Durable Remission Following “Off-the-Shelf” Chimeric Antigen Receptor (CAR) T-Cells in Patients with Relapse/Refractory (R/R) B-Cell Malignancies

Introduction CAR T-cells provide benefit in patients (pts) with R/R hematologic malignancies. Limitations including: cost, production complexity, and life-threatening toxicity impede this therapy. An \"off-the-shelf\" CAR product could overcome these limitations. Objectives/Methods We developed an \"off-the-shelf\" CD19-specific CAR T-cell by transducing the 19-28z CAR into donor EBV-specific cytotoxic lymphocytes (19-28z CAR EBV-CTL). Pts with R/R B-cell malignancies were stratified into two treatment cohorts: cohort 1 (relapse after allo/auto HSCT) or cohort 2 (CAR-EBV-CTLs as consolidative therapy after auto-HSCT; NCT 01430390). Objectives: determine dose limiting toxicity (primary endpoint), optimal dose for multiple infusions, and disease response (dz evaluation: 1 month (B-ALL/CLL) or 3 months (NHL)). Results Ten pts were treated with 19-28z CAR-EBV-CTLs with seven in cohort 1 (B-ALL n=5; Burkitt lymphoma n=1; CLL n=1), and three in cohort 2 (PMBCL n=2; DLBCL n=1). Median age at treatment was 14.7 yrs (range 1.3-70.5 yrs). Median dose infused: 2.4 × 106 EBV-CTLs/kg (range = 0.6 – 7.5 × 106 EBV-CTLs/kg) with variable transduction (median 20.5%; range 7.4-41%). Six pts received multiple doses (median 2, range 1-3) with 3 × 106 T cells/kg determined to be optimal (allowing for multiple doses per cell line). EBV-CTL source: primary HSCT donors (n=4) and 3rd Party donors (n=6). HLA-matching between (pts to donor): 10/10-match (n=3); 6/10 (n=2); 5/10 (n=1), 4/10 (n=2), and 2/10 (n=2). Eight of the pts were EBV-seropositive. Response was seen in 70% (7/10) of treated pts including pts with B-ALL (n=2), CLL (n=1) and NHL (n=4). The clinical response was striking in pts treated for NHL (100% CR; 4/4) and recipients of 3rd Party cells (83% CR; 5/6) who exhibited durable response (NHL median OS 30.8; range 8-72.9 months and 3rd Party recipient median OS 23.6, range 8-72.9 - Figure 1). CRS or neurotoxicity did not occur post infusion and no DLT was noted in the trial. Two pts developed diffuse skin rash which was biopsy positive (n=1; HLA-matched HSCT donor) and biopsy negative (n=1; haploidentical 3rd Party donor) for GVHD and one pt (cohort 2) developed reversible pneumonitis following external beam radiation/auto-HSCT/CAR T-cells. Symptoms resolved after a course of topical corticosteroids (skin rash) and systemic steroids (pneumonitis). Conclusions We have successfully treated ten pts with encouraging preliminary results: CR in 70% (7/10) of treated pts including 100% (4/4) in NHL and 83% in recipients of 3rd party products. The absence of CRS and ICANS (neurotoxicity) is a salient feature of this therapy and this trial demonstrates that a readily accessible source of \"off-the-shelf\" CAR T cell product can be made available for pts without alternative therapy.