Research

J Clin Immunol. 2024 May 17;44(5):122. doi: 10.1007/s10875-024-01729-2.

NO ABSTRACT

PMID:38758474 | DOI:10.1007/s10875-024-01729-2

Mol Ther. 2024 May 14:S1525-0016(24)00320-4. doi: 10.1016/j.ymthe.2024.05.022. Online ahead of print.

ABSTRACT

Natural Killer (NK) cells have high intrinsic cytotoxic capacity, and clinical trials have demonstrated their safety and efficacy for adoptive cancer therapy. Expression of chimeric antigen receptors (CARs) enhances NK cell target-specificity, with these cells applicable as ‘off-the-shelf’ products generated from allogeneic donors. Here, we present for the first time an innovative approach for CAR NK cell engineering employing a non-viral Sleeping Beauty (SB) transposon/transposase-based system and minimized DNA vectors termed minicircles. SB-modified peripheral blood-derived primary NK cells displayed high and stable CAR expression and more frequent vector integration into ‘genomic safe harbors’ than lentiviral vectors. Importantly, SB-generated CAR NK cells demonstrated enhanced cytotoxicity compared to non-transfected NK cells. A strong antileukemic potential was confirmed using established acute lymphocytic leukemia (ALL) cells and patient-derived primary B-ALL samples as targets in vitro and in vivo in a xenograft leukemia mouse model. Our data suggest that the SB-transposon system is an efficient, safe and cost-effective approach to non-viral engineering of highly functional CAR NK cells, which may be suitable for cancer immunotherapy of leukemia as well as many other malignancies.

PMID:38751112 | DOI:10.1016/j.ymthe.2024.05.022

Kidney Dis (Basel). 2024 Jan 10;10(2):143-152. doi: 10.1159/000536194. eCollection 2024 Apr.

ABSTRACT

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy represents a significant advancement in the field of immunotherapy, providing targeted eradication of abnormal cells through the recognition between CAR and target antigens. This approach has garnered considerable attention due to its promising results in the clinical treatment of hematological malignancies and autoimmune diseases. As the focus shifts toward exploring novel targets and expanding the application of CAR-T cell therapy to solid tumors, including renal malignancies, researchers are pushing the boundaries of this innovative treatment. However, it is crucial to address the observed comorbidities associated with CAR-T cell therapy, particularly nephrotoxicity, due to the superseding release of cytokines and impairment of normal tissue.

SUMMARY: Our review discusses the research strategies and nephrotoxicity related to CAR-T cell therapy in various kidney-related diseases and provides insights into enhancing investigation and optimization.

KEY MESSAGES: CAR-T cell therapy has captured the attention of researchers and clinicians in the treatment of renal malignancies, multiple myeloma, systemic lupus erythematosus, and acquired immunodeficiency syndrome, which may lead to potential nephrotoxicity as they involve primary or secondary kidney complications. Understanding and summarizing the current research progress of CAR-T cell therapies can provide valuable insights into novel targets and combinations to optimize research models and enhance their clinical value.

PMID:38751795 | PMC:PMC11095583 | DOI:10.1159/000536194

Clin Immunol. 2024 May 12:110252. doi: 10.1016/j.clim.2024.110252. Online ahead of print.

ABSTRACT

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.

PMID:38744408 | DOI:10.1016/j.clim.2024.110252

Pediatr Int. 2024 Jan-Dec;66(1):e15752. doi: 10.1111/ped.15752.

NO ABSTRACT

PMID:38742681 | DOI:10.1111/ped.15752

Blood Cancer Discov. 2024 May 15. doi: 10.1158/2643-3230.BCD-23-0268. Online ahead of print.

ABSTRACT

Somatic variants in DNA damage-response genes such as ATM are widespread in hematologic malignancies. ATM protein is essential for double-strand DNA break repair. Germline ATM-deficiencies underlie ataxia-telangiectasia (A-T), a disease manifested by radio-sensitivity, immunodeficiency and predisposition to lymphoid malignancies. A-T patients diagnosed with malignancies have poor tolerance to chemotherapy or radiation. We investigated chimeric-antigen receptor (CAR) T cells using primary T-cells from patients with A-T (ATM-/-), heterozygote donors (ATM+/-) and healthy donors. ATM-/- T-cells proliferate and can be successfully transduced with CARs, though functional impairment of ATM-/- CAR-T cells was observed. Retroviral transduction of the CAR in ATM-/- T-cells resulted in high rates of chromosomal lesions at CAR insertion sites, as confirmed by next-generation long-read sequencing. This work suggests that ATM is essential to preserve genome integrity of CAR-T cells during retroviral manufacturing, and its lack poses a risk of chromosomal translocations and potential leukemogenicity.

PMID:38747501 | DOI:10.1158/2643-3230.BCD-23-0268

Surg Neurol Int. 2024 Apr 26;15:143. doi: 10.25259/SNI_65_2024. eCollection 2024.

ABSTRACT

BACKGROUND: Primary central nervous system (CNS) lymphoma is a very rare extranodal non-Hodgkin lymphoma. The bilateral pattern, as we call it “mirror type”, has been identified in other CNS lesions such as gliomas, metastases, and demyelinating lesions, so the differential diagnosis includes imaging studies such as magnetic resonance imaging contrasted with spectroscopy, ruling out immunodeficiency or metastatic disease.

CASE DESCRIPTION: A 65-year-old female presented progressing headache, loss of memory and language alterations, as well as sensory alterations. Neuroimaging showed the presence of two equidistant periventricular lesions at the level of both ventricular atria, a spectroscopy study suggestive of malignancy. Serological studies showed no evidence of immunodeficiency or the presence of positive tumor markers; however, a biopsy was performed, which revealed a histopathological result of primary lymphoma of the CNS.

CONCLUSION: In neuro-oncology, primary CNS tumors with multiple lesions are rare, even more, the “mirror type” lesions. Lymphomas are lesions that can present in different ways on imaging and clinical presentation. These tumors that present a vector effect due to their size, perilesional edema, or that lead to loss of neurological function are highly discussed in diagnostic and surgical treatment. Due to their prognosis, action on diagnosis and treatment must be taken as quickly as hospital resources allow.

PMID:38741983 | PMC:PMC11090529 | DOI:10.25259/SNI_65_2024

Transl Cancer Res. 2024 Apr 30;13(4):1606-1622. doi: 10.21037/tcr-23-2252. Epub 2024 Apr 12.

ABSTRACT

BACKGROUND: RNA-binding motif protein 39 (RBM39) is a well-known RNA-binding protein involved in tumorigenesis; however, its role in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the role of RBM39 in HCC.

METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze the differential expression of RBM39 in HCC and normal tissues. The prognostic and diagnostic value of RBM39 in HCC was accessed by Kaplan-Meier analysis, Cox regression, and receiver operating characteristic (ROC) curve analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to validate the mRNA and protein expression of RBM39 in HCC. Moreover, gene set enrichment analysis (GSEA) was performed to identify key pathways related to RBM39. The correlation between RBM39 expression and immune cell infiltration was evaluated using a single-sample gene set enrichment analysis (ssGSEA). CCK8 and wound healing assays were performed to investigate the proliferation and migration abilities of HCC cells with RBM39 knockdown.

RESULTS: RBM39 expression was upregulated in the HCC tissues. High RBM39 expression was significantly associated with advanced T stage, histological grade, and pathological stage and predicted poor overall survival (OS), disease-specific survival (DSS), and progress-free interval (PFI) in HCC patients. The upregulation of RBM39 expression was an independent prognostic factor for OS. Moreover, GSEA enrichment analysis indicated that RBM39 was functionally involved in pathways associated with the cell cycle, DNA replication, the p53 signaling pathway, and primary immunodeficiency. RBM39 expression was associated with infiltration of Th2 cells and dendritic cells (DC). RBM39 knockdown significantly inhibited the proliferation and migration of HCC cells.

CONCLUSIONS: These findings suggest that high RBM39 expression is associated with poor prognosis and promotes HCC cell proliferation and migration. Based on these results, RBM39 is a promising prognostic biomarker with functional significance for HCC.

PMID:38737697 | PMC:PMC11082663 | DOI:10.21037/tcr-23-2252

J Med Invest. 2024;71(1.2):184-186. doi: 10.2152/jmi.71.184.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE), a genetic disorder caused by C1-inhibitor deficiency or dysfunction, may cause mucosal edema in the upper airway during tracheal intubation and extubation.

CASE REPORT: A 57-year-old man with HAE and a history of laryngeal edema, scheduled to undergo cervical laminoplasty under general anesthesia. General anesthesia was induced by continuous injection of remimazolam and remifentanil, during which manual mask ventilation and intubation were performed without difficulty. The patient was extubated under deep anesthesia. After emergence from general anesthesia, he had no significant upper airway edema and was treated with a C1-inhibitor seven hours post-surgery because of slight tongue swelling. No additional airway edema was observed, and the patient was discharged from the intensive care unit the following day.

CONCLUSIONS: Deep anesthesia tracheal extubation with remimazolam may be effective in preventing upper airway edema during anesthetic management in patients with HAE. J. Med. Invest. 71 : 184-186, February, 2024.

PMID:38735719 | DOI:10.2152/jmi.71.184

Clin Lymphoma Myeloma Leuk. 2024 Apr 10:S2152-2650(24)00150-2. doi: 10.1016/j.clml.2024.04.002. Online ahead of print.

ABSTRACT

BACKGROUND: This retrospective cohort study compared patient characteristics and burden of infection in patients with mature B cell malignancies with and without secondary immunodeficiency disease (SID).

PATIENTS AND METHODS: Data were extracted from the Humedica database (H-DB) and Guardian Research Network (GRN) database from October 1, 2015 to March 10, 2020, including a 6-month pre-index period (PIP) and 12-month follow-up. Patients aged ≥18 years diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma, multiple myeloma, or non-Hodgkin’s lymphoma in the PIP were stratified into 2 cohorts: SID (hypogammaglobulinemia [using ICD-10-CM codes] or serum IgG levels <5.0 g/L, both with signs and symptoms of SID or at least 1 infection) and no-SID. Patients with SID or primary immunodeficiency diseases in the PIP were excluded.

RESULTS: Overall, 2221 patients with SID (H-DB/GRN: n = 1959/262), and 19,141 patients without SID (n = 17,598/1543) were included. Baseline characteristics were similar across cohorts. At 12-month follow-up, significantly more patients with SID had experienced ≥1 infection and ≥1 severe bacterial infection than those without SID (both P < .001). H-DB/GRN mean (standard deviation) number of severe bacterial infections was 7.6 (9.9)/2.9 (2.7) for the SID cohort versus 5.2 (6.8)/2.4 (2.2) for the no-SID cohort.

CONCLUSION: This study confirms that patients with mature B cell malignancies and SID face a significantly higher burden of infections than those without SID.

PMID:38734499 | DOI:10.1016/j.clml.2024.04.002