T cells (red) and tumor cells (green) incubated with control particles (left) or immunoswitch particles (right). T cells that have latched on to tumor cells are indicated by green arrows. [Alyssa Kosmides/Johns Hopkins Medicine]
T cells (red) and tumor cells (green) incubated with control particles (left) or immunoswitch particles (right). T cells that have latched on to tumor cells are indicated by green arrows. [Alyssa Kosmides/Johns Hopkins Medicine]

Those who say the best defense is a good offense may overlook a third possibility—playing defense and offense simultaneously. This third approach may prove to be especially powerful in cancer immunotherapy, a new study suggests. This study describes new “immunoswitch” nanoparticles that can dramatically slow the growth of mouse melanoma and colon cancer and even eradicate tumors in test animals.

Each nanoparticle, a tiny bit of paramagnetic iron, is coated with two different antibodies: one blocks a protein called programmed death-ligand 1 (PD-L1), which cancer cells use to cloak themselves from immune cells, and one  stimulates T cells, a type of immune cell that fights cancer. Essentially, one antibody improves immune defenses by helping them stay alert to the presence of cancer cells that would otherwise stay camouflaged. Another one helps press T-cell attacks.

The immunoswitch nanoparticles were created by scientists at Johns Hopkins University School of Medicine, who recently reported that their defense/offense approach instigated a robust anticancer immune response in mice. Details appeared June 7 in the journal ACS Nano, in an article entitled “Dual Targeting Nanoparticle Stimulates the Immune System to Inhibit Tumor Growth.” The article’s results suggest that the nanoparticle could lead to ways to boost the effectiveness and promise of immunotherapies in people with cancer.

“These ‘immunoswitch’ particles significantly delay tumor growth and extend survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or nanoparticles separately conjugated with the inhibitory and stimulating antibodies,” the article’s authors wrote. “The use of the immunoswitch nanoparticles resulted in an increased density, specificity, and in vivo functionality of tumor-infiltrating CD8+ T cells.”

These results came from the laboratory of Jonathan P. Schneck, M.D., Ph.D., professor of pathology at Johns Hopkins University School of Medicine and co-leader of the study described in ACS Nano. “Immunotherapies have significant potential and yet room for improvement,” he said. “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.”

Dr. Schneck and study co-leader Alyssa K. Kosmides, a graduate student in his laboratory, explained that several cancer treatments designed to stimulate a patient's immune system to fight the disease have been approved by the U.S. FDA, including three known as checkpoint inhibitors. Those drugs help overcome cancer cells' ability to evade a person's immune system by using antibodies to shut down proteins on tumor cell surfaces that hide them from immune cells.

Checkpoint inhibitors, however, work only in a relatively limited number of patients and against a small number of cancers so far. Follow-up studies show that overall response rates against melanoma, bladder cancer, Hodgkin's lymphoma, and non-small-cell lung cancer is around 30%, and complete response rates, resulting in eradication of a patient's tumors, are as low as 5%.

But combining multiple forms of immunotherapy in doses high enough to be effective can cause severe, even life-threatening, side effects.

For their study, the Johns Hopkins researchers combined two different immunotherapy strategies on manmade nanoparticles about 1000 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 a free drug, Kosmides noted, 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,” Dr. Schneck added.

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% smaller than animals that received no treatment, whereas soluble antibody only reduced tumor growth by approximately 25%. Half of immunoswitch-treated mice were still alive after 30 days, whereas all untreated mice died by day 22.

“The double-duty immunoswitch particles were clearly more effective than a mixture of nanoparticles that each targeted just one protein and acted in a synergistic fashion, but we don't yet know why,” admitted Dr. Schneck. “It may be that the immunoswitch particles' success comes from bringing T cells and their targeted tumor cells into close proximity.”

The researchers say they found even more dramatic results in a mouse model of colon cancer. In those experiments, about half the mice had a complete regression of tumors, and about 70% could be considered long-term survivors, living more than 55 days.

Looking for the mechanism behind the immunoswitch particles' positive effects, further experiments showed that the particles appear to bring cancer cells and the immune cells that fight them together more easily, providing a synergy that's not possible even with the same two antibodies on separate particles. The immunoswitch particles also were retained in tumor cells significantly longer than soluble antibodies, offering more time for them to work, Dr. Schneck and Kosmides remarked.

The researchers add that they plan to work on improving the immunoswitch particles by searching for more effective combinations of antibodies to include on the platform. Because the particles are magnetic, they also plan to test whether results can be improved by using magnets to guide the particles and keep them at the tumor site.








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