K Li

Purpose: The purpose of the study was to develop a procedure using selective region mutual information image registration and anatomic landmarks transformation to improve the treatment accuracy of volume‐staged Gamma Knife (GK) radiosurgery for large arteriovenous malformations (AVMs). Methods: The procedure was implemented via Leksell Gamma Plan (LGP version 9.0) and an in‐house point registration program for multiple session staged GK treatments. A requirement of such treatments was to match the partial‐volume dose distribution of a previously delivered treatment with the current treatment. In our procedure, MR images of the current treatment plan were first imported and co‐registered with the initial reference MR studies via selective region mutual information algorithm in LGP. Then the current MR studies were re‐imported and defined for its stereotactic frame. Based on these two MR studies (one registered and one defined), four or more anatomic landmarks surrounding the target region were selected, and then a rigid‐body transformation matrix was calculated from these points to map the original treatment plan onto the current treatment plan for the existing frame coordinate system. We analyzed the accuracy of such procedures performed for a group of 12 patients with 14 staged treatments at our institution since 2007. Results: The average discrepancy in the landmark vector distance between the original treatment plan and the transformed treatment plan was 0.25±0.09 mm. This value was 3–4 times smaller than previously published results. Additional studies on the accuracy of mutual information registration of MR‐MR images of the same objects/patients on our LGP system yielded a mean standard deviation of 0.16±0.07 mm, where the largest deviation was generally observed along the image scanning direction Conclusions: Volume‐staged GK treatments can be delivered to the same level of accuracy as single fraction GK treatments.

Abstract Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by bone marrow infiltration, monoclonal immunoglobulin production, and microenvironmental dysregulation that leads to systemic organ damage. The advent of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has induced unprecedented responses and durability for patients with relapsed/refractory MM. These outcomes are rarely observed with prior salvage strategies, although relapse remains the predominant long-term challenge for most patients. The two currently approved BCMA CAR-T cell products use viral vectors to semi-randomly insert the CAR gene, which results in heterogeneous genomic composition and variability in efficacy, safety, and product consistency. To address these challenges, we integrated targeted CRISPR genome engineering with precise CAR transgene insertion at the T-cell receptor alpha constant ( TRAC ) locus, 1XX CAR signaling architecture to enhance potency and durability, and non-viral manufacturing with a single-stranded DNA repair template to improve efficiency and yield. This approach confers physiological CAR expression, reduces insertional mutagenesis, and improves persistence by mitigating tonic signaling and exhaustion. Our GMP manufacturing process consistently achieved high CAR integration (37.7–72.7%) and yields across all full-scale runs and met predefined release criteria for identity, purity, safety, and quality. In NSG mouse models of MM, the UCCT-BCMA-1 product exhibited exceptionally potent tumor control, CAR-T cell expansion 100–1000-fold greater than that of lentiviral constructs, and durable clearance of myeloma cells after multiple rechallenges. These findings establish a CRISPR-edited, fully non-viral manufacturing platform for next-generation 1XX-BCMA CAR-T therapies with enhanced persistence, safety, and efficacy. One Sentence Summary CRISPR-engineered, TRAC -targeted 1XX-BCMA CAR-T therapy with improved safety, potency, and persistence in relapsed and refractory multiple myeloma.