SAN FRANCISCO — For the 10 to 15 percent of patients who relapse or are refractory to first-line therapy, novel approaches with modified chimeric antigen receptor T cells (CART) may improve their typically poor prognosis. At an oral abstract presentation at the 2014 ASH Annual Meeting, Marco Ruella, MD, presented data demonstrating potent therapeutic activity against disseminated Hodgkin lymphoma in mice models.
Dr. Ruella, of the Abramson Family Research Cancer Institute at the University of Pennsylvania, and others previously demonstrated the efficacy of CART123 in treating refractory B cell malignancies. While there is a B-cell origin of the malignant Hodgkin Reed-Sternberg (HRS) cells, B cell antigens – and in particular CD19 – are typically not expressed in Hodgkin lymphoma.
With their latest research, the investigators attempted to translate these findings to patients with refractory Hodgkin lymphoma, using a combined approach of CART123 and rescue autologous bone marrow transplantation.
In a group of 10 mouse models of Hodgkin lymphoma, Dr. Ruella and colleagues searched for a cell membrane antigen associated with Hodgkin lymphoma that could be targeted by CART cells. The ideal target would be expressed on neoplastic cells and on infiltrating immune cells so that it could provide robust stimulation of the chimeric antigen receptor T cells. This target was found in CD123, the alpha chain of the receptor for interleukin-3, an important cytokine that has been shown to promote Hodgkin lymphoma growth. Immunohistochemistry revealed that CD123 was expressed in five out of ten patients’ HRS cells.
After defining the role of IL-3 signaling in Hodgkin lymphoma in in vitro models of the disease, Dr. Ruella and investigators confirmed these results in in vivo models, where, approximately six weeks after injection, mice were treated with 1.5 million CART123 cells or control T cells. “CART123 induced complete and durable eradication of disseminated tumor within 14 days, leading to 100 percent relapse-free and 100 percent overall survival at 6 months,” the investigators reported. Tumor elimination was also associated with extensive CART cell expansion, as detected on flow cytometry in serial peripheral blood bleedings.
“We developed anti-CD123 chimeric antigen receptor T cells and demonstrated that they are highly effective in a preclinical in vivo model of Hodgkin lymphoma,” Dr. Ruella told ASH Clinical News. “Since neoplastic cells in Hodgkin lymphoma comprise only 1 to 2 percent of the tumor mass, targeting both the tumor and microenvironment can be particularly important for the long-term eradication of the disease.”
Source: Ruella M, et al. Novel Chimeric Antigen Receptor T Cells for the Treatment of Hodgkin Lymphoma. Abstract #806. Presented at the 2014 ASH Annual Meeting. December 9, 2014.