Enhancing CAR-T Therapy: The Development and Preclinical Assessment of Prgn-3007 for Hematological and Solid Tumors

3 June 2024
The abstract discusses an innovative platform for creating chimeric antigen receptor T cells (UltraCAR-T), which seeks to mitigate the challenges associated with traditional CAR-T manufacturing methods. These methods typically involve the use of viral vectors and lengthy ex vivo T cell activation and expansion, leading to high costs and delays in treatment. The UltraCAR-T platform, however, utilizes a non-viral gene delivery system and a swift manufacturing process to produce cells within a day.

The UltraCAR-T cells are designed to express a specific antigen receptor, membrane-bound IL-15 (mbIL15), and a kill switch for safety. They are manufactured using autologous T cells at a cGMP facility and are currently being clinically tested for both hematological and solid tumors.

A significant advancement in the UltraCAR-T platform is the development of PRGN-3007, which includes an intrinsic checkpoint blockade to counteract the suppressive tumor microenvironment. This is achieved without the need for complex and costly gene editing techniques. PRGN-3007 is engineered to express a CAR targeting the ROR1 receptor, which is overexpressed in many tumors, along with mbIL15 for enhanced expansion and persistence, and a mechanism to intrinsically block PD-1 gene expression, thereby avoiding systemic toxicity and the high costs associated with checkpoint inhibitors.

The manufacturing of PRGN-3007 involves the use of healthy donor T cells, a multi-cistronic non-viral vector, and an overnight process. The resulting cells demonstrated a reduced PD-1 expression, which led to improved cytotoxicity and cytokine release when co-cultured with ROR1+ PD-L1+ tumor cells. The cells also showed robust expansion in the presence of the ROR1 antigen and durable persistence without the need for exogenous cytokines.

In preclinical studies, a single administration of PRGN-3007 significantly reduced tumor burden and improved survival rates in mice with mantle cell lymphoma compared to control CAR-T cells. The treatment also resulted in sustained downregulation of PD-1 expression and a rapid, long-term persistence of the cells with a central memory phenotype.

In conclusion, the preclinical data support the safety and efficacy of the UltraCAR-T platform with the incorporation of intrinsic PD-1 downregulation, using a non-viral gene delivery system and a rapid, decentralized manufacturing process. This provides a compelling basis for further evaluation of PRGN-3007 in treating ROR1+ malignancies.

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