Scientists at Johns Hopkins University say they have trained the immune systems of mice to fight melanoma using nanoparticles and magnetism. They report their study (“Magnetic Field-Induced T-Cell Receptor Clustering by Nanoparticles Enhances T-Cell Activation and Stimulates Antitumor Activity”) online in ACS Nano.
“Size was key to this experiment,” says Jonathan Schneck, M.D., Ph.D., a professor of pathology, medicine and oncology at the Johns Hopkins University School of Medicine’s Institute for Cell Engineering. “By using small enough particles, we could, for the first time, see a key difference in cancer-fighting cells, and we harnessed that knowledge to enhance the immune attack on cancer.”
Dr. Schneck’s team has pioneered the development of artificial white blood cells, so-called artificial antigen-presenting cells (aAPCs), which show promise in training animals’ immune systems to fight diseases such as cancer. To do that, the aAPCs must interact with naive T cells that are already present in the body, awaiting instructions about which specific invader they will battle. The aAPCs bind to specialized receptors on the T cells’ surfaces and present them with distinctive proteins called antigens. This process activates the T cells, programming them to battle a specific threat such as a virus, bacteria or tumor, as well as to make more T cells.
The team had been working with microscale particles, which are about one-hundredth of a millimeter across. But, says Dr. Schneck, aAPCs of that size are still too large to get into some areas of a body and may even cause tissue damage because of their relatively large size. In addition, the microscale particles bound equally well to naive T cells and others, so the team began to explore using much smaller nanoscale aAPCs (nano-APCs). Since size and shape are central to how aAPCs interact with T cells, Karlo Perica, a graduate student in Schneck's laboratory, tested the impact of these smaller particles.
“To enhance T-cell activation, a magnetic field was used to drive aggregation of paramagnetic nano-aAPC, resulting in a doubling of TCR cluster size and increased T-cell expansion in vitro and after adoptive transfer in vivo,” wrote the investigators. “T cells activated by nano-aAPC in a magnetic field inhibited growth of B16 melanoma, showing that this novel approach, using magnetic field-enhanced nano-aAPC stimulation, can generate large numbers of activated antigen-specific T cells and has clinically relevant applications for adoptive immunotherapy.”
The so-called nano-aAPCs were small enough that many of them could bind to a single T cell, as the team had expected. But when Perica compared naive T cells to those that had been activated, he found that the naive cells were able to bind more nanoparticles.
“This was quite surprising, since many studies had already shown that naive and activated T cells had equal numbers of receptors,” added Dr. Schneck. “Based on Karlo’s results, we suspected that the activated cells’ receptors were configured in a way that limited the number of nanoparticles that could bind to them.”
The team then treated a sample of T cells with nano-aAPCs targeting those T cells programmed to battle melanoma. The researchers next put the treated cells under a magnetic field and then put them into mice with skin tumors. The tumors in mice treated with both nano-aAPCs and magnetism stopped growing, and by the end of the experiment, they were about 10 times smaller than those of untreated mice, the researchers found. In addition, they report, six of the eight magnetism-treated mice survived for more than four weeks showing no signs of tumor growth, compared to zero of the untreated mice.
“We have a bevy of new questions to work on now: What’s the optimal magnetic ‘dose’? Could we use magnetic fields to activate T cells without taking them out of the body? And could magnets be used to target an immune response to a particular part of the body, such as a tumor’s location?” said Dr. Schneck. “We’re excited to see where this new avenue of research takes us.”