Two of the first three chronic lymphocytic leukemia (CLL) patients who participated in the study, which started in the summer of 2010, remain in remission, with tests revealing reprogrammed cells still circulating in their bodies, on guard to combat tumor cells that may reappear in the future. Additional highlights of the new research results include an 89 percent complete response rate among adult and pediatric patients with acute lymphoblastic leukemia (ALL).

"In a very short time, we've learned so much about how CTL019 works and how powerful it can be," said the research team's leader, Carl H. June, MD, Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine and director of Translational Research in Penn's Abramson Cancer Center. "Our findings show that the human immune system and these modified 'hunter' cells are working together to attack tumors in an entirely new way."

The research team, which includes investigators who treat patients at both the Hospital of the University of Pennsylvania and the Children's Hospital of Philadelphia, will announce findings from trials of three different groups of patients:

• 15 of 32 adult patients with CLL (47 percent) responded to the therapy, with seven of those experiencing a complete remission of their disease. Results of both the completed pilot study of 14 CLL patients and results thus far of the first 18 patients in a Phase II, dose-optimization trial will be presented.

• 19 of 22 pediatric patients with ALL (86 percent) experienced complete remissions. The first pediatric patient treated with the protocol, who is now 8 years old, remains in remission 20 months later. Five patients have relapsed, including one whose tests revealed new tumor cells that do not express the protein targeted by the reprogrammed cells.

• All five of the first adult ALL patients treated thus far experienced complete remissions, the longest of which continues six months after treatment. One patient subsequently underwent a bone marrow transplant and remains in remission. One patient relapsed after three months with disease that also tested negative for the engineered cell target.

Building a Cancer-Killing CAR

The investigational treatment pioneered by the Penn team begins by removing patients' T cells via an apheresis process similar to blood donation, then reprogramming them in Penn's cell and vaccine production facility with a gene transfer technique using a lentivirus vector. The newly built T cells target tumor cells using an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19, which is found on the surface of the cancerous B cells associated with both CLL and ALL.

The modified cells are then infused back into the patient's body following lymphodepleting chemotherapy. In the body, these "hunter" T cells both multiply and attack. A signaling domain built into the CAR promotes rapid growth of these cells, building an army of tumor-killing cells that tests reveal can grow to more than 10,000 new cells for each single engineered cell patients receive. Cells in the patient that do not express CD19 are left untouched by the modified T cells, which limits the prolonged, systemic side effects typically experienced during traditional cancer therapies that harm healthy tissue.

Treatment Prompts High Response Rates, Durable Remissions

Taken together, the newly announced results show promise for a range of tough-to-treat blood cancers. All study patients had exhausted conventional treatment options. In many cases, they were ineligible for bone marrow transplantation or declined that option due to the risks associated with the procedure, which carries at least a 20 percent mortality risk.

"We are tremendously excited about these results. About half of our CLL patients responded to this therapy, with most of them having several pounds of tumors eradicated by the genetically modified T cells," says study author David L. Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of Blood and Marrow Transplantation in Penn's Abramson Cancer Center, who will present the two CLL trial abstracts during the meeting. "We've now seen remissions lasting for more than three years, and there are clues that the T cells continue to kill leukemia cells in the body for months after treatment: Even in patients who had only a partial response, we often found that all cancer cells disappeared from their blood and bone marrow, and their lymph nodes continued to shrink over time. In some cases, we have seen partial responses convert to complete remissions over several months."

The research team is especially encouraged by the early results among ALL patients, since that disease progresses rapidly and is very deadly among those who relapse after standard treatments. About 85 percent of pediatric patients with the disease are cured with first-line therapies, but those whose cancers relapse and/or become refractory have limited options. And while most adults with ALL respond to drug treatment, as many as half ultimately relapse, putting the overall cure rate for the disease among adults at only around 40 percent. New therapies for both these groups of high-risk patients are acutely needed.

"Our results serve as another important milestone in demonstrating the potential of this treatment for patients who have no other therapeutic options," said study author Stephan A. Grupp, MD, PhD, of the Children's Hospital of Philadelphia and a professor of Pediatrics at the Perelman School of Medicine. "These data also demonstrate that these engineered 'hunter' cells greatly expand and then persist in patients, allowing for long-term disease control. We are looking forward to testing these cells in upcoming multicenter pediatric and adult trials."

During the pilot study for CLL, patients received a wide range of cell doses, but the Penn team saw no relationship between the number of cells infused and the responses or toxicities associated with the therapy. To refine the treatment approach, the Penn team launched a randomized Phase II study comparing two different doses, each of which is given as a single outpatient infusion. So far, however, the team has again seen no difference in which amount of cells is more effective or associated with greater toxicities.

Tests Pinpoint Cause, Management Technique for Side Effects

In the trials for both CLL and ALL, all responding patients experienced a cytokine release syndrome that the researchers now know marks the process of the engineered cells multiplying and attacking tumor cells in the body. During this time, patients typically experience varying degrees of flu-like symptoms, with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. The team has learned this reaction can be managed, if necessary, using tocilizumab, an immunosuppressant drug which tamps down elevated levels of the inflammatory cytokine IL-6, which have been found to spike during the most robust phase of the engineered cells' expansion in the body.

Tests of both CLL and ALL patients who experienced complete remissions also show that normal B cells, which also express the CD19 protein, have been eliminated along with their tumors. The researchers note that persistent loss of normal B cells is a good surrogate marker for continued activity of the gene-modified T cells. In this way, the cells appear to be providing long-term vaccine-like activity preventing B cells -- and presumably tumor cells -- from growing back. B cells are important for the body's immune system to fight infection by making antibodies, though it is possible to replace antibodies with gamma globulin treatments as a preventive measure.