Nav: Home

'Immunoswitch' particles may be key to more-effective cancer immunotherapy

June 07, 2017

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 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, M.D., Ph.D., 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."

Schneck and study co-leader Alyssa K. Kosmides, a graduate student in his laboratory, explain that several cancer treatments designed to stimulate a patient's immune system to fight the disease have been approved by the U.S. Food and Drug Administration, 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.

However, they point out, checkpoint inhibitors 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 percent, and complete response rates, resulting in eradication of a patient's tumors, are as low as 5 percent.

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 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.

"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," says 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, Schneck and Kosmides say.

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.
-end-
Other Johns Hopkins researchers who participated in this study include John-William Sidhom, Andrew Frasier and Catherine A. Bessell.

The study was funded by the National Science Foundation (grant number DGE-1232825), the National Institutes of Health Cancer Nanotechnology Training Center at the JHU Institute for Nanobiotechnology (grant number 2T32CA153952-06), the National Cancer Institute (grant numbers F31CA206344, R01-CA108835 and R21-CA185819), the National Institute of Allergy and Infectious Disease (grant number P01-AI072677), the TEDCO/Maryland Innovation Initiative and the Coulter Foundation.

Johns Hopkins Medicine

Related Cancer Articles:

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...