New Treatment Could Lead to Remission in Deadly Condition

Researcher Made Himself Guinea Pig to Test the Drug

Five years ago, David C. Fajgenbaum, MD, MBA, MSc, tested an experimental treatment on himself in the hopes of saving his own life. He has been in remission ever since. Now his research is shedding new light on why the treatment worked, paving the way for a new approach in Castleman disease, a rare and deadly condition with limited options for patients.

Fajgenbaum is the director of the Center for Study & Treatment of Castleman's & Inflammatory Lymphadenopathies (CSTL) in the Perelman School of Medicine at the University of Pennsylvania. He is also Patient 1 in the study. The research is published in the Journal of Clinical Investigation.

Castleman disease isn't actually a single disease, but a group of inflammatory disorders with a common appearance under the microscope. It’s diagnosed in about 5,000 people of all ages each year in the United States. Patients experience a range of symptoms—from a single abnormal lymph node with mild flu-like symptoms to abnormal lymph nodes located throughout their entire body, abnormal blood-cell counts, and life-threatening failure of multiple organ systems.

The most severe subtype, idiopathic multicentric Castleman disease (iMCD), has similarities to autoimmune conditions and cancer. About 35% of patients with iMCD die within five years of diagnosis. In 2014, the FDA approved siltuximab to treat iMCD, and studies have shown that it can send between one-third and one-half of patients into a remission that generally lasts for years.

However, “patients who don't respond to siltuximab have limited options. They typically receive chemotherapy but often relapse," said Fajgenbaum.

Fajgenbaum suddenly became sick in July 2010. In 2012, after not responding to other therapies and having relapsed multiple times after chemo, his research on his own condition suggested that an inhibitor drug called sirolimus that blocked the PI3K/Akt/mTOR pathway could be effective.

Fajgenbaum's study included two additional patients treated with the same approach who also achieved a sustained remission. All three patients saw an increase in two aspects of the immune system—increased numbers of activated T cells and elevated levels of a protein called VEGF-A that causes blood vessel growth—before a flare-up, then a return to normal levels once remission began.

According to Fajgenbaum, their findings are the first to link T cells, VEGF-A, and the PI3K/Akt/mTOR pathway to iMCD. Most important is that the patients improved when mTOR was inhibited. This is crucial as it gives the researchers a therapeutic target for patients who don’t respond to siltuximab.

Fajgenbaum and his team will test the treatment in a clinical trial in the coming weeks at the University of Pennsylvania. He points out the larger implications this research has for the rare disease community. "This highlights the potential for the approximately 1,500 drugs already approved for one condition to also be treatments or cures for the 7,000 diseases with no or insufficient treatment options, like ALS and many pediatric cancers."

Source:  Perelman School of Medicine at the University of Pennsylvania, August 13, 2019