More Promise With Immunotherapy in Pediatric Leukemia

Fourth Modality Has Arrived

Nick Mulcahy

April 16, 2013

WASHINGTON, DC — T-cells, one of the centerpieces of the immune system, can be genetically engineered to attack leukemia in children, according to research presented here at the American Association for Cancer Research (AACR) 104th Annual Meeting.

The immunotherapy, known as anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, puts a patient's own immune cells through a laboratory process that results in the number of T-cells being greatly expanded, "fully activated," and then reinfused, explained Daniel W. Lee, MD, from the Pediatric Oncology Branch of the National Cancer Institute.

"Anti-CD19 CAR T-cell therapy is a completely new way to attack childhood leukemia," Dr. Lee told reporters at a meeting press briefing.

In a phase 1 trial, the experimental therapy demonstrated antileukemia activity in 3 of 3 children with acute lymphocytic leukemia (ALL).

A 13-year-old boy, who had relapsed after  bone marrow transplantation, had a complete response that lasted several months.

A 16-year-old girl, who had also relapsed after  bone marrow transplantation, had an early transient complete response, but is not yet fully evaluable.

Surprisingly, an 11-year-old girl, who had not undergone transplantation, had never been in remission, and was refractory to all treatment, including chemotherapy, had a complete response. "Hopefully, it will be curative for her," said Dr. Lee. The response allowed the girl to return to her primary oncologist for  bone marrow transplantation, he noted.

"Anti-CD19 CAR T-cell therapy can induce complete remission even when chemotherapy cannot," said Dr. Lee.

A fourth patient, a 10-year-old girl with B-cell lymphoma who had relapsed after bone marrow transplantation, did not respond to the new therapy and has had progressive disease.

Dr. Lee described the 11-day treatment process his team used. Researchers collected T-cells from the patient and modified them in the laboratory so that they attach to a protein (CD19) expressed by the ALL cells and attack the cancers. The number of modified T-cells — or anti-CD19 CAR T-cells — was expanded in the laboratory to counts of up to 1 million/kg; they were then returned to the patient. All patients were pretreated with fludarabine and cyclophosphamide prior to receiving the CAR-transduced T-cells.

The treatment was well tolerated and adverse effects were manageable; so far, there has been no evidence of graft-vs-host disease, Dr. Lee reported.

"Autologous collected anti-CD19 CAR T-cell therapy is a reasonable and potentially effective strategy," Dr. Lee and colleagues conclude in their abstract.

"This is a very hot area [in cancer research] — using chimeric antigen receptor T-cells," said press-briefing moderator Louis Weiner, MD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. He was not involved in the research.

CAR-modified T-cells targeting CD19 have also been effective in adults with B-cell lymphomas and chronic lymphocytic leukemia, Dr. Lee and his colleagues note.

In a recent report of 2 children with relapsed chemotherapy-refractive ALL from the Children's Hospital of Philadelphia in Pennsylvania, CAR-modified T-cells produced complete remission, as reported by Medscape Medical News (N Engl J Med. Published online March 25, 2013).

However, in meeting press materials, Dr. Lee suggested that the process developed at the National Cancer Institute is superior in terms of timing.

"We wanted something that could be done in a more timely manner. We decided to collect the immune cells, which are called T-cells, directly from the patients, even though they'd had bone marrow transplants," he explained.

Given all of the advances in pediatric and adult cancers, Dr. Weiner proclaimed that immunotherapy should now be recognized as the "fourth modality" for cancer, along with chemotherapy, radiation, and surgery.

Immunotherapies, especially monoclonal antibodies, represent "the fulfillment of a century-long dream first had by Dr. Paul Ehrlich in the early twentieth century about creating so-called magic bullets," Dr. Weiner noted. These kind of agents include the experimental nivolumab (GlaxoSmithKline), which was highlighted here in an AACR plenary session, as reported by Medscape Medical News.

ALL Is Leading Killer

There is a substantial need for more effective treatments in ALL, said Dr. Lee. ALL is the most common childhood malignancy. Although more than 95% of children initially diagnosed with ALL achieve remission, treatment is long (averaging 2 to 3 years), toxic, and costly, he said. Furthermore, many children relapse and, at that point, have a poor prognosis because treatment is "very limited." ALL is the leading cause of cancer death among children.

Dr. Lee and colleagues are continuing to test their method in patients whose disease has returned after, or is refractory to, standard treatments, whether or not they have undergone bone marrow transplantation.

"We think that the children who have never had a transplant might experience different toxicities," he said.

In the 4 patients treated to date, the safety profile was "acceptable," Dr. Lee said. The primary adverse effects have been fever, low blood pressure, and low blood counts. But these lasted "only a few days," he said, and they were all manageable in a hospital setting.

The study was funded by the National Cancer Institute and the St. Baldrick's Foundation. Dr. Weiner reports financial relationships with a number of pharmaceutical companies.

American Association for Cancer Research (AACR) 104th Annual Meeting: Abstract LB-138. Presented April 8, 2013.

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