Cytokine "Backpacks" for T Cells Increase Immune Response in Solid Tumors

A new study published in Nature Biotechnology found that by attaching a kind of cytokine “backpack” to T-cells through the use of a nanoparticle gel enhanced their efficacy in treating tumors in mice.

Engineering the body’s immune cells to attack cancer cells has had promising results in treating blood cancers such as lymphoma and leukemia, however this strategy has proven more challenging for solid tumors. Researchers at MIT found that by developing nanoparticle “backpacks” that are able to hold immune-stimulating drugs, and attaching them to T cells, they could enhance T cell activity without causing harmful side effects in mice.

“We found you could greatly improve the efficacy of the T cell therapy with backpacked drugs that help the donor T cells survive and function more effectively. Even more importantly, we achieved that without any of the toxicity that you see with systemic injection of the drugs,” said senior author of the study Darrell Irvine, a professor of biological engineering, materials science and engineering, and associate director of MIT’s Koch Institute for Integrative Cancer Research.

Previously, researchers have attempted to boost the response to genetically modified T cells by injecting cytokines concurrently. However, cytokines tend to stimulate any T cell they encounter and can have harmful side effects, such as inflammation, which limits the amount that can be administered.

In this study, researchers created a new type of nanoparticle that can carry 100-fold more cytokines and does not release the drug until after the T cells encounter the tumor. These nanoparticles consist of a gel made from molecules of the cytokine interleukin-15 (IL-15). The researchers tested this approach in mice whose T cells were engineered to express a T cell receptor that targets a protein found in melanoma tumors.

In about 60% of the mice, the therapy was so effective that tumors disappeared entirely after multiple treatments. In addition, study authors also found that by attaching the nanoparticles to human T cells that were modified to target glioblastoma cells allowed them to kill the cells much more effectively.

“The nanogels are preferentially dissolving when the T cells are in sites where they see tumor antigen: in the tumor and in the tumor-draining lymph nodes,” said Irvine. “The drug is most efficiently being released at the sites where you want it and not in some healthy tissue where it might cause trouble.”

Irvine added that the hope is that the strategy could work for any solid or blood tumor, as long as there is a known target that can be programmed into the T cells. The study authors intend to further research the method to determine whether drugs other than IL-15 may be even more effective at stimulating T-cells.

Reference

Tang L, Zheng Y, Melo MB, et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery [published online July 9, 2018]. Nat Biotechnol. doi: 10.1038/nbt.4181.