Abstract 5229: Enhancing solid tumor treatment with engineered blood-derived Vδ1 platform: Safe and effective targeting of mesothelin-expressing tumors with Vδ1 γδT cells
Authors: Nandhu Mohan Sobhana, Andre Simoes, Sarah Edwards, Sweta Mishra, Gary Gu, George Papadopoulos, Stefan Kiesgen, Rebecca Alade, njing Li, Andrea Venuso, Jyothi Kumaran, Kristy Waddington, Tabassum Huseni, Rajeev Karattil, Lilly Reynolds, Maria Sharif, David Wotherspoon, Corina Tudor, Istvan Kovacs, Mei Rosa Ng, Yana Wang, Lan Cao
Journal: Cancer Research (2024)

Abstract Mesothelin (MSLN) is a solid tumor-associated antigen that has been thoroughly studied and is expressed in several tumor indications that have significant unmet therapeutic needs. Vδ1-enriched γδT cells differentiate themselves from other MSLN-targeted modalities by mitigating the challenges of targeting tumors with heterogeneous MSLN expression through their inherent capability to detect malignant cells while sparing normal cells. The ability to effectively combat cancer cells that express mesothelin is significantly increased by the expression of a chimeric antigen receptor (CAR). Novel armoring is being evaluated to improve engineered Vδ1 persistence in the solid tumor microenvironment. Cytokine armoring, through novel engineering, enhances sensitivity to cytokines and recovers cell fitness that is impaired by 'traditional' cytokine armoring options. Extensive in vitro and in vivo safety and efficacy studies were carried out to validate the product's potency. These studies aimed to determine cytotoxicity, expansion, and persistence. MSLN CAR cytokine-armored Vδ1 cells exhibited high post-thaw viability and survival. Furthermore, cytokine-armored Vδ1 cells displayed elevated innate receptor expression and gene-engineered cells maintained their baseline innate phenotype, indicating that they can maintain their ‘innate’ effectiveness over time. In vitro studies demonstrated broad anti-tumor activity against multiple tumor cell lines expressing various levels of mesothelin. Additionally, in long-term cytotoxicity assays, cytokine-armored cells demonstrated improved tumor-clearance capabilities. The effector cells also exhibited an enhanced innate cytotoxic phenotype that equips the cells with the capability to persist and proliferate in response to soluble cytokines and upon cytokine trans-presentation by adjacent cells. In vitro studies further revealed that there is a distinction in the killing activity between tumor and normal cells, which is important for ensuring that the product is safe for use in patients. An orthotopic lung tumor-bearing mouse model was developed to confirm their anti-tumor effectiveness in vivo. The model's outcomes demonstrated that MSLN CAR cytokine-armored Vδ1 cells exhibit higher in vivo efficacy in comparison to their unarmored counterparts at low effector-to-target ratios. With no significant healthy tissue damage found, the histopathology report confirmed an excellent safety profile. Terminal biodistribution studies demonstrated that armored drug candidates preferentially home to and persist in tumor-bearing tissues. Overall, these findings imply that the product might be highly effective in treating tumors that express mesothelin. This strategy could greatly advance our knowledge of how Vδ1-enriched γδT cells function as a platform against solid tumors. Citation Format: Nandhu Mohan Sobhana, Andre Simoes, Sarah Edwards, Sweta Mishra, Gary Gu, George Papadopoulos, Stefan Kiesgen, Rebecca Alade, njing Li, Andrea Venuso, Jyothi Kumaran, Kristy Waddington, Tabassum Huseni, Rajeev Karattil, Lilly Reynolds, Maria Sharif, David Wotherspoon, Corina Tudor, Istvan Kovacs, Mei Rosa Ng, Yana Wang, Lan Cao. Enhancing solid tumor treatment with engineered blood-derived Vδ1 platform: Safe and effective targeting of mesothelin-expressing tumors with Vδ1 γδT cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5229.