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

• Published in: Transplantation and cellular therapy Vol. 30; no. 2; p. S186
• Main Authors: Huang, Jennifer J., Hirayama, Alexandre V, Jaeger-Ruckstuhl, Carla A, Liang, Emily C., Albittar, Aya, Portuguese, Andrew J., Wuliji, Natalie, Wu, Vicky, Torkelson, Aiko, Kirchmeier, Delaney R., Chutnik, Abigail, Pender, Barbara S., Shadman, Mazyar, Till, Brian G, Kimble, Erik L., Iovino, Lorenzo, Chapuis, Aude G., Otegbeye, Folashade, Cassaday, Ryan D., Milano, Filippo, Poh, Christina, Gopal, Ajay K, Riddell, Stanley R., Maloney, David G., Gauthier, Jordan, Turtle, Cameron J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.02.2024
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2023.12.241

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.