Anti-CD19 CAR T-cells(KK Women's and Children's Hospital)

Chimeric antigen receptor (CAR) T-cell therapy has improved the historically poor outcomes for relapsed and refractory (R/R) large B-cell non-Hodgkin's lymphoma (LBCL). However, nearly 60% of patients will either fail to respond or relapse after CAR T-cell therapy. Currently, PET/CT scans are used to assess response. Cell-free circulating tumor DNA (ctDNA) is released by tumor cells into the peripheral blood and can be measured for minimal residual disease (MRD) assessment.

In this retrospective, IRB approved pilot study, archived lymphoma tissue and ctDNA from peripheral blood samples on day 0, 14, 28, 56, 90, 180, and 365 after CAR T-cell infusion from 10 patients with R/R NHL were collected for next-generation sequencing (NGS) of clonal variable-diversity-joining (VDJ) rearrangements (Adaptive biotechnologies [Seattle, WA]). Response was assessed by PET/CT on days 90 and 365 and graded according to the Lugano 2014 criteria. The primary endpoint was to determine the feasibility of detecting ctDNA to monitor disease response after anti-CD19 CAR T-cell therapy. The secondary endpoint was to compare the sensitivity/specificity of MRD assessment from ctDNA to PET/CT imaging.

Nine out of 10 patients with a trackable sequence [median age 69 (range: 56-76); 55.6% male; median LDH 224], were included in this study. Each received tisagenlecleucel (tisa-cel) CAR T-cell therapy after median 2 prior treatments (range: 2-4). 7/9 patients had R/R diffuse large B-cell lymphoma (DLBCL), and 2/9 had transformed follicular lymphoma. At a median follow up of 12.7 months (range: 1.5-30 months), 4 patients were alive. By day 90, 3 patients (33.3%) achieved a radiographic complete response (CR) whilst 6 patients (66.6%) had progressive disease (PD). Detectable MRD on day 14 or day 28 had 83% sensitivity and 100% specificity for radiographic progression at any time before 1 year. For patients with PD, the median (interquartile range) MRD at day 0, 14, and 28 were 17.31 (1.01, 96.84), 9.12 (0.30, 18.8), and 23.77 (8.01, 137.53) copies per milliliter (mL), respectively. For patients with detectable MRD at day 28, mOS and mPFS were 6.7 and 1.3 months, respectively.

Monitoring MRD was a sensitive and specific method to detect poor response to tisa-cel. Additional studies evaluating MRD more frequently and with different products are warranted.

Antiphospholipid syndrome is an autoimmune disorder characterized by the development of spontaneous venous, arterial, or microvascular thrombosis and/or pregnancy-related complications (e.g. miscarriages, fetal loss) in the presence of persistent antiphospholipid antibodies (aPL). Current state-of-the-art treatment consists of indefinite anticoagulation with vitamin K antagonists to prevent recurrence of thrombotic events. This, however, only represents a symptom-control oriented treatment approach. Until today, no curative option eradicating aPL permanently or addressing the underlying pathomechanism has been established. Here, we report the case of a woman with systemic lupus erythematosus and antiphospholipid syndrome with triple aPL-positivity who developed recurrent deep veinous thrombosis. After receiving CAR T-Cell therapy for aggressive B-Cell lymphoma, sustained eradication of all three aPL subtypes was observed, suggesting a promising role of immunotherapies targeting anti-CD19 for the treatment of pro-thrombotic autoimmune disorders.