T cell engagers control solid tumors through clonal replacement and IL2-driven effector differentiation of CD8 T...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Bispecific T cell engagers (TCEs) face challenges in solid tumors due to immunosuppressive tumor microenvironments and low target antigen expression.
• Improving TCE sensitivity and T cell function is crucial for effective cancer immunotherapy.

Purpose of the Study:

• To engineer TCEs targeting low-abundance antigens (TRP2/K^b, DLL3) and evaluate their efficacy in solid tumors.
• To investigate strategies for overcoming TCE treatment failure in vivo.
• To elucidate the mechanisms underlying enhanced anti-tumor responses through combination therapy.

Main Methods:

• Engineering of TCEs against TRP2/K^b and DLL3 antigens.
• In vitro assessment of T cell activation.
• In vivo tumor growth studies in immunocompetent mice.
• Combination therapy with TCEs and a CD25-biased Interleukin-2 (IL2).
• Multimodal single-cell transcriptomic and immune repertoire analyses.

Main Results:

• Engineered TCEs showed in vitro T cell activation against low-abundance antigens.
• TCE monotherapy demonstrated limited control of tumor growth in vivo.
• Combination therapy with TCE and IL2 rescued anti-tumor activity.
• TCE-IL2 therapy promoted the recruitment and activation of CD8+ T cells within the tumor microenvironment.

Conclusions:

• TCE efficacy in solid tumors can be limited by the tumor microenvironment.
• Combination therapy with TCE and IL2 enhances anti-tumor responses.
• TCE-mediated responses involve CD8+ T cell clonal replacement, augmentable by cytokine therapy.