Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) given AUTO3 in combination with pembrolizumab experienced durable complete remissions (CRs), according to data presented by Aravind Ramakrishnan, MD, Sarah Cannon Blood Cancer Center, St. David's South Austin Medical Center, Texas, and colleagues at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

“CD19-directed CAR T cells are effective in patients with relapsed/refractory DLBCL. However, relapses due to CD19 loss or PDL1 upregulation are common. In this study, we evaluate the safety and efficacy of AUTO3, a CAR T targeting CD19/22 with limited duration of PD-1 blockade,” explained Dr Ramakrishnan and colleagues.

With this in mind, Dr Ramakrishnan et al generated a dual-targeting CAR-T therapy that was both anti-CD19 and an anti-CD22.

Patients were included in the study if they had relapsed/refractory DLBCL or transformed DLBCL (tDLBCL), an Eastern Cooperative Oncology Group performance status <2, and adequate organ function. Of 33 participants, 12 patients underwent lymphodepletion with fludarabine and cyclophosphamide before receiving AUTO3, and bridging therapy was permitted.

AUTO3 was administered alone or with 3 doses of pembrolizumab 200 mg every 3 weeks starting on day 14 (regimen A) or with a single dose of pembrolizumab 200 mg on day 1 (regimen B). 

The primary end point was the frequency of dose-limiting toxicities and grade 3-5 adverse events (AEs). The secondary end points included objective response rate (ORR), complete response rate (CRR),  and biomarkers.

Approximately 80% of which had refractory disease, 76% were DLBCL, 18% were tDLBCL, and 6% were high-grade B-Cell Lymphoma. No dose-limiting toxicity was observed during dose escalation. 

29 patients were evaluable for efficacy (PET + disease prior to pre-conditioning). The ORR was 69% and the CRR was 52%. 14 of 15 CRs did not experience relapse with a median follow up of 3 months (1-24). Of the 15 evaluable patients treated at a dose > 50 x 106 with day 1 pembrolizumab, the ORR was 73% and the CRR was 60%; no relapse was observed.

The most common treatment-emergent AEs were neutropenia (73%), thrombocytopenia (64%), anemia (61%), cytokine release syndrome (33%), pyrexia (30%), constipation (27%), and fatigue (24%). Common treatment-emergent AEs grade 3 or higher were neutropenia (73%), thrombocytopenia (48%), and anemia (48%). A majority of the more serious AEs were hematological or infectious and largely reversible. 9% of patients across all dose levels experienced neurotoxicity/ICANS, all of which occurred in the setting of disease progression with little to no CART cells in peripheral blood and were associated with confounding factors such as sepsis, metabolic acidosis, hyponatremia, and narcotic use.

“AUTO3 at recommended phase 2 dose range of >50 x 106 CAR T-cells with D-1 pembrolizumab induces durable complete remissions. None of the patients in CR experienced severe cytokine release syndrome or neurotoxicities of any grade. Outpatient cohort is currently enrolling,” concluded Dr Ramakrishna and colleagues.—Alexandra Graziano

Ramakrishnan A, Ardeshna KM,  Batlevi C, et al. Phase 1 Alexander Study of AUTO3, the First CD19/22 Dual Targeting CAR T Cell Therapy, with Pembrolizumab in Patients with Relapsed/Refractory (r/r) DLBCL. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 600.