New strategy tested in animals could improve cancer immunotherapies.
Scientists at Johns Hopkins have created a nanoparticle that carries two different antibodies capable of simultaneously switching off cancer cells’ defensive properties while switching on a robust anticancer immune response in mice. Experiments with the tiny, double–duty “immunoswitch” found it able to dramatically slow the growth of mouse melanoma and colon cancer and even eradicate tumors in test animals, the researchers report.

The findings, described online June 7 in the journal ACS Nano, could lead to ways to boost the effectiveness and promise of immunotherapies in people with cancer, the investigators say.

“Immunotherapies have significant potential and yet room for improvement,” says Jonathan P. Schneck, MD, PhD, professor of pathology in the Johns Hopkins University School of Medicine’s Institute for Cell Engineering and a member of the Johns Hopkins Kimmel Cancer Center. “The improvement here was to make, for the first time, a nanoparticle that can interact simultaneously with multiple types of cells in the complex tumor microenvironment, dramatically increasing its effectiveness.”

For their study, the Johns Hopkins researchers combined two different immunotherapy strategies on manmade nanoparticles about 1,000 times smaller in diameter than a human hair, similar to drug–delivery platforms already in use in some cancer therapies, including chemotherapies such as Doxil, Abraxane and Myocet.

Nanoparticles have clear advantages over free drug, Kosmides explains, such as their “enhanced permeability and retention effect,” which causes nanosized particles to be taken up more readily by tumor cells than by healthy cells. Additionally, each particle can hold dozens of antibodies at once, which dramatically raises the local concentration of antibodies. This makes them more effective and reduces the chances of side effects, she says.

“Nanoparticles provide more bang for your buck,” Schneck says.

Using paramagnetic iron particles about 100 nanometers in diameter, the researchers placed two different kinds of antibodies on them: one blocks a protein called programmed death ligand 1 (PD–L1), which cancer cells use to cloak themselves from immune cells; another that stimulates T cells, a type of immune cell that fights cancer. By combining these two functions, Schneck explains, the goal was to effectively switch off a tumor’s immune–inhibiting ability while simultaneously switching on the immune system’s capacity to attack.

In mice injected with mouse melanoma cells, which grew into tumors over the course of several days, only mice who subsequently received the “immunoswitch” particles had significantly delayed tumor growth and longer survival compared to those who received the control treatments or no treatment.

Specifically, the immunoswitch–treated mice had tumors nearly 75 percent smaller than animals that received no treatment, whereas soluble antibody only reduced tumor growth by approximately 25 percent. Half of immunoswitch–treated mice were still alive after 30 days, whereas all untreated mice died by day 22.