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Newswise — WASHINGTON, D.C. — Researchers using patients’ own immune cells in an immunotherapy approach called “anti-CD19 chimeric antigen receptor (CAR) T-cell therapy,” achieved responses in children whose acute lymphocytic leukemia (ALL) had returned after a bone marrow transplant, according to preliminary results presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.
“Anti-CD19 CAR T-cell therapy using patients’ own immune cells is a completely new way of treating childhood cancer,” said Daniel W. Lee, M.D., assistant clinical investigator in the Pediatric Oncology Branch of the National Cancer Institute. “It is not chemotherapy; therefore, it has a different side effect profile — we hope better tolerated. In the limited number of post-transplant patients we have treated so far, we’re getting acceptable toxicities, and we’re not seeing graft-versus-host disease.”
More than 95 percent of children initially diagnosed with ALL achieve remission, but a significant number of them relapse, according to Lee. Once they relapse, the prognosis is poor, with ALL accounting for the most deaths from cancer among children.
Other research teams are testing anti-CD19 CAR T-cell therapy in children with ALL that has returned after a bone marrow transplant, according to Lee. However, whether they are using immune cells from the transplant donor, or collecting and preparing the patient’s cells, the process is lengthy.
“Often these children with relapsed ALL don’t have that kind of time to wait,” Lee said. “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.”
The first three patients in the phase I trial had undergone a previous bone marrow transplant, although the trial is also open to patients who have never had a transplant. One patient had B-cell lymphoma and the other two had ALL.
The researchers collected T cells from the patients and modified them in the laboratory so that they would attach to a protein expressed by the leukemia cells, called CD19, and attack the cancers. The number of modified T cells, now called anti-CD19 CAR T cells, was expanded in the laboratory before they were returned to the patients.
The results so far indicate that this approach is a feasible and active treatment for pediatric patients with ALL, even those who relapse after a bone marrow transplant, according to Lee. One patient had a complete response and a second had a transient complete response, with minimal residual disease remaining. The lone lymphoma patient did not respond.
Cell expansion was robust. “We were able to get very good expansion — on average about 60-fold expansion of these cells during the 11-day culture period,” Lee said. “And we were able to insert the receptor, the anti-CD19 CAR, into those T cells with good efficiency.”
One patient did not produce a sufficient number of cells, which was likely related to recent intensive chemotherapy and resultant low T-cell count, according to Lee. Despite this, the few cells the patient did receive expanded dramatically and the patient temporarily achieved remission.
Lee and colleagues continue to test this approach in patients whose disease has returned after, or is refractory to, standard treatments whether or not they have had a bone marrow transplant.
“We think that the children who have never had a transplant might experience different toxicities,” said Lee. “Our first patient enrolled in this arm of the trial had never achieved disease remission after her initial diagnosis of ALL despite intensive chemotherapy. Strikingly, anti-CD19 CAR T-cell therapy resulted in the complete clearance of any detectable leukemia in this patient, and we were able to send her back to her primary oncologists for a bone marrow transplant.”
Lee’s research was partially funded by the St. Baldrick’s Foundation. # # #
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Abstract Number: LB-138
Presenter: Daniel W. Lee, M.D.
Title: Autologous-collected anti-cd19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and B-cell Lymphomas in Children who have Previously Undergone Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Daniel W. Lee III, Nirali Shah, Maryalice Stetler-Stevenson, Marianna Sabatino, Kelly Richards, Cindy Delbrook, James N. Kochenderfer, Steven A. Rosenberg, David Stroncek, Crystal L. Mackall, Alan S. Wayne. National Cancer Inst., Burtonsville, MD
Relapsed and refractory pediatric acute lymphocytic leukemia (ALL) and B-cell lymphomas remain a difficult therapeutic challenge and account for a sizable number of cancer-related deaths in children despite the use of aggressive therapies such as HSCT. CAR modified T cells targeting CD19 have been effective in adults with B-cell lymphomas and chronic lymphocytic leukemia. These studies employed T cells either collected directly from non-HSCT patients or donor EBV-specific CTLs were isolated and cultured over several months before being modified with the CAR. To include children who have relapsed despite an allogeneic HSCT and deliver CAR T cells in a reasonable time frame, we developed an anti-CD19 CAR Phase I trial where T cells are collected directly from patients and manufactured in 11 days. Both HSCT-naïve and post-HSCT patients are eligible but enrolled on separate strata. Our CD19-CAR consists of a CD19-specific scFv and the CD28 and CD3ζ signaling domains. We report results with the first three patients, all of whom have undergone prior HSCT.
Peripheral blood (PB) mononuclear cells were collected on Day -11 by apheresis. In a semi-closed system, T cells were positively selected and activated by incubation with anti-CD3/anti-CD28 paramagnetic beads in IL-2 for 48 hours then transduced with the CD19-CAR gene via retroviral supernatant for an additional 48 hours. Additional expansion occurred over the next 7 days before cells were harvested for infusion. Patients were pre-treated with fludarabine (25 mg/m2/day on Days -4, -3, -2) and cyclophosphamide (900 mg/m2 on Day -2) prior to receiving 1x106 CAR-transduced T cells/kg.
A 59- to 65-fold expansion of CAR T cells with 39-65% transduction efficiency was achieved in 2 patients (ALL, DLBCL). 1 of these 2 achieved a complete response (CR). Mild cytokine release syndrome was observed in the responding patient manifested by Grade 3 fever and Grade 2 hypotension and correlated with mild elevation in IL-6, GM-CSF, INFγ and CRP. No other non-hematologic, CAR-related Grade 3 or 4 toxicities were observed. The third patient (ALL) only received 2.8% of the targeted CAR T cell dose due to lack of cell expansion, likely from prior clofarabine before apheresis, but experienced a transient CR and had the most pronounced expansion of CAR T cells (15% in PB, 5% in marrow, 6.2% in CSF) of any patient. Importantly, CAR T cell therapy was well tolerated without any evidence of graft-versus-host disease in these post-allogeneic HSCT patients. Altogether, these preliminary results indicate that autologous-collected anti-CD19 CAR T cell therapy in post-allogeneic HSCT patients is a reasonable and potentially effective strategy.
RSS