Evaluating CAR-T cells from neurofibromatosis type 1 (NF1) patients for targeting AXL in malignant peripheral nerve...

Area of Science:

• Oncology
• Immunotherapy
• Genetics

Background:

• Neurofibromatosis type 1 (NF1) is a genetic disorder with a risk of developing malignant peripheral nerve sheath tumors (MPNST).
• Current MPNST treatments are largely ineffective, highlighting the need for novel therapeutic strategies.
• AXL receptor tyrosine kinase is overexpressed in MPNST and represents a potential therapeutic target.

Purpose of the Study:

• To evaluate the immunophenotypes, efficacy, and safety of AXL-Chimeric Antigen Receptor T (CAR-T) cells derived from Neurofibromatosis type 1 (NF1) patients for MPNST treatment.
• To compare the characteristics and anti-tumor activity of NF1-derived AXL-CAR-T cells with those from healthy donors.

Main Methods:

• AXL-CAR-T cells were generated from NF1 patients (n=27) and healthy donors (n=15).
• Immunophenotyping was performed using CCR7, CD45RA, CD4, and CD8 markers.
• In vitro cytotoxicity assays against MPNST cells and in vivo efficacy/safety studies in an MPNST xenograft mouse model were conducted. Cytokine and granzyme B release were measured.

Main Results:

• AXL-CAR-T cells from both NF1 patients and healthy donors exhibited similar stem cell-like memory T cell composition and ex vivo expansion.
• Both groups of AXL-CAR-T cells demonstrated effective lysis of MPNST cells in vitro.
• In vivo studies showed significant reduction in tumor volumes in xenograft mice with no observed on-target, off-tumor toxicity.

Conclusions:

• NF1 patient-derived AXL-CAR-T cells possess comparable quality and efficacy to those derived from healthy donors.
• These findings support the potential of autologous AXL-CAR-T cell therapy for treating MPNST in NF1 patients.