“Perhaps the 4-1BB signal is durable enough to enable a sustained attack against a large tumor burden, which we see in CLL,” Sadelain said.
The median number of previous treatments administered to patients in the CLL group was five (range, 2-10). All patients had active disease when clinicians administered the infusion and had received lymphodepleting chemotherapy 4 to 6 days before infusions. One-third of the CLL cohort had disease with a p53 deletion.
One of the children with ALL had chemorefractory relapsed disease and was treated with chemotherapy 6 weeks before the infusion.
“Patients were conditioned with bendamustine, to which the patients were sensitive,” Sadelain said. “This teaches us that using an agent to which the tumor is sensitive may be very important, and that chemotherapy conditioning is likely integral to outcomes.”
By day 23 of the study by Porter, June and colleagues, five patients — three adults in the CLL group and the two children with ALL — demonstrated a complete response. Four patients in the CLL group demonstrated partial response.
The findings signify the first sustained demonstration that gene therapy can turn the body’s immune cells can be converted into a weapon against cancerous tumors, the researchers said.
“Our results show that chimeric antigen receptor modified T cells have great promise to improve the treatment of leukemia and lymphoma,” June, the Richard W. Vague professor in immunotherapy in the department of pathology and laboratory medicine and director of translational research at Penn’s Abramson Cancer Center, said in a press release. “It is possible that in the future, this approach may reduce or replace the need for bone marrow transplantation.”
The patients who demonstrated complete response showed maximal expanded cells in the blood. The researchers detected these at an average of 27-fold (range, 21-fold to 40-fold) higher than the infused dose. These patients also demonstrated elevations from baseline in interferon-gamma, interleukin-6 and IL-2R, but no significant elevation in tumor necrosis factor-alpha or IL-2.
No relapses have been reported among the patients who demonstrated complete response.
“There appear to be two keys to this result. One is that cytokines are made, and the other is that the T cells proliferate,” said Laurence J.N. Cooper, MD, PhD, who was involved with the study by Porter and colleagues.
“The proliferation is the finding that we feel is most significant. When their T cells were administered to the recipient, they synchronously activate and numerically expand,” Cooper, professor in pediatrics at The University of Texas MD Anderson Cancer Center and section chief of cell therapy at Children’s Cancer Hospital, said in an interview.
That expansion is responsible for the durability of the remission, according to Mitchell Smith, MD, PhD, director of lymphoid malignancies at Cleveland Clinic Taussig Cancer Institute.
“What is impressive is that these cells have persisted, expanded and grown for a long time,” Smith said. “These cells continue to kill off cells that express CD19.”
Most clinicians, including Smith, agree that such results will not occur in all
“But it certainly is exciting if you are a responder,” he said.
The clinical challenge is to identify why certain patients in the Porter study and other investigations responded to this therapy and others did not.
“We are all analyzing those data, trying to figure out what the differences were between the responders and the nonresponders, and why — after years of attempting this strategy — this result was achieved in this particular subset of patients,” Sadelain said. “There have not been enough patients treated yet to obtain statistically robust biological and clinical correlative data.”
A review article by Davila and colleagues published last year in Oncoimmunology summarized data from six clinical trials that investigated the use of T cells to target CD19+ malignancies. They reported data for 28 patients, including 22 with CLL.