Safety and Efficacy of Fully-Human-Binder-Bearing CD19 CAR T-Cell Therapy for Large B-Cell Lymphoma after Failure of Murine-Binder-Bearing CD19 CAR T-Cell Therapy

Durable responses after CD19 CAR T-cell therapy are only achieved in 30-40% of relapsed/refractory large B-cell lymphoma (LBCL) patients (pts). Disease recurrence is associated with poor outcomes, with low efficacy of re-infusing the same CD19 CAR T-cell product, in part due to CD8+ T-cell responses against the CAR murine single chain variable fragment (scFv) (Gauthier, Blood, 2022). We conducted a phase 2 clinical trial in LBCL pts with recurrent disease after murine scFv-bearing CD19 CAR T-cell therapy to investigate the safety and efficacy of CD19 CAR T-cells bearing a fully human scFv (JCAR021; NCT03103971). Pts with relapsed or persistent CD19+ disease after prior response to a CD19-targeted non-JCAR021 CAR T-cell therapy were eligible. Planned sample size was 27; however, the study was terminated early (n=8 treated). Pts received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d. The starting CAR T-cell dose was 7x106 CAR T cells/kg. Cytokine release syndrome (CRS) and neurologic toxicity (NT) were graded according to Lee 2014 and CTCAE v4.03 criteria, respectively. Pt characteristics and outcomes are shown in Table 1 (n=8). Median age was 63 (range 41-77). Prior to LD, 4 pts (50%) had bulky disease (largest lesion ≥5cm). LDH was elevated in 6 pts (75%). Median lines of prior therapy was 5 (range 3-7). The prior CD19 CAR T-cell product was lisocabtagene maraleucel, n=4 (50%); axicabtagene ciloleucel, n=3 (37%); or tisagenlecleucel, n=1. Median time from first CAR T-cell infusion to JCAR021 infusion was 304 days (range 202-603). JCAR021 cell dose was 7x106 (n=6, 75%) or 2x106 CAR T-cells/kg (n=2, 25%; dose reduction due to grade 5 NT in subject #6). We observed grade 1 CRS in 2 pts, grade 2 CRS in 2 pts, and dose-limiting grade 5 NT in 1 patient (intracerebral hemorrhage with concurrent acute kidney injury and toxic encephalopathy). At day +28, responses (Lugano criteria) were seen in 3 of 8 pts (37%; CR, n=2; PR, n=1), all of whom were treated with 7x106 CAR T-cells/kg. The two CR pts had CR lasting ≥ 6 months from prior CD19 CAR T-cell therapy. In the two evaluable responders (death in CR, n=1), we observed disease relapse or progression within 3 months. Median overall survival was 105 days (95%CI, 92-NA). In all pts, we observed in vivo JCAR021 CAR T-cell expansion. However, compared to a separate cohort who received JCAR021 as their first CD19 CAR-T product, in vitro CAR T-cell expansion during manufacturing (CD8+ CAR T-cell fold increase, p<0.001) and in vivo CAR T-cell expansion (peak CD8+ CAR-T, p=0.002) were lower. In summary, fully-human-scFv-bearing CD19 CAR T-cells at 7x106 CAR T-cells/kg induced CRs in LBCL pts with relapse after previous ≥ 6 month CR to murine scFv-bearing CD19 CAR T-cells. However, response duration was short, and thus, the study was terminated early. Correlative studies are ongoing to better characterize potential mechanisms of treatment failure.