Preserving TAGLN2 Function in T-cells to Enhance Immunotherapy against Solid Tumors

Background & Unmet Need

• Immunotherapy, particularly T cell-based strategies, represents a promising approach against solid tumors
• However, the efficacy of such treatments remains limited due to the immunosuppressive nature of the tumor microenvironment (TME), which impairs T cell function
• The efficient import, trafficking, and catabolism of extracellular fatty acids is crucial for T cell mitochondrial respiration and overall cytotoxic capacity, particularly under stress conditions induced by the TME
• Mechanisms governing this crucial immunometabolism axis remain unexplored, especially its anti-cancer functions
• Unmet Need: Improved molecular strategies to overcome immunotherapy suppression by the TME

Technology Overview

• The Technology: A method for restoring transgelin 2 (TAGLN2) expression to promote the anti-tumor effects of T cells in an immunosuppressive environment
• The Discovery: The cytoskeletal organizer TAGLN2 is necessary for optimal T cell fatty acid uptake and mitochondrial respiration in nutrient-restricted environments
• TAGLN2 interacts with cytoplasmic FABP5, an importer of extracellular fatty acids, enabling its optimal surface localization and function
• PoC Data: T cells present in solid tumors and ascites of HGSOC patients demonstrate low TAGLN2 expression that was associated with their dysfunction/exhaustion (p<0.0001)
• Adoptive immunotherapy using TAGLN2-overpressing chimeric endocrine receptors (CER) T cells demonstrated improved capacity to control metastatic HGSOC progression

Technology Applications

• Adoptive cell transfer therapies, such as CAR-T cells, against solid tumors
• Combination therapy with other immunotherapeutic agents for solid tumors
• Therapeutic target for the identification of drugs that upregulate or stabilize TAGLN2 expression
• Strategy to increase the metabolic fitness and local anti-tumor activity of T cell therapies

Technology Advantages

• Improved therapeutic efficacy in immunosuppressive tumors such as ovarian cancer
• Overcomes tumor microenvironment-induced ER stress responses that typically inhibit T cell function
• Easily integrated into existing CAR T vectors through simple modification of the expression cassette