title: CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL).
abstract: Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults. Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major preclinical and clinical priority. Adoptive cellular therapy with patient-derived human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CD19 CAR T cells) is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with multiply relapsed B-ALL. Investigative teams at several major cancer centers are currently conducting phase I clinical trials in children and/or adults with relapsed/refractory B-ALL to assess the safety and to identify the maximally tolerated dose of each group's CD19 CAR T-cell product. All groups have reported major clinical toxicities associated with CD19 CAR T-cell treatment, including cytokine release syndrome (CRS) and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19 CAR T cells persist in vivo. Toxicities have generally been transient or manageable with supportive care measures. Some patients with life-threatening CD19 CAR T-cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T-cell proliferation. Remarkably, 67-90% of children and adults with B-ALL treated with CD19 CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission. The duration of CD19 CAR T cell persistence in vivo has varied appreciably among treated patients and likely reflects differences in the CD19 CAR constructs utilized at each institution. CD19-positive and CD19-negative B-ALL relapses after CD19 CAR T-cell treatment have occurred in some patients. Phase II trials to assess the efficacy of CD19 CAR T-cell immunotherapy in larger cohorts of patients with relapsed/refractory B-ALL are ongoing or planned.
authors.affiliation: Children's Hospital of Philadelphia, Division of Oncology and Center for Childhood Cancer Research; University of Pennsylvania Perelman School of Medicine, Department of Pediatrics and Abramson Cancer Center; 3501 Civic Center Boulevard, CTRB 3010, Philadelphia, PA 19104, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.affiliation: Division of Hematology/Oncology and Ben Towne Center for Childhood Cancer Research/Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, USA and University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Gardner
keywords: B cell; CD19; T cell; acute lymphoblastic leukemia; chimeric antigen receptor; cytokine release syndrome; immunotherapy; pediatric