Preclinical model for evaluating human TCRs against chimeric syngeneic tumors

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptive cell transfer (ACT) using T cell receptor (TCR)-engineered T cells targeting NY-ESO-1 has shown clinical promise.
• Current preclinical models often fail to replicate the complex tumor microenvironment (TME) and endogenous immunity seen in patients.
• There is a need for improved preclinical models to accurately assess TCR-engineered T cell therapies.

Purpose of the Study:

• To develop a novel chimeric syngeneic tumor model for evaluating TCR-engineered T cells.
• To compare the efficacy of different TCR affinities in a fully competent murine immune system.
• To assess the impact of TCR-engineered T cells on the tumor microenvironment.

Main Methods:

• Engineered murine T cells with varying affinities of a NY-ESO-1 specific TCR.
• Developed a chimeric syngeneic B16 melanoma model expressing a single-chain trimer (SCT) of HLA-A2:NY-ESO-1.
• Administered ACT with engineered T cells to HLA-A*0201/H-2Kb transgenic mice bearing B16-A2Kb:NY tumors.

Main Results:

• T cells engineered with an optimally tuned affinity TCR (DMβ) demonstrated superior function, infiltration, and tumor control.
• The developed model allowed for tracking of dynamic and beneficial changes within the tumor microenvironment post-ACT.
• Significant improvements in anti-tumor activity were observed compared to control TCR-T cells.

Conclusions:

• A robust, cost-effective preclinical model was established for evaluating human TCRs within a complete murine immune system.
• This model facilitates the development of coengineered TCR-T cells and combination therapies for clinical translation.
• The findings support the use of affinity-optimized TCRs for enhanced cancer immunotherapy.