Skip Navigation
request an appointment my chart notification lp musc-logo-white-01 facebook twitter youtube blog find a provider circle arrow
MUSC mobile menu

STAT

An MUSC blog
Date: May 22, 2017

Co-administering a monoclonal antibody that neutralizes tumor-released soluble MHC I chain-related molecule (sMIC) improves anti-CTLA4 antibody therapy effectiveness and reduces treatment-related colitis, report Medical University of South Carolina (MUSC) investigators in an article published online May 17, 2017 by Science Advances.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) can be thought of as an 'off switch' or 'immune checkpoint' for effector T cells that are activated to fight cancer tumors. Researchers have developed a therapy to block CTLA4, specifically, anti-CTLA4 antibody immunotherapy, to help sustain T-cell activation and improve patient survival.

Unfortunately, while anti-CTLA4 therapy is highly effective in animals, response rates in humans vary widely and serious adverse events such as colitis (gastrointestinal inflammation) are common. For example, Ipilimumab, an FDA-approved anti-CTLA4 antibody therapy for advanced melanoma, is highly effective in controlling tumors in mice but has a response rate of only fifteen percent in humans. Clinical investigators have tried to improve the efficacy and safety of anti-CTLA4 therapy by combining it with other agents but response rates and toxicity remain suboptimal.

MUSC cancer immunologist Dr. Jennifer WuA team of MUSC researchers led by Jennifer Wu, Ph.D., professor of Microbiology and Immunology, suspected that response disparities between humans and animals may be due to differences in immune modulators that human tumors express.

"When we use animals to study therapies for humans we often neglect certain human-specific biological pathways simply because they don't exist in the animal," explains Wu. "MIC is one of those molecules that is expressed in human tumors but is absent in mice. We knew that the soluble form, sMIC, is highly immunosuppressive in humans and we knew it was important, but we had no way to study it. We had to create a new model."

Their work to unravel these molecular-level differences has now paid off, with the discovery of a new combination therapy that dramatically improves CTLA4 therapy effectiveness and avoids therapy-induced colitis.

The team developed a clinically relevant, MIC-transgenic spontaneous mouse tumor model that closely resembled the onco-immune dynamics seen in human cancers. Using this model, they investigated how tumor-derived, human sMIC affected anti-CTLA4 therapy. They found that high blood levels of sMIC not only reduced the antitumor efficacy of anti-CTLA4 therapy but also directly evoked colitis.

"It was a total surprise, and we were a little nervous about the results," says Wu. "So, we repeated the test using multiple models and antibodies and different batches of animals to make sure it was reproducible and that what we were seeing was real. Sometimes knowledge itself gets in the way. Because there are certain accepted beliefs that make you think what you're seeing can't be true-that it's impossible. But when multiple experiments are all coming up with the same results, what can you say? That's when we have to let go and come to a new understanding."

Next, the team co-administered an antibody called B10G5 that neutralizes sMIC, alongside anti-CTLA4 therapy. The new combination therapy not only remarkably improved anti-CTLA4 immunotherapy effectiveness, but also alleviated therapy-induced colitis.

"We've been studying B10G5 for a while and published a paper in Clinical Cancer Research in 2015 demonstrating that using B10G5 to target sMIC can alleviate tumor-induced immune suppression and also has a huge immune-stimulating ability," explains Wu. "So those results led us to think it would be a good strategy to combine B10G5 with antibodies that target immune checkpoint molecules, the 'off-switch' of an ongoing immune response."

Finally, inspired by a case study published in 2006, the team decided to try to validate its current findings in humans. The original case reported a melanoma patient who developed anti-MIC autoantibody during anti-CTLA4 therapy and had a superior therapeutic response. So, they contacted a long-time collaborator at Oregon Health and Science University and Knights Cancer Center to obtain plasma samples collected during a clinical trial they were conducting in metastatic prostate cancer patients.

Wu's team looked for anti-sMIC autoantibodies in samples from ten patients receiving anti-CTLA4 therapy with Ipilimumab. One sample showed high levels of anti-MIC autoantibody. When the team followed up with their colleague, it turned out that this particular cancer patient not only demonstrated a remarkable therapeutic response (his prostate-specific antigen fell from 191 to 4.6 ng/ml after eight treatment cycles) but also did not develop autoimmune colitis.

That case reinforced the team's preclinical in vivo findings that coadministering the sMIC-neutralizing antibody (B10G5; CanCure, LLC) enhances anti-CTLA4 therapy and deters colitis. Overall, these results indicate a new, powerful combination immunotherapy for cancer. They also suggest that pre-screening serum sMIC levels might help clinicians to identify patients who are most likely to have a positive therapeutic response.

"I hope that our findings will inspire investigators to revisit other cancer immunotherapies that were successful in animals but presented no efficacy in humans," says Wu. "Anti-CTLA4 therapy is approved for melanoma and also is still in trials for other cancers. Maybe our study will inspire clinical investigators to think about screening their patients to identify who will be a better responder versus a poor responder to anti-CTLA4 therapy."

Chronic pancreatitis (long-standing inflammation of the pancreas) (CP) is a challenging disease for health care practitioners because it is difficult to diagnose and treat. Although its annual incidence rate in the United States is low (five to 12 per 100,000 persons), hospital admissions due to CP are on the rise. CP is characterized by severe abdominal pain and irreversible damage to the pancreas.

In the past decade new medical and surgical treatments have emerged that enable multidisciplinary teams to better recognize and manage this disease. In 2014, gastrointestinal specialists at the Medical University of South Carolina (MUSC), led by David B. Adams, M.D. (pictured below), professor of surgery and an expert in CP, organized the first international exchange of information on these advancements.
Dr. David B. Adams
The "2014 International Symposium on the Medical and Surgical Treatment of Chronic Pancreatitis" brought together experts from the fields of medicine, surgery, psychology, physiology, pharmacology and genetics.


Examples of breakthrough information from the meeting include:

  • New research findings about the causes of CP and its pain pathways
  • Updates on the endoscopic management of CP
  • Updates on total pancreatectomy combined with auto islet transplantation

Last month, a textbook covering the information that came out of that meeting was published (Wiley-Blackwell, April 2017). "Pancreatitis: Medical and Surgical Management" (ISBN: 978-1-118-91712-1) covers acute pancreatitis (sudden inflammation that lasts a short time) as well as CP. Adams is the chief editor. Co-editors are Peter B. Cotton, M.D., professor of medicine at MUSC; Nicholas J. Zyromski, M.D., associate professor of surgery at Indiana University School of Medicine; and John A. Windsor, MBChB, M.D., professor of surgery at Mercy Hospital in New Zealand.

The book provides gastroenterologists and gastrointestinal surgeons with an evidence-based approach to the most recent developments in the diagnosis and clinical management of pancreatitis. In addition to new surgical procedures such as endoscopic biliary intervention and minimally invasive necrosectomy, these advances include medical therapies, such as antiprotease, lexipafant, probiotics and enzyme treatment.

"This book is the latest information from international experts in all of the relevant disciplines of medicine," says Adams. "This represents the first time all of these experts have come together to share their knowledge and experience."

MUSC will host a second international CP symposium in 2018 in Charleston, South Carolina. International experts from the fields of medicine, surgery, psychology, physiology, pharmacology and genetics will confer and exchange ideas to identify the direction, trends and developments in the diagnosis and management of CP that are needed to enhance clinical effectiveness, encourage adoption by healthcare providers, and engage patients in best practice and cost-effective care.

For more information, visit http://www.pancreatitissymposium.org.

MUSC Health Sports Medicine, a specialized group of orthopedic doctors and other medical providers within MUSC’s Musculoskeletal Institute, is passionate about providing comprehensive, personalized care to athletes. 

“We’re focused on the evaluation, diagnosis, treatment (both operative and nonoperative) and rehabilitation of injury or pain conditions in the muscles, bones and joints that impact athletes and active people,” says Shane Woolf, M.D., chief of orthopedic sports medicine at MUSC Health.

At MUSC Health Sports Medicine, patients have access to integrated care—from the time of injury until they’re back at play. Patients also benefit from the group’s concentration on education and research, which promotes best practices and novel techniques that demonstrate an expert level of sports medicine care.

Beyond Orthopedic Treatment for Athletes

What sets MUSC Health Sports Medicine apart from most orthopedic groups? According to Dr. Woolf, the answer is in the scope of what—and who—they treat. “I like to consider orthopedic sports medicine as primarily soft tissue orthopedic trauma, as opposed to general orthopedic trauma, which involves primarily treating fractures,” he says. “We all treat broken bones, but at MUSC Health Sports Medicine, our orthopedic sports medicine specialists are skilled in the repair or reconstruction of cartilage, muscle, ligament and tendon injuries and joint instability.”

MUSC Health’s sports medicine group is affiliated with numerous area sports teams, including local high schools as well as the Charleston River Dogs, a minor league baseball team, and the Charleston Battery, a USL pro soccer team. While the focus is on sports medicine, the team doesn’t discriminate based on athletic ability.

“We have experience in treating active and athletic people of all age ranges, activity levels and skill levels,” says Dr. Woolf.

Many athletes may require medical care outside of orthopedic injury issues. MUSC Health Sports Medicine coordinates that care, too. “When you’re playing a sport, even at a recreational level, many medical problems need to be managed differently compared to people who don’t engage in athletics or an active lifestyle,” explains Dr. Woolf.

Conditions such as exercise-induced asthma, diabetes and heart issues can benefit from a sports medicine focus. “Our primary care sports medicine colleague, Alec DeCastro, M.D., is skilled at helping patients with medical issues remain active,” says Dr. Woolf.

Importance of Coordinated Sports Medicine Care

At MUSC Health Sports Medicine, specialists take a big-picture approach to athlete care, coordinating among many specialties.

“We integrate with other specialists very closely,” says Dr. Woolf. “We work with referring primary care physicians as well as our colleagues in radiology, primary care sports medicine, neurology, cardiology and other divisions within our institution. We get athletes the evaluation they need, even if it’s not necessarily an orthopedic issue. We keep it personal, customizing treatment plans for each patient.

“We want to make sure that every patient is safe to play, and we use every resource within our disposal to find a way to allow them to participate in their chosen activity, safely,” adds Dr. Woolf.

Two examples of how patients benefit from this coordination:

  • Joint injuries: A patient receiving joint injections sees a radiologist for image-guided injections, to confirm treatments are reaching the area of concern. Physical therapy professionals can then assist the same patient with rehab of the joint.
  • Gastrointestinal issues: MUSC Health specialists work with the Women’s Tennis Association when athletes are in town for a tournament. When an athlete has a gastrointestinal issue, for example, she might be connected with an MUSC Health specialist for a quick evaluation. “Even though the condition isn’t a musculoskeletal problem, it still affects athletic performance, and we’re happy to coordinate that care,” says Dr. Woolf.

A Leader in Sports Medicine Research and Education

MUSC Health sports medicine specialists are also educating future sports medicine providers and promoting evidence-based care through evolving research.

“We are very much engaged in research and education for sports medicine. We’re not only evaluating and treating these problems, but we’re studying them as well to learn how to provide better care,” says Dr. Woolf.

Specialists teach a range of skills to sports medicine residents and students, from the intricacies of open and arthroscopic surgery techniques to education on the importance of rehabilitation after an injury.

Current research studies are delving into a range of sports medicine points of interest, such as:

  • Improving rehabilitation after ACL tears
  • How foot pain relates to weakness in an athlete’s core (the muscles and joints in the back, pelvis, abdomen and hips that make up the fundamental foundation of the body)
  • Identifying injuries and best treatment plans for cartilage problems in the shoulder and knee

Whatever an athlete’s medical concern, MUSC Health Sports Medicine can help coordinate care and ensure the best treatment, and the fastest recovery, for each individual.

For more information about the MUSC Health Sports Medicine program, contact 843-876-0111.

Primary colorectal tumors secrete VEGF-A, inducing CXCL1 and CXCR2-positive myeloid-derived suppressor cell (MDSC) recruitment at distant sites and establishing niches for future metastases, report Medical University of South Carolina (MUSC) investigators in an article published online ahead of print on April 28, 2017 by Cancer Research. Liver-infiltrating MDSCs help bypass immune responses and facilitate tumor cell survival in the new location. This research illuminates mechanisms by which primary tumors contribute to premetastatic niche formation and suggests CXCR2 antagonists may reduce metastasis.

Recent cancer research shows that premetastatic 'niches' form at sites far from the original tumor before new tumors occur. In colorectal cancer (CRC), these supportive microenvironments form in preferred secondary organs, such as the liver and lung, and facilitate the colonization, survival, and growth of metastasizing tumor cells. However, the mechanisms responsible for the formation of these premetastatic 'niches,' including what role(s) the primary tumor may play, are not well understood. It is critical to better understand the mechanics of CRC metastasis, as it is the second leading cause of cancer deaths in the US and patients with advanced cases often die because current treatments for widely metastasized disease are not effective.

MUSC investDr. Raymond N. DuBois, dean of the Medical University of South Carolina College of Medicineigators led by Raymond N. DuBois, M.D., Ph.D., dean of the MUSC College of Medicine and professor of Biochemistry and Molecular Biology, have now illuminated how primary CRC tumors contribute to premetastatic 'niche' formation.

"The idea that some sort of 'priming' needs to take place for metastasis to occur in distant organs - that there is some sort of activity in the future tumor location - is not new. But most research has focused on growth factors, chemokines and pro-inflammatory cytokines. There hasn't been much work looking at immune cell activity in distant organs prior to metastasis," explains DuBois. "We knew that the type and density of immune cells in the primary tumor plays a role in progression. For example, when more immature myeloid cells are present in the tumor, it becomes resistant to immune attack. But we didn't know what to expect in a metastatic model."

To explore this area, the team first evaluated whether the presence of a primary tumor affected immune cell profiles in premetastatic liver and lung tissues of mice. They found that the presence of a primary cecal tumor caused MDSCs to begin infiltrating the liver before metastasis began. Working backward from this finding, they used a series of experiments to reveal the chain of events that led up to MDSC infiltration.

Because CXCR2 is essential for drawing MDSCs out of the bloodstream and toward CRC tumors and colonic mucosa, the team began looking for CXCR2 and its ligands (CXCL1, CXCL2, and CXCL5) in mouse liver tissue. The team not only found that the ligand, CXCL1, attracted MDSCs from the bloodstream into premetastatic liver tissue, but also that administering a CXCR2 antagonist inhibited CXCL1 chemotaxis. This demonstrated that CXCR2 is required for CXCL1 to induce MDSC liver infiltration. In other words, the CXCL1-CXCR2 axis is required to recruit MDSCs to the liver. Importantly, they also found that liver- infiltrating MDSCs secrete factors that promote cancer cell survival and metastatic tumor formation without invoking the innate and adaptive immune responses.

Next, because VEGF is known to induce CXCL1 expression in lung cancer, the research team examined whether VEGF secreted by CRC tumors also regulated CXCL1 expression. Their results demonstrated that VEGF-A secretion by primary CRC tumor cells stimulates macrophages to produce CXCL1. Interestingly, although VEGF-A knockdown inhibited liver metastasis, it did not affect the growth of the primary tumor.

"We did not expect to find that a primary tumor could affect a distant organ before any of the cancer cells arrived on site," says DuBois. "We were surprised to see these changes before a single metastatic cell took up residence."

Together, these studies reveal that VEGF-A secreted by the primary CRC tumor stimulates macrophages to produce CXCR1, which recruits CXCR2-expressing MDSCs from the bloodstream into healthy liver tissue. The MDSCs then create a premetastatic 'niche' or micro-environment where cancer cells can grow to form new tumors. These results demonstrate for the first time that cells in the primary tumor contribute to forming distant pre-metastatic 'niches' which facilitate the spread of disease.

"Now that we know the primary tumor puts things in motion remotely prior to metastasis, we should be able to inhibit this process and have a positive impact on survival," explains DuBois. "We now know which molecules and immune cells are involved and that if we disrupt the CXCL1-CXCR2 axis we can possibly reduce the spread of disease. Both antibodies and small molecules can inhibit this pathway, but they have not yet been optimized. I hope these findings will speed up the development of inhibitors of the CXCR2 pathway."

"Juicing" Th17 cells with FDA-approved small molecule beta-catenin and p110 delta inhibitors during in vitro expansion for adoptive T cell therapy (ACT) profoundly improves their therapeutic properties, report investigators at the Medical University of South Carolina (MUSC) in an article published online ahead of print on April 20, 2017 by JCI Insight.

MUSC cancer immunologist Dr. Chrystal M. PaulosACT involves harvesting T cells, rapidly amplifying and/or modifying them in the laboratory to boost their cancer-fighting ability, and then reinfusing them back to the patient to boost anticancer immunity. One challenge for ACT has been that the rapid expansion of T cells in the laboratory can cause them to age and wear out, decreasing their longevity after reinfusion.

"Juicing" Th17 cells with the FDA-approved small molecules enhanced their potency, function and stem-like (less differentiated) quality, suggesting that they would persist better after reinfusion into patients, and also reduced regulatory T cells in the tumor microenvironment, which can blunt the immune response. These findings highlight novel investigative avenues for next-generation immunotherapies, including vaccines, checkpoint modulators, and ACT.

"This is exciting because we might be able to overcome some of the delays and disadvantages of rapid expansion in the laboratory," explains senior author Chrystal M. Paulos, Ph.D., associate professor of immunology and Endowed Peng Chair of Dermatology at MUSC and a member of the MUSC Hollings Cancer Center. "We might be able to use fewer cells (for ACT) because we can pharmaceutically 'juice' these T cells to make them more fit in the oppressive tumor microenvironment."

Building upon their previous findings that ICOS costimulation is critical for generating human Th17 cells and for enhancing their antitumor activity, an MUSC research team led by Paulos and including postdoctoral fellow Kinga Majchrzak report for the first time that repurposing FDA-approved small molecule drugs that inhibit two ICOS-induced pathways greatly enhances the antitumor potency of T cells.

Several biologic properties of the Wnt/ beta-catenin and P13K delta pathways led the team to suspect that they supported the antitumor activities of Th17 cells. For example, these pathways are active in both regulating T cell cytokine production during the immune response and in promoting self-renewal of hematopoietic stem cells (HSCs) and sustaining HSCs in an undifferentiated state. So, they designed a series of experiments to determine whether these two pathways were also active in enhancing Th17 antitumor memory and effectiveness.

To test this idea, they pharmaceutically inhibited PI3K delta and beta-catenin in Th17 cells (using idelalisib [CAL-101] to block the PI3K delta pathway and indomethacin [Indo] to inhibit beta-catenin)-anticipating that this would weaken Th17 cells' antitumor activity. To their surprise, the exact opposite occurred. ICOS-stimulated Th17 cells that were treated in vitro with CAL-101 plus Indo elicited a more potent antitumor response against melanoma in mice.

"My post-doc student came to me and said, 'I think I made a mistake because the data are going in the opposite direction to what we originally predicted!" says Paulos. "So, she repeated the experiment several times but we kept getting the same result. The data showed that using drugs to inhibit these pathways actually made the Th17 cells even better at killing tumors."

The team found that Th17 cells treated with CAL-101 express less FoxP3, suggesting that the drug suppresses Treg conversion while sustaining central memory-like Th17 cells. This finding is highly important because the phenotypic plasticity of Th17 cells in vivo allows their conversion to Tregs or Th1 cells with weak antitumor properties. These data suggest that treatment with CAL-101 can halt the development of these poorly therapeutic phenotypes and, thus, enhance the T cells' antitumor activity.

While the findings were initially counterintuitive and perplexing from a mechanistic perspective, in retrospect Paulos sees that they make sense. "Essentially, the T cells are younger," explains Paulos. "We know that T cells used for ACT age and wear out over time. Somehow these drugs sustain their youth and function. They're able to keep all the properties of their youth-they expand better and they're more functional and handle the oppressive tumor microenvironment better."

The discovery that existing FDA-approved drugs that block p110 delta and beta-catenin can make T cells more efficient tumor killers in vivo is an exciting prospect for Paulos' team. "From a clinical standpoint, this finding indicates that the therapeutic effectiveness of ACT could be improved by simple treatments with readily available drugs. It opens a lot of new investigative avenues for next-generation immunotherapy trials," she says.

"This research offers tremendous promise for the treatment of patients with serious forms of skin cancer," says Dirk M. Elston, M.D., chair of the Department of Dermatology and Dermatologic Surgery at MUSC.

Paulos has a patent on ICOS signaling in adoptive T cell transfer therapy (US 9133436), and Paulos, Majchrzak, and J.S. Bowers have a patent on pharmaceutical drug combinations or genetic strategies that instill durable antitumor T cell memory and activity (patent application P1685).

For many of the millions of patients treated annually in hospitals for upper gastrointestinal (GI) bleeding, there is little value in placing a nasogastric (NG) tube in patients to determine the source of that bleeding or size of a lesion, report investigators in an article published online ahead of print on January 9, 2017 by the Journal of Investigative Medicine.

Study authors, including Don C. Rockey, M.D., Medical of University of South CarDr. Don C. Rockeyolina (MUSC) Department of Medicine chair and professor of gastroenterology, position the research as improving patient care by doing less when possible, in terms of procedures or treatments that don't provide significant benefit to patients and are costly and uncomfortable.

"Placing a tube through the nose and down into the stomach makes sense if we are talking about delivering nutrition to a patient or to get an idea of what is in someone's stomach, but the value of placing this tube for patients who have an upper GI bleed has been unclear," Rockey said. "Our goal was to examine that value, and our results suggest that for millions of patients with an upper GI bleed, placing this tube had little clinical benefit and produces unnecessary cost and discomfort for all involved. If it doesn't help the patient or the clinician trying to diagnose the cause of this kind of bleed, we don't need it as a standard of care when there is no value."

The single-blind, randomized, prospective, non-inferiority study compared NG placement (with aspiration and lavage) to no NG placement (control) and demonstrated that NG tube placement in patients with typical upper GI bleeding had no impact on outcomes. In addition, the placement of NG tubes was often unsuccessful or associated with patient discomfort.

Subscribe to Progressnotes

Submit a Story Idea


Current Issue of Progressnotes

Digital EditionPDF | Home

Progressnotes - Spring 2017 cover thumb

Back Issues of Progressnotes

past issues of progressnotes