On the TRAIL of new lung cancer treatment

Mesenchymal stem (or stromal) cells (MSCs) have several properties that make them attractive for clinical use - more than 500 trials involving MSCs have been launched to date. Most trials are in regenerative medicine, but Professor Janes and his team are using MSCs as a vehicle to deliver an anti-cancer signal, in a pioneering clinical trial recruiting its first patients in 2018.

This innovative approach takes advantage of the fact that MSCs are immunologically benign, triggering little or no immune response when given to patients, and also show a natural tendency to home to tumour sites. The team has identified the key factors contributing to this chemotactic response [1].

Professor Janes has 'armed' the MSCs by genetically modifying them so that they express a ligand known as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) on their surface. TRAIL binds to a receptor preferentially expressed on tumour cells, causing them to undergo apoptosis. Engineered MSCs have proven highly effective against cancer cell lines and animal models of cancer, including metastatic cancer [2]. They also target cancer stem cells, which are resistant to many conventional chemotherapies, and act synergistically with chemotherapy [3].

Working with Professor Mark Lowdell and colleagues, who manage the cell therapy facility at the Royal Free Hospital, Professor Janes' team has developed clinical-grade engineered MSCs, and showed that they retain their potency after freezing [4]. Patients with advanced metastatic lung cancer are now being recruited for an MRC-funded phase I/II trial which will compare a combination of TRAIL-armed MSCs and chemotherapy with the current chemotherapy standard of care.

Since donor umbilical cord MSCs can be used in TRAIL therapy, stem cell banks could be developed, allowing 'off-the-shelf' use of MSC therapy. Moreover, as other tumour types express TRAIL receptor - and expression can be enhanced by chemotherapy and other treatments - the approach could potentially be applied to other cancers.

1. Lourenco S et al. Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors. J Immunol. 2015;194(7):3463-74.
2. Loebinger MR, Eddaoudi A, Davies D, Janes SM. Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res. 2009;69(10):4134-42.
3. Loebinger MR, Sage EK, Davies D, Janes SM. TRAIL-expressing mesenchymal stem cells kill the putative cancer stem cell population. Br J Cancer. 2010;103(11):1692-7.
4. Yuan Z et al. Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy. Cytotherapy. 2016;18(7):860-9.