Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung...

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Natural killer (NK) cells can be engineered to express PD-L1 and activated by cytokines.
• Tumor-reactive and cytokine-activated (TRACK) NK cells represent a promising cell therapy approach.

Purpose of the Study:

• To investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells engineered with soluble IL15 (sIL15) for non-small cell lung cancer (NSCLC).
• To evaluate the in vitro and in vivo antitumor activity of sIL15-TRACK NK cells, alone and in combination with atezolizumab.

Main Methods:

• Human NK cells from umbilical cord blood were expanded and transduced with a retroviral vector encoding soluble IL15.
• Cells were further cytokine-activated to induce PD-L1 expression, creating sIL15-TRACK NK cells.
• Cytotoxicity was assessed in vitro against NSCLC cell lines, and in vivo efficacy was evaluated in immunodeficient mice bearing NSCLC tumors.

Main Results:

• Cryopreserved and thawed sIL15-TRACK NK cells exhibited significantly improved cytotoxicity against NSCLC compared to control NK cells.
• Intravenous administration of sIL15-TRACK NK cells slowed tumor growth and improved survival in mice with NSCLC.
• Combination therapy with anti-PD-L1 atezolizumab further enhanced NSCLC growth control, with dose-dependent efficacy and no observed toxicity.

Conclusions:

• Frozen, off-the-shelf allogeneic sIL15-TRACK NK cells are safe and demonstrate potent antitumor activity in preclinical NSCLC models.
• sIL15-TRACK NK cells hold promise as a cell therapy for NSCLC, both alone and in combination with PD-L1 blockade.
• A Phase I clinical trial is underway to evaluate sIL15-TRACK NK cells in patients with relapsed or refractory NSCLC.