by ecancer reporter Clare Sansom

Many recently developed therapies for cancer rely on stimulating the patient’s immune system to attack the tumour, rather than doing so directly.

Immunotherapy is a primary treatment option for malignant melanoma, an aggressive solid tumour that is often refractory to surgery, radiation and chemotherapy.

However, only a minority of melanoma patients have durable complete responses when treated with the immuno-stimulatory cytokine, interleukin-2 (IL-2).

One important reason for this is the ability of tumour cells to secrete chemicals that suppress the immune system, including transforming growth factor-b (TGF-b), into their micro-environment. As the dose of IL-2 is limited by toxicity, scientists are investigating methods of increasing its half-life in circulation.

Tarek Fahmy and his co-workers, all based at Yale University, New Haven, Connecticut, USA have now designed a novel system for the sustained delivery of a combination of IL-2 with an inhibitor of TGF-b receptor signalling to the site of a solid tumour.

This system, which the researchers have termed a “nanolipogel” (nLG) particle, comprises a spherical core of degradable hydrogel, approximately 120nm in diameter, surrounded by a lipid bilayer. It is possible to encapsulate both therapeutic proteins and small-molecule drugs within the particle core.

The test system used for the nLG particles involved a combination of IL-2 with the commercially available TGF-b receptor inhibitor, SB505124. It is always a challenge to release protein and small-molecule drugs in combination, as proteins are significantly more water-soluble than, for example, a typical receptor blocker.

However, Fahmy and co-workers were able to show that both the cytokine and the inhibitor were released from the nLG particles in a more sustained fashion than from either liposomes or more conventional PLGA nanoparticles.

Furthermore, no significant toxicities were observed when empty nLG particles were administered to healthy mice, and administration of fluorescence-labelled particles showed the particles accumulating mainly in the lungs, liver and kidneys. The liver and the lungs are two of the main sites of metastasis from primary melanoma.

Next, the researchers tested the nLG particles loaded with both cytokine and inhibitor in a mouse model of malignant melanoma.

As a control experiment, mice bearing subcutaneous melanomas were treated with weekly doses of both IL-2 and SB505124, and little or no effect on tumour growth was observed. Some delay in tumour growth was noticed when either the cytokine or the inhibitor was delivered alone using the nLG system, and a more striking reduction occurred with the simultaneous delivery of both drugs in nanolipogel particles.

The survival time of mice treated with both drugs delivered using nLGs was also significantly increased over treatment with either a single nLG-delivered drug or both drugs delivered systemically, and there was also a significant decrease in the number of metastases.

Fluorescence labelling was then used to discover the main sites of accumulation of the drug-loaded nano-particles in mice bearing subcutaneous melanomas and in similar mice with lung metastases.

The nLG particles were found to accumulate in the tumours and the areas surrounding them in both types of mice.

Finally, the researchers sought to elucidate the immunostimulatory mechanisms through which this combination of cytokine and inhibitor prevent tumour growth by probing various parameters of the innate and adaptive immune systems in the mice. They found an increase in the number and activity of natural killer (NK) cells and in the infiltration of CD8⁺ T-cells at the tumour sites of treated mice. 

Taken together, these results provide a proof of the concept that simultaneous, sustained delivery of IL-2 with a TGF-b receptor inhibitor in nLG particles can promote NK-mediated anti-tumour immune responses and so shrink tumours. As the lipid used to form the outer surface of the particles has already been approved by the FDA as safe for use in humans, it is possible that a very similar drug delivery system may ultimately enter clinical use.

Source: Park, J., Wrzesinski, S.H., Stern, E. and 15 others (2012). Combination delivery of TGF inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nature Materials, published online ahead of print 15 July 2012. doi: 10.1038/nmat3355