The functional state of chimeric antigen receptor T (CAR T) cells determines their efficacy in vivo. Exhausted CAR T cells exhibit decreased proliferative capacity, impaired anti-tumor activity, and attenuated persistence. CAR T cell exhaustion has been recognized as a vital cause of nonresponse and relapse after CAR T cell therapy. However, the triggers and mechanisms leading to CAR T cell exhaustion remain blurry and complicated. Therefore, it is essential to clear the regulation network of CAR T cell exhaustion and explore potent solutions. Here, we review the diverse inducers of CAR T cell exhaustion in terms of manufacture process and immunosuppressive tumor microenvironment. In addition to the admitted immune checkpoint blockade, we also describe promising strategies that may reverse CAR T cell exhaustion including targeting the tumor microenvironment, epigenetics and transcriptomics.

Chimeric antigen receptor (CAR) T-cell immunotherapy following autologous stem cell transplantation (ASCT) is a promising method for refractory or relapsed multiple myeloma, but explicit data for central nervous system lymphoma (CNSL) are lacking. Here, we treated 13 CNSL patients with ASCT sequential CD19/22 CAR T-cell infusion and simultaneously evaluated the clinical efficacy and toxicity. The 13 CNSL patients analyzed included four primary CNSL and nine secondary CNSL patients. Patients 1 and 10, who had complete remission status before enrollment, maintained clinical efficacy without recurrence. Nine of the remaining 11 patients responded to our protocol with a median durable time of 14.03 months, and the overall response and complete remission rate were 81.81% and 54.55%, respectively. No patient suffered grades 3–4 cytokine-release syndrome (CRS), and only patient 10 experienced severe immune effector cell-associated neurotoxicity syndrome (ICANS). In addition, increases in serum ferritin and interleukin-6 levels were often accompanied by CRS and ICANS. After a median follow-up time of 14.20 months, the estimated 1-year progression-free survival and overall survival rates were 74.59% and 82.50%, respectively. Sequential CD19/22 CAR T-cell immunotherapy following ASCT as a novel method for CNSL appears to have encouraging long-term efficacy with relatively manageable side effects.

Background: Outcomes of chronic myeloid leukemia (CML) has been improved dramatically in the past two decades, but survival levels of CML patients varied in regions. Comprehensive epidemiological research is necessary to evaluate the global burden of CML.Methods: All data used in our study came from the Global Burden of Disease (GBD) study 2017. Incidence cases, death cases, disability-adjusted life-years (DALYs), and its corresponding age-standardized rate between 1990 to 2017 were used to describe the distribution of CML burden, according to age, sex, social-demographic index (SDI), and countries. Data about attributable risk factors contributing to CML deaths and DALYs were also extracted and analyzed.Results: Globally, the disease burden of CML gradually decreased from 1990 to 2017. Higher SDI countries achieved a remarkable effect on diminishing the CML burden. Conversely, due to population growth, the incidence cases, death cases, and DALYs of CML in lower SDI quintiles showed an upward trend. India had the most incidence cases and death cases of CML in the world. Additionally, smoking was the most significant attributable risk factor contributing to CML deaths and DALYs, followed by high body mass index.Conclusion: The disease burden of CML decreased globally, especially in higher SDI countries in the past 28 years. The increasing incidence cases and death cases were mainly observed in lower SDI countries. Additionally, strategies to control modifiable risk factors such as smoking and high body mass index might be useful in diminishing mortality and DALYs.

Background: Chimeric antigen receptor T‐cell (CAR‐T) therapy for acute myeloid leukaemia (AML) has thus far been elusive, in part due to target restriction and phenotypic heterogeneity of AML cells. Mutations of the FMS‐like tyrosine kinase 3 (FLT3) and DNA methyltransferase 3A (DNMT3A) genes are common driver mutations that present with a poor prognosis in AML patients. We found that AML patients with FLT3 or DNMT3A mutations had higher expression of CD44 isoform 6 (CD44v6) compared to normal specimens. Therefore, we intended to demonstrate CD44v6 could be a specific option for AML with FLT3 or DNMT3A mutations.Methods: Internal tandem duplication (ITD) mutations of FLT3 (FLT3/ITD) knock‐in clone and DNMT3A‐R882H mutant clones of SKM‐1 cells were generated using CRISPR/Cas9 and lentiviral transfection, respectively. CD44v6 CAR‐T cells were constructed by transfecting T cells with lentivirus containing CD44v6 CAR. CD44v6 expression in AML cell lines, AML patients and healthy donors was evaluated by flow cytometry. DNA methylation assays were used to analyse the mechanisms of FLT3 and DNMT3A mutations affecting CD44v6 expression.Results: Aberrant overexpression of CD44v6 was observed in AML cell lines with FLT3 or DNMT3A mutations compared to the wild‐type SKM‐1 or K562 cells. AML patients with FLT3 or DNMT3A mutations had higher expression of CD44v6 compared to normal specimens. Then we constructed CD44v6 CAR‐T cells and found that CD44v6 CAR‐T specifically lysed CD44v6⁺ cells, accompanied by cytokines release. No significant killing effect was observed from CD44v6^‐ AML cells and normal cells after co‐culture with CD44v6 CAR‐T. These results were also observed in vivo. Furthermore, we found that FLT3 or DNMT3A mutations induced CD44v6 overexpression by downregulating the CpG methylation of CD44 promoter.Conclusions: Collectively, CD44v6 is a promising target of CAR‐T for AML patients with FLT3 or DNMT3A mutations.

Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classification. Moreover, this review focuses on the major challenges encountered by CAR-T-cell therapies, including the nonspecific killing due to T-cell target antigen sharing and contamination with cell products during preparation. This review discusses strategies to overcome these challenges, presenting novel therapeutic approaches that could enhance the efficacy and applicability of CAR-T-cell therapy in the treatment of T-cell malignancies. These ideas and strategies provide important information for future studies to promote the further development and application of CAR-T-cell therapy in this field.