Anbalcabtagene Autoleucel Elicits Meaningful Responses in Relapsed/Refractory LBCL

The CAR T-cell therapy anbalcabtagene autoleucel (anbal-cel; CRC01; Curocell) generated strong overall response rates (ORRs) in patients with relapsed/refractory large B-cell lymphoma (LBCL), according to data from a phase 1 dose-escalation trial (NCT04836507) presented during the 2022 EHA Congress.¹

Among all evaluable patients (n = 11), anbal-cel induced an ORR of 82%, with all responders achieving a complete response. Specifically, at dosages of 2 x 10⁵ cells/kg (n = 4), 7 x 10⁵ cells/kg (n = 3), and 2 x 10⁶ cells/kg (n = 4), the ORRs experienced with the therapy were 75%, 67%, and 100%, respectively. The 2 patients who did not experience a CR achieved stable disease.

Anbal-cel is a novel, second-generation, autologous CD19-directed CAR T-cell therapy that has been knock-downed for PD-1 and TIGIT. Preclinical studies have suggested that anbal-cel can better eradicate CD19-positive tumor cells—both in vitro and in vivo—than other conventional CD19-targeted CAR T-cell therapies.

“With this downregulation of the immune checkpoint genes, we can overcome the exhaustion of CAR T cells,” lead study author Won-Seog Kim, MD, PhD, a professor in the Division of Hematology-Oncology at Samsun Medical Center in Seoul, South Korea, said in a presentation of the data. “Therefore, the efficacy [with this approach] can be sustained for a long time.”

The phase 1 dose-escalation study enrolled patients with diffuse LBCL (DLBCL) not otherwise specified, high-grade B-cell lymphoma (BCL), primary mediastinal LBCL, and transformed follicular lymphoma. Patients were required to have relapsed/refractory disease after having received at least 2 prior lines of therapy, an ECOG performance status of 0 or 1, and acceptable organ function. Those who received prior CD19-targeted therapy were excluded.

Once enrolled, patients underwent leukapheresis, followed by lymphodepletion, which consisted of 30 mg/m² of fludarabine and 500 mg/m² of cyclophosphamide for the duration of 3 days. On day 1, anbal-cel was administered at 1 of the following doses: 2 x 10⁵ cells/kg (dose level 1), 7 x 10⁵ cells/kg (dose level 2), or 2 x 10⁶ cells/kg (dose level 3).

A total of 15 patients were enrolled in the trial and underwent leukapheresis, although 4 were not ultimately infused with anbal-cel; 1 patient was no longer eligible and 3 had cells manufactured below the target dose. Eight patients received bridging therapy prior to CAR T-cell infusion.

Eleven patients received lymphodepletion and the CAR T-cell therapy, and these patients comprised the efficacy and safety set. Nine patients were included in the dose-limiting toxicity (DLT) set; 1 patient had been excluded for receiving prohibited medication and another for enrolling after the DLT evaluation was completed.

The primary end point of the trial was safety, including evaluating DLTs and identifying the maximum tolerated dose of the CAR T-cell therapy. Secondary end points included ORR, duration of response, progression-free survival, and overall survival.

Among all patients evaluable for efficacy and safety, the median age was 46 years (range, 26-71), with 36% being 65 years of age or older. Additionally, 55% of patients were male and 36% had an ECOG performance status of 1. Ten patients had DLBCL, and 1 patient had transformed follicular lymphoma.

Thirty-six percent of patients received 1 or 2 prior lines of therapy, 27% had 3 prior lines of therapy, and 36% received at least 4 prior lines of therapy. Most patients (73%) were refractory to their last line of therapy, did not undergo prior autologous stem cell transplant (64%), and were refractory to their first line of therapy (55%). The median tumor burden by sum of the products of diameters (SPD) was 3520 mm² (range, 570-7719), and 45% of patients had an SPD of at least 5000 mm².

The most common treatment-related adverse effects (TRAEs) of any grade included cytokine release syndrome (CRS; 46%), anemia (18%), neutropenia (18%), fever (18%), and thrombocytopenia (18%).

Notably, rates of any-grade TRAEs were lower in the cohorts of patients who received the therapy at dose level 1 or 2. Only 1 any-grade TRAE was reported in those who received dose level 1 (fever). Among those who received dose level 2, all 3 patients experienced any-grade CRS with the therapy, and 1 patient had herpes zoster. The patient who experienced herpes zoster was the only patient to experience a grade 3 or higher TRAE in the cohorts who received anbal-cel at dose level 1 or 2. In the cohort who received anbal-cel at dose level 3, 2 patients each experienced grade 3 or higher anemia, CRS, neutropenia, and thrombocytopenia, and 1 patient reported grade 3 or higher sepsis.

Both CRS cases reported in the cohort that received the therapy at dose level 3 were grade 3 in severity. The 3 cases reported in the cohort that received anbal-cel at dose level 2 were grade 1 (n = 2) and grade 2 (n = 1), and no patients in the cohort that received the therapy at dose level 1 experienced CRS of any grade.

Among all patients to develop CRS, the median onset time was 7 days (range, 1-16) and the median duration was 5 days (range, 1-19). Six patients with CRS were treated with tocilizumab (Actemra), 1 received steroids, and 2 patients were given a vasopressor.

Neurological AEs were not observed in any patients in the those who received the agent at dose level 1 or 2. In the cohort that received anbal-cel at dose level 3, 1 patient experienced grade 2 confusion and grade 1 delirium; the median onset time was 7 days and the effect lasted for a median for 13 days. The patient was treated with tocilizumab and steroids.

Cytokinetics showed that C_MAX, AUC_0-28d, and AUC_0-2M were all proportionally increased to anbal-cel’s dose. T-cell concentration peaked on day 15 following infusion.

“Now, the 2 x 10⁶ cells/kg [dose of anbal-cel] will be [explored in the] phase 2 [portion of the research,” Kim concluded.

Reference

Kim WS, Kim SJ, Yoon SE, et al. Phase 1/2 study of anbalcabtagene autoleucel novel anti-CD19 CAR-T therapy with dual silencing of PD-1 and TIGIT in relapsed or refractory large B-cell lymphoma. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S214