Whether you spare the rod or wield it freely, you risk spoiling the cell-based cancer therapy. The rod in this case is interleukin-2 (IL-2), a signaling chemical that awakens T cells to their cancer-fighting duties. Letting up on the IL-2 allows T cells to err on the side of sloth. Persistent administration, however, raises the risks of serious side effects.
To circumvent this dilemma, scientists based at Stanford University School of Medicine worked out a unique approach. They would brandish a modified IL-2, one that would bind only to a modified IL-2 receptor. Of course, both the modified signaling molecule and the modified receptor would have to be engineered. Also, the modified receptor would have to be introduced to T cells.
Accomplishing these tasks would allow the scientists to develop an adoptive cell therapy regimen that could maintain T-cell discipline without inflicting tissue-damaging inflammation. That, at least, was the plan, which the scientists put into action.
“We engineered a slightly tweaked version of one of IL-2’s constituent subunits so that a receptor containing this subunit can no longer bind to IL-2,” said Christopher Garcia, Ph.D., a professor of molecular and cellular physiology and of structural biology. “And we generated a slightly altered IL-2 molecule that can’t bind to its normal receptor.” But the modified protein and modified receptor bind with high affinity to one another.
Using laboratory methods to snap the modified receptors onto T cells from mice, Dr. Garcia’s group showed in a series of experiments that these T cells responded to modified IL-2 exactly as natural T cells would be expected to respond to ordinary IL-2. But unmodified T cells didn’t respond to the modified IL-2 at all.
Next, Garcia’s team and colleagues turned to the laboratories of two of the study’s co-authors, University of California, San Francisco, immunologist Jeffrey Bluestone, Ph.D., and UCLA cancer specialist Antoni Ribas, M.D. There, further disease-based experiments were conducted, including some with mice in which a well-characterized type of melanoma had been induced.
For these experiments, T cells were engineered to respond to the modified IL-2 and attack the tumors. Bolstered with regular doses of tweaked IL-2, these T cells shrunk the tumors—but without side effects.
Detailed results appeared March 2 in the journal Science, in an article entitled “Selective Targeting of Engineered T Cells Using Orthogonal IL-2 Cytokine-Receptor Complexes.”
“Introduction of orthoIL-2Rb into T cells enabled the selective cellular targeting of orthoIL-2 to engineered CD4+ and CD8+ T cells in vitro and in vivo, with limited off-target effects and negligible toxicity,” wrote the article’s authors. “OrthoIL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells.”
“Adoptive cell therapy is on the cusp of becoming a revolutionary new approach to cancer treatment,” commented Dr. Garcia. “It’s undergoing explosive growth—it’s a multibillion-dollar biotechnology industry already, and it’s going to become as routine as bone marrow transplants are now. But all of the approaches in development today need IL-2, so new and better ways of delivering IL-2 are a critical unmet need. Our approach is also applicable to other important immune substances and cell types.”
Dr. Garcia said his group has now generated human odd-couple IL-2/receptor pairs that, like their mouse counterparts, bind only to one another. He is looking for collaborators in academia or industry to launch a clinical trial based on the new technology. And, he said, he believes the same approach, employed to stimulate regulatory T cells rather than killer T cells, should, in principle, be effective in combating autoimmune disease.