Early Results Promising for Next-Generation CAR T-cell Therapy for Solid Tumors

Early safety and functional persistence data for ATA2271, a next-generation autologous chimeric antigen receptor (CAR) T-cell therapy targeting mesothelin (MSLN), were considered promising in preclinical and preliminary clinical results presented at the European Society for Medical Oncology Immuno-Oncology Congress 2021.

ATA2271 is an investigational, autologous, second-generation CAR-T immunotherapy that is designed to treat certain aggressive solid tumors, including malignant pleural mesothelioma (MPM). According to the investigators, even when chemotherapy, aggressive surgical resection, and radiation therapy are completed successfully, the median survival of treated patients in this report is only 9 to 17 months. Through the novel inclusion of armoring, in the form of a programmed cell death protein 1 (PD-1) DNR construct, ATA2271 is capable of overcoming checkpoint inhibition and a 1XX costimulatory domain on the CAR to enhance expansion and functional persistence of the CAR T cells.

“CAR T-cell therapies have made incredible in-roads in the treatment of hematological malignancies, but new technology and targeting approaches are needed to apply these gains to aggressive solid tumors,” said Cokey Nguyen, senior vice president and chief scientific officer at Atara, in a press release. “We are extremely encouraged by these early data assessing ATA2271 in advanced mesothelioma from a first-in-human phase 1 study. Early findings represent the first report of CAR T cells persisting over 4 weeks in a solid tumor microenvironment without need for additional agents, such as checkpoint inhibitors.”

According to the investigators, in vitro functional studies demonstrate potent antitumor activity of ATA2271 following repeat antigen stimulation. Enhanced expansion was observed in cells equipped with a PD-1 dominant negative receptor that provides T cell intrinsic checkpoint blockade compared to CAR T-cells with a modified CD3z (1XX) alone. The study authors said these data support the design of ATA2271, which expresses a dominant negative version of the PD-1 receptor, to maintain function in the presence of suppressive checkpoint ligands commonly associated with solid tumor microenvironments.

Further, the results of in vivo studies modeling mesothelioma in mice demonstrated that intrapleural administration of ATA2271 CAR T cells eradicated mesothelioma and prolonged survival.

In the ongoing phase 1 dose-finding study, ATA2271 was found to be well-tolerated at the lowest dose levels with no CAR T-cell related adverse events (AEs) above grade 2 observed. Further, no AEs above grade 3 were observed to date. All 4 patients being evaluated had 4 or more prior lines of therapy.

REFERENCE

Atara Biotherapeutics announces preliminary results for ATA2271, a next-generation autologous mesothelin-targeted CAR T-cell therapy for solid tumors, at ESMO Immuno-Oncology Congress 2021 [news release]. Atara Bio; December 9, 2021. Accessed December 10, 2021. https://www.businesswire.com/news/home/20211209005155/en