By tripping two parallel "on switches" at once, instead of the customary single switch, physicians at the University of Chicago Medical Center may at last have found a way to bring the full power of the immune system into play against cancer. Early results from the first clinical trial of this approach will be presented December 5th at the American Society of Hematologists meeting in Miami Beach, Florida.
This phase-1 clinical trial -- designed not to assess effectiveness but to determine the optimal dose and measure toxicity -- involved patients with advanced or recurrent lymphoma who had not responded to prior chemotherapy. Although patients in phase-1 studies like this rarely have a lasting recovery, several of those enrolled in this trial have experienced noteworthy anti-tumor effects.
"When you consider that none of these patients had responded to any other therapy, you can begin to understand our enthusiasm," said David Liebowitz, M.D., Ph.D., director of stem-cell transplantation at the University of Chicago and principal investigator of the study. "Although this is a complex and difficult treatment regimen, all the early signs suggest that it can be a uniquely effective one."
The treatment is based on recent recognition of the importance of "co-stimulation" in triggering an immune response. Previous efforts to activate the immune system have relied on stimulation of a single signaling system, the T-cell receptor for antigen, known as CD3, a cell-surface molecule that recognizes foreign tissue.
Nearly ten years ago, however, Chicago researchers Craig Thompson and Jeffrey Bluestone and others discovered that the immune system often requires two parallel lines of communication -- through both CD3 and a second receptor, known as CD28 -- before girding for battle. Stimulation of both CD3 and CD28 triggers an aggressive immune response; tweaking only CD3 produces little or no response.
"This discovery addresses the basic question facing cancer immunotherapy," said Liebowitz: "Why are the T cells that should attack tumors content to sit idly by? Previous efforts to jump start an immune response have not been able effectively to reverse the immune tolerance that develops between a patient's T cells and their cancer."
But by growing billions of a patient's T cells in the laboratory, away from tumor cells and under constant co-stimulation with CD3 and CD28, Liebowitz's team has been able to reactivate the immune response, returning a population of aggressive, "motivated" cells to seek out and attack cancerous cells.
"Co-stimulation gives us a completely different population of T cells," said Liebowitz. Prior attempts have produced large numbers of cytotoxic T cells, which are the end product of an immune response. Growth in the presence of CD3 and CD28, however, produces primarily T-helper cells, so called because they coordinate the actions of the entire immune system."
This is the only system currently in use that favors the growth of T-helper cells over cytotoxic cells.
A few weeks after receiving their new, improved T-helper cells, some patients have experienced fevers and lethargy while their T-cell counts continue to rise. Over the following weeks and months, much too slowly to be a late response to prior chemotherapy, their tumors get smaller and in some cases have disappeared.
"We know we are affecting the immune response with this therapy because the toxicities we have seen after reinfusion look exactly like autoimmune disorders," (in which an over-aggressive immune system attacks its host) said Liebowitz.
Although the side effects of reinfusing the rejuvenated T cells appear to be limited, the entire treatment protocol is quite rigorous. Treatment involves collecting and storing stem cells from the patient's blood, administering high-dose chemotherapy which destroys the bone marrow, then giving the patient his stem cells back to repopulate the marrow. Fourteen days later, the patients receive their expanded, co-stimulated T cells.
So far the team has enrolled nearly 20 patients. Some are still receiving therapy. Because of advanced disease, rapid progression of the cancer during therapy, or the difficulties of harvesting and growing T cells, only eight patients have so far received their expanded T cells.
Six of those eight patients have had what appear to be complete remissions, but it remains unclear how long they will last. After an average of 305 days, two of those patients had relapsed. The recurrent disease "in some cases," said Liebowitz "appears to be less aggressive."
"We can't claim to have cured anyone," added Liebowitz, "but we seem to have altered the natural history of the disease, to have significantly slowed progression in selected patients."
The co-stimulation technology, which uses tiny magnetic beads covered with monoclonal antibodies to CD3 and CD28, was developed and patented by Thompson at the University of Chicago and Dr. Carl June at the Uniformed Services University of the Health Sciences. The University of Chicago's ARCH Development Corporation has licensed the technology for development to Xcyte Therapies, based in Seattle. Thompson, Bluestone and June are founding scientists at the company.