Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM). This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 106 cells/kg [range, 0.07 to 2.1 × 106]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group. At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached. LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM. ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered

The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity. The objective of this study was to determine whether Paeonol (Pae) has the ability to protect against Dox-induced cardiotoxicity and if so, what are the underlying mechanisms involved. Sprague-Dawley rats and primary cardiomyocytes were used to create Dox-induced cardiotoxicity models. Pae's effects on myocardial damage, mitochondrial function, mitochondrial dynamics and signaling pathways were studied using a range of experimental methods. Pae enhanced Mfn2-mediated mitochondrial fusion, restored mitochondrial function and cardiac performance both in vivo and in vitro under the Dox conditions. The protective properties of Pae were blunted when Mfn2 was knocked down or knocked out in Dox-induced cardiomyocytes and hearts respectively. Mechanistically, Pae promoted Mfn2-mediated mitochondria fusion by activating the transcription factor Stat3, which bound to the Mfn2 promoter in a direct manner and up-regulated its transcriptional expression. Furthermore, molecular docking, surface plasmon resonance and co-immunoprecipitation studies showed that Pae’s direct target was PKCε, which interacted with Stat3 and enabled its phosphorylation and activation. Pae-induced Stat3 phosphorylation and Mfn2-mediated mitochondrial fusion were inhibited when PKCε was knocked down. Furthermore, Pae did not interfere with Dox's antitumor efficacy in several tumor cells. Pae protects the heart against Dox-induced damage by stimulating mitochondrial fusion via the PKCε-Stat3-Mfn2 pathway, indicating that Pae might be a promising therapeutic therapy for Dox-induced cardiotoxicity while maintaining Dox's anticancer activity.