Technique brings immune-based therapies closer to reality

Johns Hopkins researchers have developed an inexpensive, reliable way to make large quantities of targeted immune cells that one day may provide a life-saving defense against cancers and viral infections.

Using artificial antigen presenting cells, or aAPCs, the scientists converted run-of-the-mill immune cells into a horde of specific, targeted invader-fighting machines, they report in the advance online version of Nature Medicine on April 21.

“The ability to make vast quantities of targeted, antigen-specific immune cells in the lab broadens their potential in tackling a wide array of diseases, especially cancers,” says Jonathan Schneck, Ph.D., professor of pathology and medicine at the Johns Hopkins School of Medicine. “Our technique provides an off-the-shelf way to create these cells.”

The immune system normally defends the body against invaders. However, in cancer, tumor cells aren’t recognized as “foreign,” and after bone marrow and organ transplant the immune system has to be suppressed to avoid rejection of the transplant, opening the door to viral infections. Specially targeted immune cells that fill these defensive gaps are already being tested as experimental “cancer vaccines” in patients with melanoma and multiple myeloma and as virus fighters after bone marrow transplant.

However, the technological advance reported by the Johns Hopkins team overcomes a major weakness of current methods for making these targeted immune cells, known as antigen-specific cytotoxic T cells (CTLs) — namely the methods’ reliance on a patient’s own dendritic cells. Dendritic cells are immune system sentries that wave the proteins, or antigens, of foreign invaders like flags, teaching immune system T cells to recognize the invading cells and kill them.

“But dendritic cells vary in quality and number from patient to patient,” says first author Mathias Oelke, Ph.D., a postdoctoral fellow in pathology at Johns Hopkins. “Many patients simply can’t provide the number of dendritic cells needed to get a vaccine that would work.”

The aAPCs made by the Hopkins team created twice as many specific, targeted CTLs as using dendritic cells, and could have made even more, says Oelke, who researched dendritic cell-derived CTLs in Germany. Both aAPCs and dendritic cells convert generic immune cells in the blood into targeted CTLs.

The aAPCs were made using a protein called HLA-Ig, which in 1998 Schneck showed could mimic the antigen-waving ability of dendritic cells. In the latest research, Oelke turned tiny magnetic beads into aAPCs by coating them with HLA-Ig and another protein that stimulates cell growth and exposing the beads to antigens from either melanoma or cytomegalovirus.

“Using the aAPCs, we were able to make a tremendous amount of CTLs while maintaining their specificity,” says Schneck. “Losing specificity as CTL numbers rise has been a problem with other techniques.”

Before aAPCs could be used to make CTLs for testing in patients, the production method must be modified to produce clinical grade cells, a process Oelke suggests could take two to four years.

Authors on the report are Oelke, Schneck and Dominic Didiano of Johns Hopkins; Marcela Maus and Carl June of the Abramson Family Cancer Research Institute at the University of Pennsylvania; and Andreas Mackensen of the University of Regensburg, Germany. The Johns Hopkins researchers were funded by the National Institutes of Health and the Dr. Mildred-Scheel-Stiftung Deutsche Krebshilfe Foundation.

Under a licensing agreement between Pharmingen and the Johns Hopkins University, Schneck is entitled to a share of royalty received by the University on sales of products related to technology described in this article. Schneck is a paid consultant to Pharmingen. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.