consensus has been updated to reflect additional evidence for the application of allo-HSCT in specific groups of patients with hematological malignancies (intermediate-risk acute myeloid leukemia (AML), favorable-risk AML with positive minimal residual disease, and standard-risk acute lymphoblastic leukemia). (4) The consensus has been updated to reflect additional evidence for the application of HSCT in patients with nonmalignant diseases, such as severe aplastic anemia and inherited diseases. (5) The consensus has been updated to reflect additional evidence for the administration of anti-thymocyte globulin, granulocyte colony-stimulating factors and post-transplantation cyclophosphamide in HID-HSCT.

Cancers are a group of heterogeneous diseases characterized by the acquisition of functional capabilities during the transition from a normal to a neoplastic state. Powerful experimental and computational tools can be applied to elucidate the mechanisms of occurrence, progression, metastasis, and drug resistance; however, challenges remain. Bulk RNA sequencing techniques only reflect the average gene expression in a sample, making it difficult to understand tumor heterogeneity and the tumor microenvironment. The emergence and development of single-cell RNA sequencing (scRNA-seq) technologies have provided opportunities to understand subtle changes in tumor biology by identifying distinct cell subpopulations, dissecting the tumor microenvironment, and characterizing cellular genomic mutations. Recently, scRNA-seq technology has been increasingly used in cancer studies to explore tumor heterogeneity and the tumor microenvironment, which has increased the understanding of tumorigenesis and evolution. This review summarizes the basic processes and development of scRNA-seq technologies and their increasing applications in cancer research and clinical practice.

Haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) is an alternative treatment method for severe aplastic anemia (SAA) patients lacking suitable identical donors and those who are refractory to immunosuppressive therapy (IST). The current study evaluated the feasibility of upfront haploidentical HSCT in SAA patients. We conducted a multicenter study based on a registry database. One hundred fifty-eight SAA patients who underwent upfront transplantation between June 2012 and September 2015 were enrolled. Eighty-nine patients had haploidentical donors (HIDs), and 69 had matched related donors (MRDs) for HSCT. The median times for myeloid engraftment in the HID and MRD cohorts were 12 (range, 9–20) and 11 (range, 8–19) days, with a cumulative incidence of 97.8 and 97.1% (P = 0.528), respectively. HID recipients had an increased cumulative incidence of grades II–IV acute graft-versus-host disease (aGVHD) (30.3 vs. 1.5%, P < 0.001), grades III–IV aGVHD (10.1 vs. 1.5%, P = 0.026), and chronic GVHD (cGVHD) (30.6 vs. 4.4%, P < 0.001) at 1 year but similar extensive cGVHD (3.4 vs. 0%, P = 0.426). The three-year estimated overall survival (OS) rates were 86.1 and 91.3% (P = 0.358), while the three-year estimated failure-free survival (FFS) rates were 85.0 and 89.8% (P = 0.413) in the HID and MRD cohorts, respectively. In multivariate analysis, survival outcome for the entire population was significantly adversely associated with increased transfusions and poor performance status pre-SCT. We did not observe differences in primary engraftment and survival outcomes by donor type. Haploidentical SCT as upfront therapy was an effective and safe option for SAA patients, with favorable outcomes in experienced centers.

Purpose: Although mesenchymal stromal cells (MSCs) possess immunomodulatory properties and exhibit promising efficacy against chronic graft-versus-host disease (cGVHD), little is known about the efficacy of MSCs in the prophylaxis of cGVHD after HLA-haploidentical hematopoietic stem-cell transplantation (HLA-haplo HSCT). Patients and Methods: In this multicenter, double-blind, randomized controlled trial, we investigated the incidence and severity of cGVHD among patients, and the changes in T, B, and natural killer (NK) cells after the repeated infusion of MSCs. Results: The 2-year cumulative incidence of cGVHD in the MSCs group was 27.4% (95% CI, 16.2% to 38.6%), compared with 49.0% (95% CI, 36.5% to 61.5%) in the non-MSCs control group (P = .021). Seven patients in the non-MSCs control group had severe lung cGVHD, but no patients in the MSCs group developed typical lung cGVHD (P = .047). After the MSC infusions, increasing memory B lymphocytes and regulatory T cells, as well as the ratio of type 1 T helper to type 2 T helper cells, were observed, whereas the number of NK cells decreased. Conclusion: Our findings suggest that the repeated infusion of MSCs might inhibit cGVHD symptoms in patients after HLA-haplo HSCT, accompanied by changes in the numbers and subtypes of T, B, and NK cells, leading to the acquisition of immune tolerance.