Effective Killing of Acute Myeloid Leukemia by TIM-3 Targeted Chimeric Antigen Receptor T Cells

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Acute myeloid leukemia (AML) is characterized by high relapse rates, primarily driven by minimal residual disease (MRD).
• Therapy-resistant leukemic stem cells (LSCs) present at diagnosis are the source of AML relapse, and conventional therapies struggle to eradicate them.
• Effective strategies to eliminate LSCs and achieve long-term remission in AML are urgently needed.

Purpose of the Study:

• To develop a novel therapeutic strategy targeting T-cell immunoglobulin and mucin domain 3 (TIM-3) for the treatment of MRD in AML.
• To evaluate the efficacy of anti-TIM-3 chimeric antigen receptor (CAR) T-cell therapy in eradicating AML LSCs.

Main Methods:

• Isolated an anti-human TIM-3 antibody using a phage display library.
• Designed and constructed a second-generation anti-TIM-3 CAR T-cell therapy.
• Assessed the antileukemic activity of anti-TIM-3 CAR T cells against AML cell lines, primary AML blasts, and patient-derived LSCs in vitro and in mouse models.

Main Results:

• TIM-3 is highly expressed on AML blasts and LSCs across various subtypes, with minimal expression on normal hematopoietic stem cells and other tissues.
• Anti-TIM-3 CAR T cells demonstrated potent antileukemic activity against AML cell lines and primary AML blasts.
• Crucially, anti-TIM-3 CAR T cells effectively eliminated primary LSCs isolated directly from AML patients.

Conclusions:

• Anti-TIM-3 CAR T-cell therapy shows significant potential for eradicating therapy-resistant LSCs in the MRD of AML patients.
• This novel approach may offer a promising strategy to improve long-term remission rates and clinical outcomes for AML patients.
• Targeting TIM-3 represents a viable therapeutic avenue for overcoming AML relapse by eliminating the root cause: LSCs.