A Phase 1 Study of P-BCMA-ALLO1, a Non-Viral, Allogeneic BCMA Directed CAR-T in Relapsed/Refractory Multiple Myeloma (RRMM): Results from Optimized Lymphodepletion Cohort
Year: 2024
Type: conference-abstract
Abstract: Introduction: P-BCMA-ALLO1 is an allogeneic BCMA targeting CAR-T for the treatment of RRMM. It is manufactured at an in-house GMP facility from healthy donor T cells using Cas-CLOVER™ gene editing and non-viral transposon-based integration (piggyBac® DNA Delivery System) to express a human anti-BCMA VH-based CAR. These technologies enable P-BCMA-ALLO1 to be a T stem cell memory (TSCM)-rich product with high purity characterized by near-100% CAR+ cells. Methods: The P-BCMA-ALLO1-001 study (NCT04960579) is enrolling RRMM patients (pts) refractory to or who have relapsed following IMID, PI and CD38 mAb. Pts previously treated with BCMA-targeted therapy were allowed. The study employs a 3 + 3 dose escalation design to test multiple P-BCMA-ALLO1 doses from multiple product lots manufactured from different donors. Several lymphodepletion (LD) regimens are being investigated to enable optimal CAR-T expansion. The primary objective is to assess the safety and determine maximum tolerated dose of P-BCMA-ALLO1. The key secondary objective is to evaluate its anti-myeloma effect. Here, we present data on pts treated with a dose of approximately 2 x 106 cells/kg, after completing a 3-day LD regimen (cyclophosphamide 750 mg/m2/day and fludarabine 30 mg/m2/day). Results: At the time of data cutoff, 21 pts with 4+ weeks of follow up had been treated in this LD arm. None required bridging therapy and the median time from enrollment to start of study treatment was just 1 day (range: 0-9 days), highlighting the rapid availability of P-BCMA-ALLO1, being an off-the-shelf CAR-T. 100% of the intent to treat (ITT) population received P-BCMA-ALLO1. The median pt age was 61 (39-76) years, 53% were female and 42% were minorities. The median time since multiple myeloma diagnosis was 7.0 (1.0-15.1) years. Pts were heavily pretreated, with a median of six (2-14) prior lines of therapy. 62% had undergone prior BCMA-targeted CAR-T and/or T cell engager (TCE) therapy, 29% had previously received both a BCMA-targeted CAR-T and/or TCE and Talquetamab. Thirteen (62%) pts had high-risk FISH anomalies. P-BCMA-ALLO1 was well tolerated with no DLTs or GvHD. The most common treatment-emergent adverse events (TEAEs) were neutropenia (71%), leukopenia (67%), anemia (52%), thrombocytopenia (48%), and CRS (43%). The most common ≥ G3 TEAEs were neutropenia (67%), leukopenia (67%) anemia (43%), and thrombocytopenia (33%). Most AEs were considered unrelated to P-BCMA-ALLO1. Of nine (43%) pts with CRS, seven (33%) had G1 CRS and two (10%) had G2 CRS; no pt had > G3 CRS. Three (14%) pts experienced ICANS, all were G1. P-BCMA-ALLO1 demonstrated an encouraging overall response rate (ORR) in all relevant pt subsets. The ORR in the ITT population was 90%, including 6 CR/sCR, 5 VGPRs, and 8 PRs. The ORR was 100% in BCMA naïve pts and 85% in pts who previously received BCMA-targeted therapy. The ORR was 83% in the subset of 6 pts who received both prior BCMA-targeted agents, and Talquetamab. To assess whether BCMA expression impacted clinical activity, baseline BCMA levels (BCMA MESF on CD138+CD38+ bone marrow cells) were evaluated for 12 pts, showing a median MESF of 4,685 (2,125-23,537). The median BCMA MESF for the 6 BCMA-naïve pts tested was 8,859 (4,098-23,537), while the median for the 6 pts with prior BCMA therapy was 2744 (2125-5912). P-BCMA-ALLO1 cellular kinetics (CK) were assessed (n=15) using ddPCR demonstrating a median Cmax of 49,430 (66-501,678) cp/µg of the CAR transcript at a median Tmax of 10 (7-21) days. The median CK for the BCMA naïve pts (n=7) was 72.077 (10,904 - 501,678) cp/µg, while the median CK for BCMA exposed pts (n=8) was 27,878 (66 - 310,209) cp/µg. There was no statistical difference between these groups. Conclusions: P-BCMA-ALLO1 is a non-viral, TSCM-rich, allogeneic BCMA-targeting CAR-T quickly delivered to all eligible pts without the need for bridging therapy. P-BCMA-ALLO1 demonstrates a promising ORR and favorable safety profile when administered with optimized LD. It is highly active, regardless of prior exposure to BCMA-targeted autologous CAR-T or TCE therapy. As an allogeneic therapy, it also offers significant practical advantages over autologous CAR-T, which require apheresis, prolonged, often uncertain manufacturing, and bridging therapy; and TCE, which require chronic administration. The P-BCMA-ALLO1-001 clinical trial is actively enrolling pts. Updated safety and efficacy data will be presented at ASH 2024.
Source: Blood
Authors: Bhagirathbhai Dholaria, Leyla O. Shune, Mehmet H. Kocoglu, Andrew Kin, Aravind Ramakrishnan, Ehsan Malek, Siddhartha Ganguly, Christopher Strouse, Jose Carlos Cruz, Edward Anthony Faber, Katherine McArthur, Jeff D Eskew, Joanne McCaigue, Samuel DePrimo, Chris E Martin, Sabrina Haag, Hamid Namini, Ellen Christie, Rajesh Belani, Syed Rizvi, Stacey A Cranert, Julia Coronella, Devon J Shedlock, Caitlin Costello
Institutions: Vanderbilt University Medical Center, University of Kansas, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Wayne State University, The Barbara Ann Karmanos Cancer Institute, St David's Medical Center, Roswell Park Comprehensive Cancer Center, Houston Methodist, University of Iowa Hospitals and Clinics, University of Cincinnati, Poseida Therapeutics (United States), University of California San Diego
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405039381