PHILADELPHIA—Three researchers from the Perelman School of Medicine at the University of Pennsylvania are among the recipients of the 2019 Clinical Research Achievement Awards from the Clinical Research Forum, which recognizes the ten most outstanding clinical research accomplishments in the United States during the preceding twelve months. Researchers from all ten winning studies will be recognized at a dinner and reception at the National Press Club on March 5th in Washington, D.C.
The Penn awardees are Lindsey A. George, MD, an assistant professor of Pediatrics at Penn and an attending physician in the division of Hematology at Children's Hospital of Philadelphia, for the first gene therapy trial to report a clinical cure for hemophilia B patients; Courtney A. Schreiber, MD, an associate professor of Obstetrics and Gynecology, for the only randomized clinical trial to date to test the efficacy of miscarriage management medications; and Joseph A. Fraietta, PhD, an assistant professor of Microbiology, for a study predicting the response of patients with chronic lymphocytic leukemia to chimeric antigen receptor (CAR) T cell therapy.
Clinical Cure for Hemophilia B Patients
George is being recognized for a highly promising clinical trial, of which she was lead investigator, involving a bioengineered, one-dose intravenous gene therapy that produces a clotting factor to safely and effectively stop bleeding in male hemophilia B patients. This is the first gene therapy trial to report a clinical cure for hemophilia B patients. The study was published in the New England Journal of Medicine.
Hemophilia B is a hereditary bleeding disorder caused by a lack of blood clotting factor IX (FIX). Occurring in approximately one in 25,000 male births, hemophilia B is less prevalent than hemophilia A, which occurs in about one in 5,000 male births. Without enough FIX, the blood cannot clot properly to control bleeding. This results in frequent, unprompted joint bleeding that is treated with life-long recurrent approximate weekly intravenous administration of the missing FIX protein concentrate. This therapy is hard to comply with, only partially effective, and expensive.
In the trial, the research team used a naturally occurring clotting factor called Factor IX-Padua (FIX-Padua) that is eight to ten times stronger than the normal clotting factor, delivering a corrective gene into the patient with the objective of producing therapeutic levels of FIX activity. The new treatment resulted in the cessation of the painful bleeding episodes. The novel gene therapy eliminated the need for conventional intravenous infusions of FIX concentrate in nine members of a cohort of ten patients, enabling them to live free of both the disease and the restrictive treatments. And the one-dose feature of the therapy will result in lower overall health care costs. The researchers found the clinical benefits continued for up to 78 weeks of follow-up.
The only participant who had to be administered conventional FIX after the novel treatment already had major joint damage, but he needed 91 percent less of the clotting factor than before the novel treatment. The next step is a licensing clinical trial involving a larger number of patients.
Early pregnancy loss is the most common complication in pregnancy and occurs about one million annually times in the United States alone. For these women, waiting for natural resolution of a first trimester nonviable pregnancy is often slow and always unpredictable, while surgical management to complete the miscarriage is invasive, time consuming, and costly. These burdens have highlighted the need for new effective miscarriage management strategies.
The Schreiber study, published in the New England Journal of Medicine, reports the results of a comparative effectiveness trial of 300 women with a nonviable first trimester pregnancy in which women were randomized to receive one of two possible medical therapies to complete their miscarriage: either receiving a combination therapy of mifepristone, a progesterone receptor antagonist, plus misoprostol, a prostaglandin analogue, or receiving misoprostol alone. By an average of three days after treatment, 84 percent of women who received both drugs and 67 of women who received misoprostol alone completed their miscarriage process. Uterine aspiration to complete the miscarriage process was required for only 9 percent of women in the combination arm as compared with 24 percent of women in the misoprostol-alone arm. Side effects between the two treatment groups were similar.
This trial supports the use of mifepristone and misoprostol for miscarriage management, and can improve the care of millions of women globally.
CAR T Cell Therapy
In a study published in Nature Medicine, a team of researchers led by Fraietta identified the reason nearly three-fourths of patients with advanced chronic lymphocytic leukemia (CLL), the most common leukemia in adults, don’t respond to chimeric antigen receptor (CAR) T cell therapy.
A common reason for failure of the immune system to eradicate leukemia is that it does not recognize and kill cancer cells, since they come from within the body itself and are not perceived as foreign. But it is now possible to use gene engineering to introduce synthetic molecules, such as chimeric antigen receptors (CARs) into T cells (a key part of the immune system), allowing them to recognize and destroy a patient’s own cancer. But only 26 percent of CLL patients respond to this approach in clinical trials – compared to 80 percent of patients with another form of leukemia known as advanced acute lymphoblastic leukemia (ALL).
Using a simple blood test, the researchers found that CLL patients who had a subset of certain crucial, healthier T cells before CAR T cell therapy had a partial or complete clinical response to the treatment, while those lacking enough of these vital T cells did not respond well. Additionally, in a separate, small group of patients, they predicted with 100-percent accuracy who would experience complete remission based on the presence of these crucial T cells.
The findings would allow physicians to identify CLL patients most likely to benefit from current CAR T treatment. It would also allow CLL patients who are unlikely to respond to pursue other options without losing valuable time by first trying the CAR T treatment. This would also lower overall health care costs, while laying a foundation to improve responses in the other patients by enhancing their immune cells with emerging cell-manufacturing techniques before they begin CAR T cell therapy.
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The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.
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