LV20.19 CAR T cells(Medical College of Wisconsin)

Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies^1-5. Despite impressive outcomes, relapse with CD19^- disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB-CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10⁵-2.5 × 10⁶ cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10⁶ cells per kg was chosen for expansion. Grade 3-4 cytokine release syndrome occurred in one (5%) patient, and grade 3-4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10⁶ cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.

Chimeric antigen receptor (CAR) T-cell therapy utilization has risen sharply in recent years, becoming a standard approach for refractory B-cell malignancies.The current study population (n=15) is derived from the previously reported parent study (n=22) evaluating patients with relapsed, refractory B-cell malignancies treated with LV20.19 CAR T cells on a phase I/Ib clin. trial ( clinicaltrials gov. Identi fi er: NC T03019055 ).All participants provided written informed consent and all procedures were approved in advance by the MCW Institutional Review Board.Patient income was self-reported based on household annual income as either above (high SES) or below (low SES) the 2021 Wisconsin median of$54,660. Further details are described elsewhere.This study is limited by the small sample size.These provocative findings need to be further evaluated in a largercohort wherein addnl. patient-, disease-, and CAR T- related variables can be appropriately controlled for and mediational analyses conducted.