February 2014, Vol 3, No 1
Novel CAR-T Therapy Topped the News at ASH
Excitement was palpable at ASH this year over a novel approach to treating subtypes of leukemia and lymphoma. Although still limited to pilot studies in small numbers of patients, the findings for engineered T cells – so called CAR-T therapy – are very impressive. Patients with highly aggressive and refractory disease have had dramatic responses to therapy, achieving complete remissions and no longer demonstrating signs of tumor on CT scans. Some remissions are ongoing for up to 3 years.
“It looks like the disease has disappeared after a single infusion of these engineered T cells,” said James Kochenderfer, MD, from the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI).
The pace of research is rapid, with several pharmaceutical companies now working in partnership with the NCI and the University of Pennsylvania. Other studies are ongoing at MD Anderson Cancer Center. Researchers estimate the therapy could become available as early as 2016.
The approach takes advantage of the fact that the CD19 protein is expressed almost universally on B cells. The process involves extracting T cells from the patient, subjecting the cells to chimeric antigen receptor (CAR) cell engineering, and then infusing the engineered T cells back into the patient. The engineering takes about 10 days and alters the T cell through 1) the addition of a receptor that targets the CD19 antigen on leukemic cells, and 2) the insertion of a viral vector into the cells that triggers the T cells to expand, proliferate, and seek out and destroy all remaining cancer cells.
Michael Kalos, PhD, from the University of Pennsylvania, maintained that engineered T cells are “poised to replace bone marrow transplants with a therapy that is less expensive and is more widely available.”
NCI Study Results in Lymphoma
Kochenderfer presented results from the NCI’s study of 15 adult patients with advanced B-cell lymphomas, including 9 patients with chemotherapy-refractory disease (some with up to 10 prior lines of treatment). Patients received reduced-intensity conditioning and then an infusion of their own T cells that had been CAR engineered. Of 13 evaluable patients, 12 responded: 7 patients had complete remissions, 5 had partial remissions, and 1 had stable disease.
“Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” Kochenderfer said at a press briefing.“We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options…and who are not generally thought to be good candidates for hematopoietic stem cell transplantation,” he added.
Lymphoma patients are also being treated at MD Anderson Cancer Center, with a nonviral gene transfer approach that expresses “second-generation” CD19-specific T cells. Four patients with non-Hodgkin lymphoma treated with a high T-cell dose are in remission after 3 months, according to Partow Kebriaei, MD.
Summary of Trial Data in CLL and ALL
Kalos summarized the clinical results to date for adult patients with advanced relapsed or treatment-refractory chronic lymphocytic leukemia (CLL) and both adult and pediatric patients with treatment-refractory acute lymphocytic leukemia (ALL).
In 2 studies, 32 adult patients with CLL have been treated, of whom 15 achieved partial responses and 7 achieved complete responses. All of these complete responses are ongoing, Kalos reported.
Coinvestigator at the University of Pennsylvania, David Porter, MD, added, “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.”
“We’ve now seen remissions lasting for more than 3 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,” Porter said.
Also at the University of Pennsylvania, 22 children with ALL have been treated, of whom 19 (86%) achieved a complete response, which is ongoing in 14 patients. Five adults with ALL have been treated, all achieving a complete response and 4 of which are ongoing, some out to 18 months.
“Our results demonstrate the potential of this treatment for patients who truly have no other therapeutic option,” said Stephan Grupp, MD, a coinvestigator. “In the relatively short time that we’ve observed these patients, we have reason to believe that this treatment could become a viable therapy for their relapsed, treatment-resistant disease.”
The treatment is not without toxicity. Most patients have developed cytokine release syndrome, which produces high fever, hypotension, respiratory problems, delirium, and other concerning symptoms that usually require a stay in the intensive care unit. However, most patients recover within 2 days, and symptoms resolve within 3 weeks.
Grupp said the symptoms associated with delayed cytokine release can be severe but can be managed with the monoclonal antibody tocilizumab, which he called a “game changer” for controlling these toxicities.
Those frustrated with low long-term remission rates in adult acute lymphocytic leukemia (ALL) can find hope in the superior outcomes associated with treatment for pediatric ALL. Overall survival with therapy reaches 85% in children but lags at 45% in adults. Targeting specific pathways and adding novel agents to standard therapy [ Read More ]
Obinutuzumab, a novel, glycoengineered, type II CD20 antibody, in combination with chlorambucil was superior to rituximab plus chlorambucil in prolonging progression-free survival (PFS) in previously untreated patients with chronic lymphocytic leukemia (CLL) with comorbidities. Treatment with obinutuzumab also led to a significantly higher objective response rate, and more patients treated [ Read More ]