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.

Keywords: B cell; CD19; T cell; acute lymphoblastic leukemia; chimeric antigen receptor; cytokine release syndrome; immunotherapy; pediatric.

Figure 1.

Generations of chimeric antigen receptors (CARs) utilized in clinical testing. Constructs encoding synthetic CARs targeting tumor-associated antigens (such as CD19) can be stably transduced into human T cells for infusion into patients with relapsed/refractory cancer. CARs are comprised of (1) an extracellular MHC-independent antigen-binding domain usually derived from a monoclonal antibody single chain variable fragment (ScFv), (2) an extracellular spacer domain or ‘hinge’ (in some CARs), (3) a transmembrane linking domain and (4) an intracellular co-stimulatory T cell signaling domain or multiple domains.

Figure 2.

Binding of CD19 CAR T cells to CD19-expressing cells can induce potent on target/on tumor and on target/off tumor sequelae. B-ALL, B-cell acute lymphoblastic leukemia; CNS, central nervous system.