Harnessing the Power of ATA3271: Advancing Mesothelin-Targeted Allogeneic CAR T Cell Therapy for Solid Tumors

Mesothelin (MSLN) is a significant membrane protein that is highly expressed in various cancers, such as mesothelioma, ovarian, non-small cell lung, and pancreatic cancers. It has become a target for developing immune therapies. The initial clinical trials of autologous MSLN-targeted CAR-T cell therapies for malignant pleural mesothelioma have shown promising safety and have been enhanced with next-generation CAR co-stimulatory domains and the inclusion of a PD-1 dominant negative receptor (PD1DNR) to counteract intrinsic checkpoint inhibition.

However, the widespread application of autologous CAR-T therapies faces manufacturing and commercial challenges. The EBV T cell approach offers a non-gene edited, off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently under evaluation in phase 3 trials and have shown a favorable safety profile, with minimal risks of graft-versus-host disease (GvHD) and cytokine release syndrome.

The CAR transduced allogeneic EBV T cell therapies have demonstrated acceptable safety and durable responses, particularly in targeting CD19. This study presents the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy that targets MSLN and includes PD1DNR, intended for solid tumor treatment.

The allogeneic MSLN CAR+ EBV T cells (ATA3271) were created using retroviral transduction. The therapy features a novel 1XX CAR signaling domain, which has been linked to improved signaling and reduced CAR-mediated exhaustion. It also incorporates PD1DNR for intrinsic checkpoint blockade and aims to maintain functional persistence.

The study characterized ATA3271 both in vitro and in vivo, showing stable and proportional CAR and PD1DNR expression. ATA3271 exhibited potent antitumor activity against MSLN-expressing cell lines, including those with high PD-L1 expression. In an orthotopic mouse model of pleural mesothelioma, ATA3271 displayed potent antitumor activity and provided a significant survival benefit, with 100% survival exceeding 50 days compared to a median of 25 days for the control group, without any apparent toxicities. ATA3271 also maintained persistence and retained a central memory phenotype in vivo, and it retained its endogenous EBV TCR function with reduced allotoxicity in the context of HLA mismatched targets.

In conclusion, ATA3271 has shown potent anti-tumor activity without allotoxicity, both in vitro and in vivo, indicating that allogeneic MSLN-CAR-engineered EBV T cells are a promising therapeutic approach for MSLN-positive cancers and deserve further clinical exploration.