Background Despite T-cell receptors’ (TCRs) unique capability to target intracellular antigens with high sensitivity and harness the natural T-cell machinery, TCR cell therapy remains in its early stages. Currently, there are fewer than 100 published clinical trials focusing on TCR therapies, contrasting with over 1000 ongoing clinical trials for CAR (Chimeric Antigen Receptor) cell therapies.

Here, we introduce an innovative off-the-shelf TCR cell therapy product that integrates specific targeting of Preferentially Expressed Antigen in Melanoma (PRAME)-expressing tumors with the unique capabilities of invariant Natural Killer T (iNKT) cells, offering potential advancements in the effectiveness, safety, and scalability of TCR-based immunotherapy for solid tumors.

1. Targeting PRAME: PRAME is highly expressed in various solid tumors but is minimally expressed in normal tissues, primarily limited to the testis.

2. Highly Potent and Specific CD8-independent TCR: The therapy utilizes a TCR that is potent and specific, independent of CD8 co-receptor interactions.

3. Utilization of iNKT Cells: iNKT cells possess potent immunostimulatory properties, intrinsic cytotoxicity targeting CD1d and NK receptor ligands, tissue-homing capabilities, and the ability to modulate the tumor microenvironment (TME).

4. Scalable Manufacturing Approach: The therapy employs a scalable and cost-effective manufacturing process capable of producing over 5000 doses from a single healthy donor, ensuring consistent product quality and availability.

Methods We utilized our proprietary Trx^TM platform to enhance the potency of a natural TCR¹ while maintaining its safety. We developed a manufacturing method to engineer and selectively expand PRAME TCR-expressing allogeneic iNKT cells. Lead candidates were evaluated in vitro for cytotoxicity, cytokine secretion, exhaustion markers, and specificity.

Results Our MiNK discovery platform enhanced a natural PRAME TCR while preserving its safety. The optimized MiNK PRAME TCR is CD8-independent and demonstrates superior killing compared to a clinical benchmark. PRAME iNKT cells can function through both their endogenous TCR and the engineered PRAME TCR without any signs of mispairing. Additionally, MiNK PRAME TCR iNKT cells can be expanded using a robust and cost-effective manufacturing process.

Conclusions MiNK PRAME TCR iNKT cells can target a wide range of solid tumors, either as a monotherapy or in combination with checkpoint inhibitors. Being off-the-shelf and potentially usable without lymphodepletion, they are suitable for pediatric cancers such as sarcomas, which have high PRAME expression. Thus, we believe PRAME-TCR iNKT cell therapy will offer significant benefits and address substantial unmet medical needs.

Reference

1. Amir AL, van der Steen DM, van Loenen MM, Hagedoorn RS, de Boer R, Kester MDG, de Ru AH, Lugthart G-J, van Kooten C, Hiemstra PS, et al. PRAME-Specific Allo-HLA-Restricted T cells with Potent Antitumor Reactivity Useful for Therapeutic T-Cell Receptor Gene Transfer. Clin. Cancer Res. 2011;17:5615–5625.