ABSTRACT
Myasthenia gravis (MG) is a heterogeneous autoimmune disease, which is characterized by a postsynaptic neuromuscular transmission defect, with antibodies directly targeting the acetylcholine receptor (AChR) or other structural proteins of the neuromuscular junction. The majority of MG cases are associated with thymic pathologies, including thymoma, thyroiditis, autoimmune diseases or malignant hematologic neoplasia. The present study reported a rare case of AChR-positive and late-onset ocular MG, which rapidly progressed to a generalized myasthenic syndrome as an initial presentation of a pancreatic neuroendocrine neoplasia (pNEN). Following complete surgical resection of the pNEN, the myasthenic syndrome was improved and the anti-AChR antibody titers were reduced. It has been reported that MG is a paraneoplastic syndrome in thymic neoplasms and less common in hematologic malignancies. However, currently, only few cases of MG as initial presentation of a solid tumor, and more particular of a neuroendocrine neoplasm, have been reported in the literature. In conclusion, surveillance for extrathymic solid malignancies in newly diagnosed patients with MG could promote the early diagnosis of associated tumor diseases.
ABSTRACT
Acute myeloid leukemia (AML) and B-cell acute lymphocytic leukemia (B-ALL) are severe blood malignancies affecting both adults and children. Chimeric antigen receptor (CAR)-based immunotherapies have proven highly efficacious in the treatment of leukemia. However, the challenge of the immune escape of cancer cells remains. The development of more affordable and ready-to-use therapies is essential in view of the costly and time-consuming preparation of primary cell-based treatments. In order to promote the antitumor function against AML and B-ALL, we transduced NK-92 cells with CD276-CAR or CD19-CAR constructs. We also attempted to enhance cytotoxicity by a gene knockout of three different inhibitory checkpoints in NK cell function (CBLB, NKG2A, TIGIT) with CRISPR-Cas9 technology. The antileukemic activity of the generated cell lines was tested with calcein and luciferase-based cytotoxicity assays in various leukemia cell lines. Both CAR-NK-92 exhibited targeted cytotoxicity and a significant boost in antileukemic function in comparison to parental NK-92. CRISPR-Cas9 knock-outs did not improve B-ALL cytotoxicity. However, triple knock-out CD276-CAR-NK-92 cells, as well as CBLB or TIGIT knock-out NK-92 cells, showed significantly enhanced cytotoxicity against U-937 or U-937 CD19/tag AML cell lines. These results indicate that the CD19-CAR and CD276-CAR-NK-92 cell lines' cytotoxic performance is suitable for leukemia killing, making them promising off-the-shelf therapeutic candidates. The knock-out of CBLB and TIGIT in NK-92 and CD276-CAR-NK-92 should be further investigated for the treatment of AML.
