Preliminary Progress with Genetically Engineered T Cells in Treating Childhood ALL 

Get Permission

Anti-CD19 CAR T cells represent a unique way to attack childhood leukemia. Preliminary evidence suggests that we can induce complete remission in patients refractory to other therapies.

—Daniel W. Lee, MD

Two small phase I studies at separate centers demonstrated encouraging results in the treatment of children with acute lymphoblastic leukemia (ALL) using reinfused autologous genetically engineered T cells. Results of both studies were presented at the Annual Meeting of the American Association for Cancer Research (AACR) in Washington, DC.1,2 These studies add to a growing body of small early clinical trials suggesting that the technique can achieve complete remission of leukemia in children with limited treatment options.

The treatment, called anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, involves collection of the patient’s own immune cells, which are then genetically modified and expanded in the laboratory to attach to the CD19 protein expressed on the surface of ALL cells. The modified cells are then reinfused into the patient.

The technique is under study in children at several centers, including the Pediatric Oncology Branch at the National Cancer Institute, Children’s Hospital of Philadelphia, Memorial Sloan-Kettering Cancer Center, and the Fred Hutchinson Cancer Research Center. Each center employs modifications of the technique related to in vitro expansion and genetic modification of the cells, but all the centers are using autologous T cells modified to recognize the CD19 antigen. CAR T-cell therapy is also being explored in adults with chronic lymphocytic leukemia (CLL, see sidebar).

NCI Study

The first study1 included four patients aged 10 through 16. Following treatment with the genetically engineered T cells, one of two patients with ALL previously treated with bone marrow transplantation achieved complete responses, while a third child with ALL who had never been in remission despite intensive chemotherapy achieved a minimal residual disease–negative complete response. A fourth child with B-cell non-Hodgkin lymphoma who had a prior bone marrow transplant had progressive disease despite the T-cell therapy. It was too early to evaluate a fifth child who had been treated.

Presenting author Daniel W. Lee, MD, Assistant Clinical Investigator in the Pediatric Oncology Branch of the NCI in Bethesda, Maryland, said, “Childhood ALL is the most common malignancy in pediatric patients. The majority of children can achieve remission, but this comes with the price of long therapy, toxicity, and cost, with no guarantee of long-term cure. Children who relapse have limited therapeutic options, and new therapies are sorely needed.”

The first four patients to undergo the technique at NCI were treated with fludarabine and cyclophosphamide prior to receiving the CAR T cells. Side effects were temporary and not seen in every patient, Dr. Lee continued. They included fever, low blood pressure, and low blood counts and were easily managed in hospital. No evidence of graft-vs-host disease was observed in the three post-transplant patients who had undergone previous bone marrow transplantation.

“Anti-CD19 CAR T cells represent a unique way to attack childhood leukemia. Preliminary evidence suggests that we can induce complete remissions in patients refractory to other therapies,” Dr. Lee stated.

Philadelphia Study

The second study2 treated five pediatric patients with CAR T-cell therapy. Four of the first five patients achieved complete responses, said study coauthor David M. Barrett, MD, Instructor in Pediatric Oncology at The Children’s Hospital of Philadelphia. Three of these complete responses have been durable, with the longest response being 12 months (range, 2–12 months), and one was transient. The fifth patient did not respond.

“The main takeaway message is that this therapy is effective in pediatric ALL. We are learning about the toxicity. The toxicity is significant but manageable. We need to learn more about how the leukemia can escape by removing its CD19 expression.” Dr. Barrett said.  “This therapy has the potential to save lives when chemotherapy cannot.”

In children, one of the important toxicities is the macrophage activation syndrome, also called hemophagocytic lymphohistiocytosis, which is part of the cytokine release syndrome—the part most responsible for hypotension and fever. Interrupting macrophage activation syndrome with tocilizumab (Actemra), an antirheumatic drug, can alleviate the toxicity, without potentially interfering with the therapeutic response, Dr. Barrett explained.

“We have seen the success of this therapy sustained and reproduced at other centers,” Dr. Lee stated. “Going forward in children, the technique will be studied as a potential alternative to bone marrow transplantation or some of the harsh conditioning associated with transplant. In the future we hope the technique, along with chemotherapy, will be studied in newly diagnosed children in an effort to minimize the chance of relapse and the subsequent need for additional chemotherapy or bone marrow transplantation. We are excited to pursue this. Further study is needed to characterize the long-term effects of this therapy because normal B cells can also be affected,” he added.

Dream Team Grant

The successes of these two studies and other reports from investigators at Memorial Sloan-Kettering Cancer Center and Fred Hutchinson Cancer Center have led to a “dream team” collaboration supported by a grant from SU2C (Stand Up To Cancer) to study immunogenomics and immunotherapy for treatment of high-risk pediatric cancers.

“The primary method of delivering immunotherapy is via the chimeric T cells,” Dr. Barrett explained.

Part of the SU2C’s dream team grant is for a collaboration among Children’s Hospital of Philadelphia, Pediatric Oncology Branch of the NCI, Fred Hutchinson Cancer Center, Baylor Medical Center, the University of Wisconsin, the Hospital for Sick Children in Toronto, and the University of British Columbia in Vancouver. This joint effort will integrate the experience at these centers with chimeric receptors and standardize and expand the approach in order to move forward with the treatment in children, Dr. Barrett said.

“There has been enough sustained success with the technique that the dream team is now possible. This therapy can put patients into remission who have no other treatment option, and it looks like it can be widely applicable with durable responses. There hasn’t been anything like this to treat cancer in a long time,” he noted.

“The biggest parallel I can think of was radiation therapy for central nervous system leukemia, which had a profound and dramatic increase in survival for children with leukemia. Very few discoveries have matched that level of impact,” Dr. Barrett continued. ■

Disclosure: Drs. Lee and Barrett reported no potential conflicts of interest.


1. Lee DW, Shah N, Stetler-Stevenson M, et al: Autologous-collected anti-CD19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and B-cell lymphoma in children who have previously undergone allogeneic hematopoietic stem cell transplant. AACR Annual Meeting. Abstract LB-138. Presented April 8, 2013.

2. Grupp S, Kalos M, Barrett DM, et al: Use of CD19-targeted chimeric antigen receptor-modified T (CART19) cells in ALL and CLL produce transient cytokine release syndrome, macrophage activation syndrome, and durable responses. AACR Annual Meeting. Abstract 4574. Presented April 9, 2013.

Related Articles

SIDEBAR: Personal Testimonial: CAR-modified T Cells in Adults

Twelve adults with chronic lymphocytic leukemia (CLL) have been treated with CD19-targeted chimeric antigen receptor (CAR) T-cell therapy at the University of Pennsylvania in Philadelphia by Carl June, MD, Richard W. Vague Professor in Immunotherapy, and colleagues. These were all end-stage...

Expert Point of View: Richard Bram, MD, PhD

“This is a very exciting breakthrough even though it is preliminary at this point. Previous immune approaches to cancer that initially looked promising have often turned out to have durable responses, therefore we need to study this new technology in controlled clinical trials before it is widely...