Researchers have kept cancer at bay in three patients with chronic lymphocytic leukemia by genetically engineering the patients’ own T-cells to recognize leukemia cell antigens, then kill the cancer cells. The approach, which is described today (August 9) in two papers in the New England Journal of Medicine and Science Translational Medicine, could potentially be developed to fight not just leukemia, but other cancers as well.
“This is the touchdown that I think the field’s been looking for,” said Donald Kohn, a pediatric gene therapist at the University of California, Los Angeles, who was not involved in the research. “It’s a really spectacular clinical response to have patients with unresponsive, end-stage disease have complete remission without a lot of toxicity.”
Chronic lymphocytic leukemia (CLL) is a slowly progressing cancer that targets B-cells, immune cells that fight infection. While treatments can keep the disease in check for a while, the cancer inevitably becomes resistant and progresses until patients get a bone marrow transplant or die, said co-author David Porter, an oncologist at the University of Pennsylvania Medical School.
Researchers have been trying to get T-cells to recognize and kill ovarian cancer, renal cell carcinoma, and mesothelioma (the asbestos-caused form of lung cancer). In the past, the researchers had even developed a technique for getting T-cells to recognize antigens in CLL, but in all those cases, “responses have been limited and not overly impressive,” Porter said, namely because the T-cells never proliferated and didn’t stick around long enough to make a lasting impact.
As in previous attempts to engineer T cells, the researchers used a viral vector—in this case, part of the HIV virus—to infiltrate the T-cell, carrying with it a designed gene for an antibody to CD-19, a surface receptor found only on B-cells and CLL cancer cells. But this time, the group also added a gene for a more powerful stimulatory factor which activates T-cells and fuels their replication in the body.
To test the therapy, Porter and his colleagues withdrew a small number of T-cells from three patients with advanced-stage CLL, infected them with the virus, then expanded them in cell culture for 8 to 12 days. When injected back into patients, the modified T-cells replicated over a thousand fold and stuck to the CD-19 antigen on the cancer cells “like Velcro,” Porter said, then ripped the malignant cells apart. Two of the three patients experienced a complete remission that has persisted for a year. The third patient is stable and had a partial response, which doctors think may have been reduced because the immune-suppressing corticosteroids he received during the treatment decimated his engineered T-cell count.
The next step is to expand the treatment to a larger patient population to see if it achieves similarly successful results, Kohn said.
The therapy also caused a few side effects. Because mature B-cells also express CD-19, for example, the engineered T-cells didn’t distinguish between them and the cancer. As a result, the patients needed regular transfusions with immunoglobulin to replace the destroyed infection-fighting antibodies that B-cells provide. Whether there are other, more long-term consequences to the engineered T-cells remains to be seen, Kohn said
Furthermore, the malignant cells could eventually evolve a change in the CD-19 protein, thereby evading the T-cell killers and fueling the reemergence of cancer in the patients, Porter said. “It’s still too early to say they have been cured,” Porter said.
But if the therapy does proves successful long-term, the technique could also be developed for other cancers, which express other cell surface markers, said Renier Brentjens, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York who was not involved in the study. Finding a good candidate could be tricky, however, he added. “Not all cancers have convenient or acceptable target antigens such as CD-19, which is largely restricted to a small population of cells in the body.”
M. Kalos, et. al, "T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia," Science Translational Medicine, 3(95), 2011.