CLEVELAND- Newly designed chimeric antigen receptor (CAR) T-cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies, especially when produced under place-of-care manufacturing which is available at University Hospitals (UH) Seidman Cancer Center. That’s the conclusion of a recent study published in the prestigious journal Nature Communications, detailing two Phase I clinical trials of CAR19 T-cells used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL) or adult B-cell Lymphoma.
“Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities,” says study co-author Jane Reese Koc, Cellular Therapy Operations Director at UH Seidman Cancer Center and the National Center for Regenerative Medicine at Case Western Reserve University. The Cellular Therapy Lab is shared by the National Center for Regenerative Medicine, Case Comprehensive Cancer Center and UH Seidman Cancer Center. “The results of this study support the safety and efficacy of this approach.”
“One of the major advantages of this approach is the ability to treat patients significantly quicker than is feasible with commercial CAR T products,” adds study co-author David Wald, MD, PhD, Associate Director for Basic Research at the Wesley Center for Immunotherapy at UH Seidman Cancer Center and Associate Professor of Pathology Case Western Reserve University School of Medicine. “Commercial products can take three to six weeks to be manufactured. The time savings to treatment with the method is important for these patients that have advanced malignancies. We are working with partners to develop even more rapid methods to shorten the manufacturing method down to a single day.”
The Phase I trials involved 31 pediatric and 23 adult patients, located in both Russia and Cleveland. After a median follow-up of 17 months, one-year survival rate of ALL complete responders was 79.2% and median duration of response is 10.2 months. For non-Hodgkin lymphoma (NHL), complete responders one-year survival was 92.9%, and median duration of response has not been reached. The CAR19 T-cells were first tested in cancer cell lines and mouse xenograft models, with positive results.
“For NHL, the results were excellent,” says hematologist Leland Metheny, MD, who is also involved in these clinical trials at UH Seidman Cancer Center. “The results showed they were curative for a significant portion.”
Importantly, in the mouse xenograft experiments, fresh CAR19 T-cells produced in the local facility were shown to provide an advantage over cryopreserved cells more commonly used in CAR T applications. Administration of fresh CAR19 T-cells yielded significantly lower tumor burden as compared to dose-matched frozen CAR19 T-cells on study days 11 and 13. On study days 21 and 28, tumors were similarly and potently rejected by both fresh and frozen cell-treated groups. However, fresh cells reduced the tumor burden sooner by eight days, and immediately started reducing the tumor burden, while frozen CAR19 T-cells first permitted tumor growth before controlling growth.
“The cells that were given fresh acted much better and more effective in mice in getting rid of the NHL than the frozen cells,” Dr. Metheny says. “There is something we don’t know yet about the impact of the freezing technique that is impacting the CAR T-cells.”
In addition to these two clinical trials, Dr. Metheny’s colleagues at UH Seidman Cancer Center are also conducting a CAR T trial that uses fully human protein – one just a handful of sites nationwide to offer this option to patients.
“The antibody part of the antigen receptor that we’re putting on the surface of the T cell is a fully human sequence,” says UH Seidman oncologist Benjamin Tomlinson, MD, who is leading this trial. “In theory, it may have fewer adverse events, so be slightly safer, while still attacking the same target. The biggest question is whether by not having a foreign component, it may be a little bit more effective in instigations in the signaling. Human to human should connect a little bit better than human to mouse, and it may not generate the type of reactions that we are used to seeing with a regular CAR Ts. So that's what we're exploring. We have opened this humanized CAR T trial and have treated patients with lymphoma and ALL successfully.”
In addition, Dr. Wald and colleagues recently reported at the American Society of Hematology meeting on their work identifying potential biomarkers that may help predict outcomes of the patients receiving CAR T-cell therapy.
“We hope this will help to design next generation CAR T-cell therapies,” he says.
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About University Hospitals Seidman Cancer Center
UH Seidman Cancer Center is the only freestanding cancer hospital in Northeast Ohio, where all clinicians and staff are dedicated to the prevention, diagnosis and treatment of cancer while researching new and innovative treatment options through clinical trials. Nationally ranked cancer care is also available to patients through the 11-county region at 18 community-based locations. Our UH Seidman specialists make up 14 cancer-specific teams focused on determining integrated care plans tailored to patient’s needs. UH Seidman Cancer Center is part of the National Cancer Institute (NCI)-designated Case Comprehensive Cancer Center at Case Western Reserve University, one of 51 comprehensive cancer centers in the country. Patients have access to advanced treatment options, ranging from a pioneering stem cell transplant program founded more than 40 years ago and a wide range of immunotherapy to the first and only proton therapy center in northern Ohio for adults and children. Go to UHhospitals.org/Seidman for more information.
About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 23 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Oxford University and the Technion Israel Institute of Technology. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.
Method of Research
Randomized controlled/clinical trial
Subject of Research
People