PD1 Blockade Enhances ICAM1-Directed CAR T Therapeutic Efficacy in Advanced Thyroid Cancer

Area of Science:

• Immunotherapy
• Oncology
• Molecular Biology

Background:

• Advanced thyroid cancers, including anaplastic thyroid cancer (ATC), are aggressive with limited treatment options.
• Current treatments like programmed death 1 (PD1) blockade show limited efficacy in ATC patients.
• Novel therapeutic strategies are urgently needed for these lethal malignancies.

Purpose of the Study:

• To investigate the expression of PD-L1 and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors.
• To evaluate the efficacy of combining ICAM1-targeting chimeric antigen receptor (CAR) T cells with PD1 blockade in an ATC model.
• To understand the impact of this combination therapy on T-cell dynamics and tumor clearance.

Main Methods:

• Examined ICAM1 and PD-L1 expression in thyroid tumors and ATC cell lines.
• Assessed PD1 expression in peripheral T cells from thyroid cancer patients.
• Utilized a xenograft model of ATC to test monotherapy and combination treatments of CAR T cells and anti-PD1 antibody.

Main Results:

• Advanced thyroid cancers exhibited increased ICAM1 and PD-L1 tumor expression and elevated PD1 on T cells.
• ICAM1-targeted CAR T cells combined with PD1 blockade showed enhanced tumor eradication compared to CAR T cells alone.
• Combination therapy led to rapid tumor clearance and prolonged survival in a preclinical ATC model.

Conclusions:

• Targeting both ICAM1 and PD-L1, which are IFNγ-inducible antigens, offers a promising therapeutic strategy.
• This complementary targeting approach may effectively control advanced thyroid cancers in vivo.
• Combination immunotherapy holds potential for treating lethal thyroid malignancies.