Phase 1 study of CD19 CAR T-cell therapy harboring a fully human scFv in CAR-naïve adult patients with B-ALL

Abstract

CD19-directed chimeric antigen receptor-engineered (CAR) T-cell therapy elicits high response rates but fails to induce durable responses in most adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). In a previous clinical trial, we observed anti-CAR immune responses associated with impaired in vivo CAR T-cell expansion after second infusions. Because these CD8+ T-cell responses were predominantly directed at peptides derived from the murine single-chain variable fragment (scFv) in the CAR, we conducted a clinical trial investigating the safety and efficacy of CD19 CAR T-cells engineered with a CAR incorporating a fully human scFv (JCAR021) in adults with R/R B-ALL (NCT03103971). Twenty-three patients received lymphodepletion chemotherapy and JCAR021 infusion. Nineteen patients developed cytokine release syndrome (any grade, 83%; grade 2, 61%) and 12 developed neurotoxicity (52%; grade ≥3, 35%). The overall response and complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 82% and 64%, respectively. We observed measurable residual disease-negative bone marrow (BM) responses in 82% of those with BM disease and extramedullary responses by positron emission tomography-computed tomography in 79% (CR, 50%) of those with measurable fluorodeoxyglucose-avid disease. The median duration of remission (DOR) was 10 months with a 4-year DOR probability of 29%. Four patients underwent allogeneic hematopoietic cell transplantation while in CR/CRi after JCAR021. Durable remissions were observed in patients with low BM disease burden. In contrast, the DOR was limited in those with high BM burden. We observed similar outcomes in CAR-naïve adult patients with B-ALL receiving CD19 CAR T cells expressing a fully human or murine scFv-containing CAR. This trial was registered at www.ClinicalTrials.gov as #NCT03103971.

Graphical abstract

Figure 1.

Patient flow diagram. HMB: >5% blasts in BM before LD chemotherapy by morphology or MFC; LMB: ≤5% blasts in BM before LD chemotherapy.

Figure 2.

Best response rates after JCAR021 CD19 CAR T-cell therapy. (A) Overall response by NCCN criteria. (B) MRD-negative BM response by MFC in patients with measurable BM disease before LD. (C) EM PET-CT response by NCCN imaging criteria in patients with FDG-avid measurable EMD before LD. ORR, overall response rate; PR, partial response.

Figure 3.

Long-term outcomes after JCAR021 CD19 CAR T-cell therapy. Kaplan-Meier estimates for (A) OS; (B) RFS; (C) DOR; and (D) cumulative incidence of relapse in CR/CRi patients after JCAR021 with death and allo-HCT as competing events, landmarked at day +28.

Figure 4.

Clinical course relative to in vivo CAR T-cell persistence and B-cell recovery in CR/CRi patients after JCAR021 data from 14 patients in CR/CRi after JCAR021 treatment. Black horizontal bars, follow-up duration. Due to severe leukocytosis, patient ALL-HMB-3 had ≤1% B cells in a CD45⁺ leukocyte gate at the time of relapse, but a B-cell count of 94/μL, indicating B-cell recovery had occurred.