Novel CAR-T Therapy Topped the News at ASH 2013

Impressive results in treating subtypes of leukemia, lymphoma
February 2014 Vol 7, No 1, Special Issue ASH 2013 Payers' Perspectives in Oncology

New Orleans, LA—Excitement was palpable at the 2013 ASH meeting over a novel approach to treating subtypes of leukemia and lymphoma. Although still limited to small pilot studies in small numbers of patients, the findings for engineered T-cells—so-called chimeric antigen receptor (CAR)-T therapy­—are very impressive. Patients with very aggressive and refractory disease have had dramatic responses to therapy, achieving complete remissions and no longer demonstrating signs of tumor on computed tomography scans. Some remissions are ongoing for up to 3 years, at this point.

“It looks like the disease has disappeared after a single infusion of these engineered T-cells,” said James N. 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 M.D. Anderson Cancer Center, Houston, TX. Researchers estimate that 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 CAR cell engineering, and then infusing the engineered T-cells back into the patient. The engineering takes approximately 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, Adjunct Associate Professor of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 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
Dr 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 previous lines of treatment). The patients received reduced-intensity conditioning, followed by an infusion of their own T-cells that had been CAR-engineered. Of 13 evaluable patients, 12 responded: 5 patients had complete remissions, 6 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,” Dr 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.

Patients with lymphoma are also being treated at M.D. Anderson Cancer Center, with a nonviral gene transfer approach that expresses “second-generation” CD19-specific T-cells. Four patients with non-Hodg­kin lymphoma who were treated with a high T-cell dose are in re­mission after 3 months, according to Partow Kebriaei, MD, Associate Professor, Department of Stem Cell Transplantation, M.D. Anderson Can­cer Center.

Summary of Trial Data from Patients with CLL and ALL
Dr Kalos summarized the clinical results to date for adult patients with advanced relapsed or treatment-refractory chronic lymphocytic leukemia (CLL), and for adult and pediatric patients with treatment-refractory acute lymphocytic leukemia (ALL).

In 2 studies, 32 adult patients with CLL have been treated with engineered T-cells, of whom 15 achieved partial responses and 7 achieved complete responses. All of these complete responses are ongoing, Dr Kalos reported.

Coinvestigator David L. Porter, MD, Jodi Fisher Horowitz Professor in Leukemia Care Excellence, University of Pennsylvania, 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,” Dr Porter said.

Also at the University of Pennsylvania, 22 children with ALL have been treated with engineered T-cells, of whom 19 (86%) achieved a complete response, which is ongoing in 14 patients. A total of 5 adults with ALL have been treated, and all achieved a complete response—4 of which are ongoing—some as long as 18 months.

“Our results demonstrate the potential of this treatment for patients who truly have no other therapeutic option,” said coinvestigator Stephan A. Grupp, MD, PhD, Director of Translational Research, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia. “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.”

Toxicity Profile
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.

Dr Grupp said that 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. n

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