Nanoparticle doubles-up tumor targeting

An emerging approach to treating cancer known as immunotherapy targets the body’s own immune response to tumor-associated antigens. Now researchers from Johns Hopkins University have developed dual-targeting nanoparticles that simultaneously block immune-inhibitory molecules that help tumor cells hide from the immune system and activate immune-stimulating molecules that recruit T cells to destroy tumors [Kosmides et al., ACS Nano (2017), doi: 10.1021/acsnano.6b08152].

“The idea is that the particles target two separate blocks in the cancer immunity cycle on a single therapeutic and also bring together cytotoxic T cells and tumor cells to increase efficacy,” explains Jonathan P. Schneck, who led the work.

Two immunotherapy agents, one of which is already FDA-approved for clinical use, were coated onto iron-dextran nanoparticles 80 nm in diameter. ‘Immunoswitch’ nanoparticles with both antibodies significantly delay or even eliminate melanoma and colon tumors growing in mice. But not only that, unexpectedly the researchers found that physically constraining the two different antibodies onto a single nanoparticle leads to a synergistic effect.

“Our immunoswitch nanoparticles represent a new genre of nanoparticle-based therapy for cancer or any other immune/inflammatory disease,” says Schneck. “No one has ever made a nanoparticle that simultaneously targets two different cells and reverses the immune-inhibitory tumor microenvironment.”

The researchers believe the enhanced effectiveness of the approach system hinges on the bringing together of two immune pathways simultaneously. In effect, the approach allows the immune system to find the ‘correct’ antitumor immune response without a priori knowledge of the relevant tumor antigen. Moreover, the physical size of the nanoparticles limits their ability to diffuse away from the tumor site, increasing the time for the on-board immunotherapy agents to have an effect while also reducing ‘off-target’ toxicity.

“These particles show the potential benefit of engineering synthetic platforms to enhance the activity of current therapeutics,” says Schneck.

The researchers report responses that would usually be seen with 10—100 fold higher drug doses. Using immunoswitch nanoparticles could enable the reduction of drug doses in patients, leading to dramatically reduced side effects and lower treatment costs.

“If successful, this approach could leapfrog nanoparticle-based therapies and advance them to the front line of cancer immunotherapy,” suggests Schneck.

There are no major obstacles holding back the approach, he believes, which could be enhanced even further by injecting the immunoswitch nanoparticles intravenously and using magnetic fields to improve targeting, since the particles are paramagnetic.

There is renewed interest in cancer immunotherapy at the moment, comments Juan C. Mareque-Rivas of CiC biomaGUNE in Spain and Swansea University in Wales, thanks to recent clinical successes in immune checkpoint blockade therapy.

“The field is now turning attention to combinatorial immunotherapy, where novel combinations of immuno-modulators work in a complementary fashion,” he explains. “Nanoparticles, as nicely shown in this work, are ideal to ensure dual targeting and improve in vivo delivery.”

Although immunoswitch nanoparticles may not be the ultimate ‘silver bullet’, cautions Mareque-Rivas, the work is novel and is likely to give rise to a fertile area of research over the next few years that could yield new treatments, which work for more patients.

This article was originally published in Nano Today (2017), 10.1016/j.nantod.2017.06.002