Combo treatment harnesses immune system to fight skin cancer

By combining two treatment strategies, both aimed at boosting the immune system’s killer T cells, Johns Hopkins researchers report they lengthened the lives of mice with skin cancer more than by using either strategy on its own. And, they say, because the combination technique is easily tailored to different types of cancer, their findings — if confirmed in humans — have the potential to enhance treatment options for a wide variety of cancer patients.

“To our knowledge, this was the first time a ‘biomimetic,’ artificial, cell-like particle — engineered to mimic an immune process that occurs in nature — was used in combination with more traditional immunotherapy,” says Jonathan Schneck, M.D., Ph.D., professor of pathology, who led the study together with Jordan Green, Ph.D., associate professor of biomedical engineering, both of whom are also members of the Kimmel Cancer Center and the Institute for NanoBioTechnology.

A summary of their study results will be published in the February issue of the journal Biomaterials.

Scientists know the immune system is a double-edged sword. If it’s too weak, people succumb to viruses, bacteria and cancer; if it’s too strong, they get allergies and autoimmune diseases, like diabetes and lupus. To prevent the immune system’s killer T cells from attacking them, the body’s own cells display the protein PD-L1, which “shakes hands” with the protein PD-1 on T cells to signal they are friend, not foe.

Unfortunately, many cancer cells learn this handshake and display PD-L1 to protect themselves. Once scientists and drugmakers figured this out, cancer specialists began giving their patients a recently developed class of immunotherapy drugs including a protein, called anti-PD-1, a so-called checkpoint inhibitor, that blocks PD-1 and prevents the handshake from taking place.

Screen Shot 2016-12-21 at 11.53.42 AM

(Alyssa Kosmides and Randall Meyer, Johns Hopkins Medicine) This immunotherapy technique combines artificial antigen presenting cells (orange) with anti-PD-1 antibodies (yellow) to activate killer T cells (pink) and prevent tumor cells (brown) from damping that response. « Dual Strategy Teaches Mouse Immune Cells to Overcome Cancer’s Evasive Techniques

PD-1 blockers have been shown to extend cancer survival rates up to five years but only work for a limited number of patients: between 15 to 30 percent of patients with certain types of cancer, such as skin, kidney and lung cancer. “We need to do better,” says Schneck, who is also a member of the Institute for Cell Engineering.

For the past several years, Schneck says, he and Green worked on an immune system therapy involving specialized plastic beads that showed promise treating skin cancer, or melanoma, in mice. They asked themselves if a combination of anti-PD1 and their so-called biomimetic beads could indeed do better.

Made from a biodegradable plastic that has been FDA-approved for other applications and outfitted with the right proteins, the tiny beads interact with killer T cells as so-called antigen-presenting cells (APCs), whose job is to “teach” T cells what threats to attack. One of the APC proteins is like an empty claw, ready to clasp enemy proteins. When an untrained T cell engages with an APC’s full claw, that T cell multiplies to swarm the enemy identified by the protein in the claw, Schneck explains.

“By simply bathing artificial APCs in one enemy protein or another, we can prepare them to activate T cells to fight specific cancers or other diseases,” says Green.

To test their idea for a combined therapy, the scientists first “primed” T cells and tumor cells to mimic a natural tumor scenario, but in a laboratory setting. In one tube, the scientists activated mouse T cells with artificial APCs displaying a melanoma protein. In another tube, they mixed mouse melanoma cells with a molecule made by T cells so they would ready their PD-L1 defense. Then the scientists mixed the primed T cells with primed tumor cells in three different ways: with artificial APCs, with anti-PD-1 and with both.

To assess the level of T cell activation, they measured production levels of an immunologic molecule called interferon-gamma. T cells participating in the combined therapy produced a 35 percent increase in interferon-gamma over the artificial APCs alone and a 72 percent increase over anti-PD-1 alone.

The researchers next used artificial APCs loaded with a fluorescent dye to see where the artificial APCs would migrate after being injected into the bloodstream. They injected some mice with just APCs and others with APCs first mixed with T cells.

The following day, they found that most of the artificial APCs had migrated directly to the spleen and liver, which was expected because the liver is a major clearing house for the body, while the spleen is a central part of the immune system. The researchers also found that 60 percent more artificial APCs found their way to the spleen if first mixed with T cells, suggesting that the T cells helped them get to the right spot.

Finally, mice with melanoma were given injections of tumor-specific T cells together with anti-PD-1 alone, artificial APCs alone or anti-PD-1 plus artificial APCs. By tracking blood samples and tumor size, the researchers found that the T cells multiplied at least twice as much in the combination therapy group than with either single treatment. More importantly, they reported, the tumors were about 30 percent smaller in the combination group than in mice that received no treatment. The mice also survived longest in the combination group, with 45 percent still alive at day 20, when all the mice in the other groups were dead.

“This was a great indication that our efforts at immunoengineering, or designing new biotechnology to tune the immune system, can work therapeutically,” says Green. “We are now evaluating this dual strategy utilizing artificial APCs that further mimic the shapes of immune cells, such as with football and pancake shapes based on our previous work, and we expect those to do even better.”

Other authors of the report include Alyssa Kosmides, Randall Meyer, and John Hickey (all of who are INBT training grant students) as well as Kent Aje and Ka Ho Nicholas Cheung of the Johns Hopkins University School of Medicine.

This work was supported in part by grants from the National Institute of Allergy and Infectious Diseases (AI072677, AI44129), the National Cancer Institute (CA108835, R25CA153952, 2T32CA153952-06, F31CA206344), the National Institute of Biomedical Imaging and Bioengineering (R01-EB016721), the Troper Wojcicki Foundation, the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, the JHU-Coulter Translational Partnership, the JHU Catalyst and Discovery awards programs, the TEDCO Maryland Innovation Initiative, the Achievement Rewards for College Scientists, the National Science Foundation (DGE-1232825), and sponsored research agreements with Miltenyi Biotec and NexImmune.

Under a licensing agreement between NexImmune and The Johns Hopkins University, Jonathan Schneck is entitled to a share of royalty received by the university on sales of products derived from this article. Jordan Green is on the scientific advisory board for NexImmune. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Read more about the Jordan Green Group here.

Read more about the Jonathan Schneck Lab here.

Read more about NexImmune here.

SOURCE: Johns Hopkins School of Medicine

Researchers honored with Presidential career awards

Two Johns Hopkins researchers were honored by the White House for their research achievements, including one biomedical engineer affiliated with Johns Hopkins Institute for NanoBioTechnology (INBT).

Namandje Bumpus, Ph.D., and Jordan Green, Ph.D., of the Johns Hopkins University School of Medicine are among 105 winners of Presidential Early Career Awards for Scientists and Engineers, which were announced by the White House on Feb. 18. The awards recognize young researchers who are employed or funded by federal agencies “whose early accomplishments show the greatest promise for assuring America’s pre-eminence in science and engineering and contributing to the awarding agencies’ missions,” according to a White House statement.

“These early-career scientists are leading the way in our efforts to confront and understand challenges from climate change to our health and wellness,” President Barack Obama said in the statement. “We congratulate these accomplished individuals and encourage them to continue to serve as an example of the incredible promise and ingenuity of the American people.”

Namandje Bumpus, left, and Jordan Green. CREDIT Keith Weller, Johns Hopkins Medicine

Namandje Bumpus, left, and Jordan Green.
CREDIT
Keith Weller, Johns Hopkins Medicine

Bumpus, an associate professor of medicine and of pharmacology and molecular sciences, also serves as the school of medicine’s associate dean for institutional and student equity. Her research focuses on how the body processes HIV medications, converting them into different molecules, and the actions of those molecules. In recent studies, she has found genetic differences in how people process popular HIV drugs, suggesting genetic testing should have a greater role to play in combating the virus. “Since joining Johns Hopkins in 2010, Namandje has made tremendous progress toward ultimately making HIV treatment more personalized and effective,” says Mark Anderson, M.D., Ph.D., director of the Department of Medicine. “This is a well-deserved recognition of her work, and I look forward to seeing how she will continue to advance the field.”

Green, an associate professor of biomedical engineering, neurosurgery, oncology and ophthalmology, and a member of INBT, was named one of Popular Science’s Brilliant Ten in 2014. He develops nanoparticles that could potentially deliver therapeutics to the precise place in the body where they’re needed — to make tumor cells self-destruct, for example, while leaving healthy cells intact. “Jordan’s innovations and productivity are exceptional, and his findings have very exciting implications for patients,” says Leslie Tung, Ph.D., interim director of the Department of Biomedical Engineering. “He is truly an extraordinary and exemplary early-career scientist, and a wonderful colleague as well.”

The 105 award winners will be recognized at a White House ceremony this spring.

Source: Johns Hopkins Medicine

Symposium speakers 2015: Jordan Green

Neuro X is the title and theme for the May 1 symposium hosted by Johns Hopkins Institute for NanoBioTechnology. The event kicks off with a continental breakfast at 8 a.m. in the Owens Auditorium, between CRB I and CRB II on the Johns Hopkins University medical campus. Talks begin at 9 a.m. Posters featuring multidisciplinary research from across many Hopkins divisions and departments will be on display from 1 p.m. to 4 p.m.

One of this year’s speakers is Jordan J. Green, PhD.

Jordan Green, PhD

Jordan Green, PhD

Jordan Green is an associate professor in the Department of Biomedical Engineering at Johns Hopkins University. He graduated from Carnegie Mellon University with a bachelor’s degree in Biomedical Engineering, Chemical Engineering and then attended Massachusetts Institute of Technology to earn his doctorate in Biological Engineering. Green joined the Johns Hopkins faculty in 2008 His research focuses on cellular engineering and nanobiotechnology, with special interests in biomaterials, controlled drug delivery, and gene therapy. The potential of gene therapy and genetic medicine to benefit human health is tremendous as almost all human diseases have a genetic component, from cancer to cardiovascular disease. Methods for drug and gene delivery that are both safe and effective have remained elusive. New insights into understanding and controlling the mechanisms of delivery are required to further advance the field. To accomplish this, Green’s research team is developing a framework where biomaterials and nanoparticles can be rationally designed and computationally modeled. These same biomedical insights can also be used more broadly in the fields of regenerative medicine and nanomedicine.

Dr. Green is working at the chemistry/biology/engineering interface to answer fundamental scientific questions and create innovative technologies and therapeutics that can directly benefit human health. In 2014, Dr. Green was named one of Popular Science magazine’s “Brilliant Ten” list, highlighting young scientists who are revolutionizing their fields. He is also a member of the USA Science and Engineering Festival’s Nifty Fifty, which includes 200 of the most dynamic scientists and engineers in the United States who were selected for their unique ability to inspire the next generation of students to pursue careers in the STEM fields. He and Dr. Alfredo Quiñones-Hinojosa recently won a BioMaryland Center Biotechnology Development Award to advance their work on a biodegradable nanoparticle therapy enabling effective transfection of a patient’s stem cells derived from adipose tissue that are applied directly to the post-operative site of brain cancer.

Additional speakers will be profiled in the next few weeks. To register your poster and for more details visit http://inbt.jhu.edu/news/symposium/

For all press inquiries regarding INBT, its faculty and programs, contact Mary Spiro, mspiro@jhu.edu or 410-516-4802.

 

 

 

INBT’s fall student symposium Nov. 7

An important opportunity in graduate school is to get peer and mentor feedback on results. One of the best ways to do that is to share what you have been working on with your colleagues at a symposium.

Jordan Green

Jordan Green

Come hear the latest updates from Johns Hopkins Institute for NanoBioTechnology’s research centers on Friday, November 7 from 9 a.m. to 12:30 p.m. in the Great Hall at Levering on the Homewood campus! Students affiliated with laboratories from the Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins Center of Cancer Nanotechnology Excellence and INBT will present at this student-organized symposium. This event is free and open to the Johns Hopkins community. Refreshments provided.

The keynote faculty speaker is Jordan Green, associate professor at Johns Hopkins Department of Biomedical Engineering. Green was recently named one of Popular Science magazine’s “Brilliant 10.” Breakfast, networking and introductions begin at 9 a.m.

Student speakers and topics include:
**Kristen Kozielski – Bioreducible nanoparticles for efficient and environmentally triggered siRNA delivery to primary human glioblastoma cells. Jordan Green Lab. 9:30-9:45 a.m.

**Angela Jimenez – Spatio-temporal characterization of tumor growth and invasion in three-dimensions (3D). Denis Wirtz Lab. 9:50-10:05 a.m.

**Amanda Levy – Development of an in vitro system for the study of neuroinflammation. Peter Searson Lab. 10:10- 10:25 a.m.

**Max Bogorad – An engineered microvessel platform for quantitative imaging of drug permeability and absorption.  Peter Searson Lab. 10:30-10:45 a.m.

**Greg Wiedman – Peptide Mediated Methods of Nanoparticle Drug Delivery. Kalina Hristova Lab. 10:50 to 11:05 a.m.

**Jordan Green – Particle-based micro and nanotechnology to treat cancer 11:10 a.m. – 12:10 p.m.

Please RSVP on our Facebook event page here.

For all press inquiries regarding INBT, its faculty and programs, contact Mary Spiro, mspiro@jhu.edu or 410-516-4802.

Jordan Green named to PopSci’s Brilliant Ten

Jordan Green, Johns Hopkins University associate professor of biomedical engineering and executive committee member for the Johns Hopkins Institute for NanoBioTechnology, was named one of Popular Science magazine’s Brilliant Ten. The magazine recognized “inspired young scientists and engineers … whose ideas will transform the future.”

Jordan Green (Photo by Marty Katz)

Jordan Green (Photo by Marty Katz)

Green’s work focuses on using nanoscale particles made in the shape of footballs that can train the body’s own immune system to tackle cancer cells. Turns out, particles with the elongated ovoid shape have a slightly larger surface area, which gives them an edge over spherical particles. The football-shaped particles did a better job of triggering the immune system to attack the cancer cells.

Green collaborated with Jonathan Schneck, M.D., Ph.D., professor of pathology, medicine and oncology at Johns Hopkins School of Medicine. Both are affiliated faculty members of Johns Hopkins Institute for  NanoBioTechnology. Their work was published in the journal Biomaterials on Oct 5, 2013.

Read more about their research here.

Congratulations to Dr. Green for the recognition of your interesting and promising work!

Watch a video where Green explains his work in simple terms using toys.

In cancer fight, one sportsball-shaped particle works better than another

Apparently in the quest to treat or cure cancer, football trumps basketball. Research from the laboratory of Jordan Green, Ph.D., assistant professor of biomedical engineering at the Johns Hopkins University School of Medicine, has shown that elliptical football-shaped microparticles do a better job than basketball-shaped ones in triggering an immune response that attacks cancer cells.

football particles-greenGreen collaborated with Jonathan Schneck, M.D., Ph.D., professor of pathology, medicine and oncology. Both are affiliated faculty members of Johns Hopkins Institute for NanoBioTechnology. Their work was published in the journal Biomaterials on Oct 5.

The particles, which are essentially artificial antigen presenting cells (APCs), are dotted with tumor proteins (antigens) that signal trouble to the immune response. It turns out that flattening the spherical particles into more elliptical, football-like shapes provides more opportunities for the fabricated APCs to come into contact with cells, which helps initiate a stronger immune response.

If you think about it, this makes sense. You can’t tackle someone on the basketball court the way you can on the gridiron.

Read the Johns Hopkins press release here:

FOOTBALL-SHAPED PARTICLES BOLSTER THE BODY’S DEFENSE AGAINST CANCER

Read the journal article here:

Particle shape dependence of CD8+ T cell activation by artificial antigen presenting cells

Nanotechnology for gene therapy

Editor’s Note: The following is a summary of one of the talks from the 2013 Nano-bio Symposium hosted by Johns Hopkins Institute for NanoBioTechnology held May 17. This summary was written by Randall Meyer, a doctoral candidate in the biomedical engineering and a member of the Cancer Nanotechnology Training Center. Look for other symposium summaries on the INBT blog.

One of the key features of nanotechnology is its wide range of applicability across multiple biological scenarios ranging from gene therapy to immune system modulation. Jordan Green, an assistant professor of Biomedical Engineering at Johns Hopkins University, summarized some of the fascinating applications of nanotechnology on which his laboratory has been working. Green is an INBT affiliated faculty member.

One of the Green lab projects involves the design and implementation of nanoparticle based vectors for delivery of genetic material to the cell. Green demonstrated how these particles could be used to deliver DNA and induce expression of a desired gene, or small interfering RNA (siRNA) to silence the expression of a target gene. These genetic therapeutics are being developed to target a wide variety of retinal diseases and cancers.

Jordan Green (Photo by Marty Katz)

Jordan Green (Photo by Marty Katz)

 

As opposed to viral based vectors for gene therapy, nonviral vectors such as nanoparticles are safer, more flexible in their range of cellular targets, and can carry larger cargoes than viruses, Green explained.

 

Another project in the Green lab involves the development of micro and nano dimensional artificial antigen presenting cells (aAPCs) for cancer immunotherapy. These aAPCs mimic the natural signals that killer T-cells receive when there is an invader (bacteria, virus, cancer cell, etc.) in the body. The Green lab is currently working with these particles to stimulate the immune system to fight melanoma.

 

Green Group