Danying Liao

PURPOSE OF REVIEW: The purpose of this article is to describe the function of the vascular cell adhesion and signaling molecule, platelet/endothelial cell adhesion molecule-1 (PECAM-1), in endothelial cells, with special emphasis on its role in maintaining and restoring the vascular permeability barrier following disruption of the endothelial cell junction. RECENT FINDINGS: In addition to its role as an inhibitory receptor in circulating platelets and leukocytes, PECAM-1 is highly expressed at endothelial cell-cell junctions, where it functions as an adhesive stress-response protein to both maintain endothelial cell junctional integrity and speed restoration of the vascular permeability barrier following inflammatory or thrombotic challenge. SUMMARY: Owing to the unique ability of antibodies that bind the membrane proximal region of the extracellular domain to trigger conformational changes leading to affinity modulation and homophilic adhesion strengthening, PECAM-1 might be an attractive target for treating vascular permeability disorders.

Multiple myeloma (MM) bears heterogeneous cells that poses a challenge for single-target immunotherapies. Here we constructed bispecific CS1-BCMA CAR-T cells aiming to augment BCMA targeting with CS1. Sixteen patients with relapsed or refractory (RR) MM received CS1-BCMA CAR-T infusion. Six patients (38%) had cytokine release syndrome, which was of grade 1-2 in 31%. No neurological toxicities were observed. The most common severe adverse events were hematological, including leukopenia (100%), neutropenia (94%), lymphopenia (100%) and thrombocytopenia (31%). Three patients with solitary extramedullary disease (sEMD) did not respond. At a median follow-up of 246 days, 13 patients (81%) had an overall response and attained minimal residual disease-negativity, and six (38%) reached a stringent complete response (sCR). Among the 13 responders, 1-year overall survival and progression-free survival were 72.73% and 56.26%, respectively. Four patients maintained sCR with a median duration of 17 months. Four patients experienced BCMA+ and CS1+ relapse or progression. One patient responded after anti-BCMA CAR-T treatment failure. Lenalidomide maintenance after CAR-T infusion and the resistance mechanism of sEMD were preliminarily explored in three patients. CAR-T cells persisted at a median of 406 days. Soluble BCMA could serve as an ideal biomarker for efficacy monitoring. CS1-BCMA CAR-T cells were clinically active with good safety profiles in patients with RRMM. Clinical trial registration: This study was registered on ClinicalTrials.gov, number NCT04662099.

BACKGROUND: T cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer. METHODS: We previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific γ/δ TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with γ/δ TCR constant chain plus adding an ET190L1-scFv/CD28 co-stimulatory molecule. ET019003 cells were tested in preclinical studies followed by a phase 1 clinical trial. RESULTS: ET019003 cells produced less cytokines but retained comparable antitumor potency than ET190L1-CAR-T cells in vivo and in vitro. In the first-in-human trial, eight patients with relapsed or refractory DLBCL were treated. CRS of grade 1 was observed in three (37.5%) patients; ICANS of grade 3 was noted in one (12.5%) patient. Elevation of serum cytokines after ET019003 infusion was almost modest. With a median follow-up of 34 (range 6-38) months, seven (87.5%) patients attained clinical responses and six (75%) achieved complete responses (CR). OS, PFS and DOR at 3 years were 75.0%, 62.5%, and 71.4%, respectively. Notably, patient 1 with primary CNS lymphoma did not experience CRS or ICANS and got an ongoing CR for over 3 years after infusion, with detectable ET019003 cells in CSF. ET019003 showed striking in vivo expansion and persisted in 50% of patients at 12 months. Three patients received a second infusion, one for consolidation therapy after CR and two for salvage therapy after disease progression, but no response was observed. ET019003 expansion was striking in the first infusion, but poor in the second infusion. CONCLUSIONS: CD19-specific γ/δ TCR-T cells, ET019003, had a good safety profile and could induce rapid responses and durable CR in patients with relapsed or refractory DLBCL, even primary CNS lymphoma, presenting a novel and potent therapeutic option for these patients. TRIAL REGISTRATION: NCT04014894.

The ongoing outbreak of Coronavirus Disease 2019 (COVID-19) is hitting the world hard, but the relationship between coagulation disorders and COVID-19 is still not clear. This study aimed to explore whether early coagulation tests can predict risk stratification and prognosis. PubMed, Web of Science, Cochrane Library, and Scopus were searched electronically for relevant research studies published up to March 24, 2020, producing 24 articles for the final inclusion. The pooled standard mean difference (SMD) of coagulation parameters at admission were calculated to determine severe and composite endpoint conditions (ICU or death) in COVID-19 patients. Meta-analyses revealed that platelet count was not statistically related to disease severity and composite endpoint; elevated D-dimer correlated positively with disease severity (SMD 0.787 (0.277-1.298), P= 0.003, I2= 96.7%) but had no significant statistical relationship with composite endpoints. Similarly, patients with prolonged prothrombin time (PT) had an increased risk of ICU and increased risk of death (SMD 1.338 (0.551-2.125), P = 0.001, I2 = 92.7%). Besides, increased fibrin degradation products (FDP) and decreased antithrombin might also mean the disease is worsening. Therefore, early coagulation tests followed by dynamic monitoring is useful for recognizing coagulation disorders accompanied by COVID-19 and guiding timely therapy to improve prognosis.