In an interim analysis of a small phase I study reported in The New England Journal of Medicine, Chiesa et al found that base-edited CAR7 T cells were active in pediatric patients with relapsed T-cell acute lymphoblastic leukemia (ALL).
As stated by the investigators: “Cytidine deamination that is guided by…CRISPR can mediate a highly precise conversion of one nucleotide into another—specifically, cytosine to thymine—without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is currently being investigated.”
Study Details
Base editing was used to generate universal, off-the-shelf chimeric antigen receptor (CAR) T cells. T cells from healthy donors were transduced using a lentivirus to express a CAR with specificity for CD7 (CAR7), a protein expressed in T-cell ALL. Base editing was used to inactivate three genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-vs-host disease.
The current analysis involved use of base-edited CAR7 in three pediatric patients.
Key Findings
In one 13-year-old patient with relapsed T-cell ALL after allogeneic stem cell transplantation (SCT), complete morphologic remission and molecular remission were achieved within 28 days after infusion of a single dose of base-edited CAR7. The patient then received reduced-intensity (nonmyeloablative) allogeneic SCT from the original donor and had successful immunologic reconstitution and ongoing leukemic remission.
A second 13-year-old patient diagnosed with T-cell ALL 3 years prior to study enrollment experienced relapse while receiving maintenance treatment. After a base-edited CAR7 infusion, the patient achieved morphologic remission within 28 days, with evidence of residual disease; however, the patient died of complications of a fungal infection on day 33.
A third patient who was 15 years old had undergone allogeneic SCT. With detection of residual disease, two donor lymphocyte infusions were performed, followed by relapse. After a base-edited CAR7 infusion, the patient had complete morphologic remission and molecular remission by day 28 and was able to undergo consolidative matched, unrelated donor allogeneic SCT during remission.
Serious adverse events in patients receiving base-edited CAR7 infusions included cytokine-release syndrome, multilineage cytopenia, and opportunistic infections.
The investigators concluded: “The interim results of this phase I study support further investigation of base-edited T cells for patients with relapsed leukemia and indicate the anticipated risks of immunotherapy-related complications.”
Waseem Qasim, MB, BS, PhD, of the Great Ormond Street Hospital for Children NHS Trust, London, is the corresponding author of The New England Journal of Medicine article.
Disclosure: The study was funded by the UK Medical Research Council and others. For full disclosures of the study authors, visit nejm.org.
