WASHINGTON, DC—A chimeric antigen receptor (CAR) T-cell therapy is active against multiple myeloma (MM), according to preclinical research.
The therapy, known as P-BCMA-101, demonstrated persistent anti-tumor activity in a mouse model of MM.
Treatment with P-BCMA-101 eliminated tumors after relapse and prolonged survival in the mice, when compared to other CAR-T cell therapies.
These results were presented in a poster at the AACR Annual Meeting 2017 (abstract 3759).
The research was conducted by employees of Poseida Therapeutics Inc., the company developing P-BCMA-101, as well as others.
The researchers explained that P-BCMA-101 employs a B-cell maturation antigen (BCMA)-specific Centyrin™ rather than a single-chain variable fragment (scFv) for antigen detection.
Centyrins™ are fully human and have similar binding affinities as scFvs. However, Centyrins are smaller, more thermostable, and predicted to be less immunogenic.
P-BCMA-101 is engineered using the PiggyBac™ DNA modification system. PiggyBac eliminates the need to use lentivirus or gamma-retrovirus as a gene delivery mechanism, resulting in improved manufacturing and cost savings.
In addition, the increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be “flipped” to enable depletion in case adverse events occur. And the selectable gene allows for enrichment of CARTyrin+ cells using a non-genotoxic drug.
The researchers found that more than 70% of P-BCMA-101 cells possessed a stem cell memory phenotype, creating a significant population of self-renewing, multipotent progenitors capable of reconstituting the entire spectrum of memory and effector T-cell subsets required to prevent cancer relapse. Similar competitor products typically report 0% to 20% stem cell memory phenotype.
In addition, P-BCMA-101 was enriched with more than 95% of T cells successfully modified, which compares favorably to the roughly 30% to 50% commonly expected with clinical manufacture using lentivirus.
P-BCMA-101 did not exhibit effects of CAR-mediated tonic signaling, a common cause of T-cell exhaustion that leads to poor durability. Tonic signaling is caused by oligomerization of unstable binding domains commonly seen with traditional scFv CARs.
The researchers tested P-BCMA-101 in NSG mice bearing luciferase+ MM.1S cells. The mice received a single administration of either 4 x 106 or 12 x 106 P-BCMA-101 cells.
P-BCMA-101 treatment reduced tumor burden to the limit of detection within 7 days. Conversely, all untreated control mice succumbed to MM within 4 weeks.
P-BCMA-101 expanded and persisted in the treated mice, eliminated tumors following relapse, and prolonged survival.
Most treated mice survived 110 days, and none of them died from tumor burden during the study. This compares favorably to lentivirus-based products that have shown roughly 50-day survival in the same model.
Based on these results, Poseida plans to initiate a phase 1 trial of P-BCMA-101 in patients with relapsed or refractory MM.