Sensitive CAR T cells redefine targetable CD70 expression in solid tumors.

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Solid tumor antigen heterogeneity presents a significant hurdle for effective cancer immunotherapy, particularly for chimeric antigen receptor (CAR) T cells.
• The absence of a universal tumor antigen with restricted expression in vital normal tissues complicates solid tumor treatment strategies.
• CD70 is identified as a promising target due to its limited physiological expression in immune cells and aberrant upregulation in various cancers.

Purpose of the Study:

• To address the challenge of solid tumor antigen heterogeneity in cancer immunotherapy.
• To investigate the potential of CD70 as a pan-cancer target for T cell-based therapies.
• To develop and evaluate a novel T cell receptor strategy for targeting heterogeneous CD70 expression in solid tumors.

Main Methods:

• Investigated the epigenetic regulation of CD70 expression heterogeneity in solid tumors.
• Developed a highly sensitive CD70-targeting HLA-independent T cell (HIT) receptor.
• Engineered HIT receptor to coexpress costimulatory molecules CD80 and 4-1BBL for enhanced T cell activation.

Main Results:

• Demonstrated that CD70 expression in solid tumors is epigenetically regulated, leading to significant heterogeneity.
• Showcased that conventional detection methods may fail to identify low CD70-expressing cells.
• Confirmed efficient elimination of CD70-heterogeneous tumors by the developed HIT receptor, outperforming prototypic CAR T cells.

Conclusions:

• The developed HIT receptor strategy offers a potential solution for overcoming antigen heterogeneity in solid tumors.
• This approach may enable effective treatment of a broad spectrum of solid tumors previously refractory to immunotherapy.
• Highlights the therapeutic potential of targeting epigenetically regulated antigens like CD70 in solid tumors.