Jefferson Investigates: A New Disease, COVID Immunity and Triple Combo Therapy for Glioblastoma
A novel fibrotic disease with surprising nerve symptoms, an explanation for COVID immunity in the immunocompromised and a new approach for brain cancer
The condition started with sensory changes: burning, numbness and electric-type pain in the genital area for both patients. But over the years that followed, the symptoms worsened and spread to other parts of their bodies despite intensive medical intervention.
For both patients, who were unrelated and unknown to each other, the condition began in a nerve that carries sensation to the area between the pubic and tailbone, including the genitals. Scans and biopsies identified a fibrotic, scarring tissue encasing and entrapping the nerves of these patients. Surgery to release the pressure verified the fibrotic encroachment and improved symptoms, but only temporarily. Over the following year and a half, both patients experienced compression of other major nerves with sensory but also motor symptoms, impairing their movement. The patients underwent a comprehensive evaluation and testing for known neurological, rheumatic and metabolic disorders. Every test result was negative.
Even after extensive testing and evaluation by a team of physician-scientists from Thomas Jefferson University, including rheumatologist Fabian Mendoza, MD, neurologist Marino Dalakas, MD and physician-scientist Sergio Jimenez, MD, and director of the Scleroderma Center, it was concluded that the patients’ symptoms didn’t line up with any known condition
The researchers then searched the medical literature for syndromes or diseases that matched the patients’ symptoms. Again, nothing fit. The syndrome, which they’ve dubbed Multifocal Progressive Fibrosing Neuropathy, is a novel disorder.
In a paper published in the journal Acta Neuropathologica Communications, the Jefferson team with collaborators from Robert Wood Johnson University describe a novel disease in which nerves across the body are progressively encroached upon by excessive accumulation of fibrotic tissue. Through the work, the researchers hope to identify additional patients, uncover the syndrome’s origin and develop effective treatment options.
Clinical trials have shown that the COVID vaccines are less effective in patients who are immunocompromised, but that the vaccines still do offer good protection. A recent study showed that effectiveness also varied greatly across patients with various causes of immune-compromise.
Research led by immunologist Botond Igyártó, PhD, recently sought to understand how the vaccine worked in the immunocompromised by studying mouse models that lacked various immune cell components. In a study published in the journal PLOS Pathogens, Dr. Igyártó’s group showed that different kinds of immune cells and inflammatory molecules play overlapping roles when producing an immune response to the vaccine in mouse models. As a result, the vaccine induced strong immune responses even in animals that were immunocompromised and lacked certain immune cells.
When the researchers infected mice with SARS-CoV-2 or the flu, they found that the mRNA vaccine platform produced a protective immune response regardless of whether or not the animals had immune cells, known as Langerhans cells, certain dendritic cells, neutrophils or an inflammatory molecule called IL-6.
The discovery demonstrates that the vaccines can help protect against infection even in those lacking these immune components. The finding, however, is a double-edged sword. That’s because in previous work, Dr. Igyártó and colleagues discovered that a part of the vaccine platform—the lipid nanoparticle, or fat droplet that encases the mRNA—is highly inflammatory in mice. They showed that the lipid nanoparticle alone revs up the immune system, leading to inflammation and likely some of the side effects associated with these vaccines.
“The platform is so inflammatory that on the one hand you see protective immune responses in the absence of certain innate immune components, which is important if you have an immunodeficiency,” says Dr. Igyártó. “But a question that this research raises is whether people who have pre-existing inflammatory conditions like autoimmunity might see a worsening of their conditions.”
Highly aggressive brain cancers known as glioblastomas currently have no cure. Patients often live just months to a year and a half beyond their diagnosis. Now an early-stage clinical trial led by radiation oncologist Wenyin Shi, MD, PhD, co-director of the Brain Tumor Center at Sidney Kimmel Cancer Center, shows that a triple-combination therapy is a safe option for curbing the cancer’s growth and extending how long glioblastoma patients lived without the disease progressing. The findings lay the foundation for a currently enrolling Phase III clinical trial to further investigate the treatment’s benefits.
Treatment for glioblastoma typically involves an initial surgery to remove as much of the tumor as possible and is followed by additional therapies to slow the growth of any remaining cancer cells. In the new study, Dr. Shi and colleagues gave 30 newly diagnosed glioblastoma patients three treatments following surgery: radiation, chemotherapy and a new therapy known as tumor treating fields or TTFields.
TTFields use mild electrical fields from small transducers attached to the scalp with adhesive bandages to specifically disrupt tumor growth. Compared with other cancer therapies, TTFields don’t tend to cause side effects such as nausea and vomiting.
Patients wore the portable devices continually at home for 18 hours or more per day for several months, while also undergoing radiation and chemotherapy treatments. While evaluating patients’ disease progression and response to the treatment, Dr. Shi and colleagues also monitored how well patients tolerated the therapy. A few patients experienced fatigue, dizziness and headaches, but most patients reported only mild to moderate scalp irritation such as itchy, dry skin that cleared up on its own or with topical medications.
With the treatment, patients’ cancers did not get worse for more than nine months, an extension of living progression-free compared with previous studies, Dr. Shi and colleagues reported April 29 in the journal Frontiers in Oncology.
“The results are encouraging and make the advanced clinical trial for which we are now enrolling possible,” Dr. Shi says.
