Results from a clinical trial investigating a new T cell receptor (TCR) therapy that uses a person’s own immune system to recognize and destroy cancer cells demonstrated a clinical response in 80% of patients. The patients had advanced multiple myeloma after undergoing autologous stem cell transplants (ASCT). This study used modified T cells to attack cancer cells expressing NY-ESO-1, an antigen found in nearly 60% of multiple myelomas and previously shown to be associated with tumor growth and poor prognosis.
The study, published in Nature Medicine (2015; doi:10.1038/nm.3910), was conducted by researchers at the University of Pennsylvania’s Abramson Cancer Center (ACC) in Philadelphia, including senior author Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and director of Translational Research in the ACC, the University of Maryland School of Medicine, and Adaptimmune Therapeutics plc (Adaptimmune).
In the phase I/II clinical trial of 20 patients, the engineered cells were deemed safe, trafficked to the site of the tumor (bone marrow), and persisted in 90% of the patients who reached 2 years follow-up after infusion. Significant antitumor activity was observed as well: nearly 70% had a near complete or complete response within 3 months after treatment, which compares favorably with the expected responses (less than 40%) in patients without high-risk disease following an ASCT.
This is the first published report of lentiviral vector mediated TCR therapy that has shown persistence beyond 1 month, June said.
“This study shows us that these TCR specific T cells are safe and feasible in patients expressing NY-ESO-1,” June said. “But it also revealed encouraging antitumor activity and showed impressive durable T cell persistence.”
For the study, patients received an average of 2.4 billion NY-ESO-engineered CD3 T cells 2 days after an ASCT. The investigational treatment begins by removing patients’ T cells via an apheresis process similar to blood donation, then genetically reprogramming them using a cell production process originally developed by Penn’s Clinical Cell and Vaccine Production Facility. After being infused back into patients’ bodies, these newly built cells both multiply and seek out a peptide expressed by the antigens NY-ESO-1 and LAGE-1 found in multiple myeloma cancer cells.
With a median follow up of 21.1 months, 15 of the 20 patients were surviving and 10 remained progression free.
Fourteen people had near complete responses, while two had a very good partial response, two had a partial response, one had stable disease, and one had progressive disease. As of April 2015, with a median follow up of 30.1 months, the media progression free survival was 19.1 months and the median overall survival had increased to 32.1 months.
Further, none of the patients experienced macrophage activate syndrome or cytokine release syndrome, an infusion reaction observed in other gene therapy trials characterized by fever, nausea, chills, hypotension, or a rash. There were no treatment-related fatalities.
Relapse was associated with a loss of gene-modified T cells, the authors report, which suggests that methods for sustaining long-term persistence of engineered T cells in more patients may improve outcomes.