Fate and Efficacy of Engineered Allogeneic Stem Cells Targeting Cell Death and Proliferation Pathways in Primary and...

Area of Science:

• Oncology
• Biotechnology
• Cancer Therapeutics

Background:

• Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a major cause of cancer mortality.
• Current therapies targeting individual receptors like epidermal growth factor receptor (EGFR) and death receptors (DR) 4/5 show limited efficacy in NSCLC.
• There is an urgent need for innovative therapeutic strategies to improve outcomes for NSCLC patients.

Purpose of the Study:

• To engineer and characterize stem cells (SC) expressing a fusion protein (EVDRL) that simultaneously targets EGFR and DR4/5.
• To evaluate the therapeutic potential of EVDRL-engineered SCs in preclinical models of primary and metastatic NSCLC.
• To elucidate the mechanisms underlying the simultaneous targeting of EGFR and DR4/5 in lung tumors.

Main Methods:

• Construction and characterization of stem cells engineered to express EGFR-targeted nanobody (EV) fused to death receptor 4/5 ligand (DRL).
• Assessment of EVDRL's ability to target EGFR and DR4/5 on NSCLC cell lines and induce apoptosis.
• In vivo studies using real-time dual imaging and immunohistochemistry to evaluate SC tumor homing, tumor burden reduction, and survival in NSCLC models.

Main Results:

• EVDRL successfully targeted both EGFR and DR4/5 cell surface receptors on a wide range of NSCLC cell lines.
• EVDRL induced caspase-mediated apoptosis in NSCLC cells.
• Allogeneic SCs engineered with EVDRL demonstrated tumor homing, alleviated tumor burden, and significantly increased survival in both primary and brain metastatic NSCLC models.

Conclusions:

• Simultaneous targeting of EGFR and DR4/5 using engineered stem cells is a viable therapeutic strategy for NSCLC.
• EVDRL-expressing stem cells show promise for treating both primary and metastatic lung cancer.
• This approach offers a potential new avenue for clinical translation in lung cancer therapy.