AUTO3 CAR T Cell Appears Promising as Treatment of Relapsed/Refractory DLBCL

Eleni Tholouli, MD, PhD

The first CD19/22-directed dual targeting chimeric antigen receptor (CAR) T cell AUTO3 demonstrated a tolerable and best-in-class safety profile as treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to findings from the phase 1 cohorts of the ALEXANDER study.

“In summary, AUTO3 is safe and well tolerated with its best-in-class safety profile. The complete remission (CR) rates off the recommended phase 2 dose (RP2D) cohort at a dose range of 150 to 450 x 106 appears promising, with overall durable remissions noted for the AUTO3 product,” said lead study author Eleni Tholouli, MD, PhD, hematologist, Manchester Royal Infirmary, during a presentation of these data at the annual 2020 European Society for Medical Oncology (ESMO) Virtual Congress.

The single-arm, open-label, multicenter study included a phase 1 dose-escalation cohort, and a phase 2 efficacy cohort. In the phase 1 portion, patients received escalating doses of the CAR T-cell therapy starting at 50 x 106 after fludarabine and cyclophosphamide. All patients except for the first 3 in cohort 1 received consolidation with a preconditioning regimen of pembrolizumab (Keytruda).

The phase 2 portion of the study included 2 cohorts of patients. The first included patients with DLBCL not otherwise specified, high-grade B-cell lymphoma, transformed DLBCL from follicular lymphoma, and > 2 prior therapies, while the second included patients with primary mediastinal, transformed DLBCL from other indolent non-Hodgkin lymphoma, and > 2 prior lines of therapy.

Thirty-five patients with relapsed/refractory DLBCL have been treated to date, according to Tholouli. The median age was 59 years, with the oldest patient to receive treatment being 83 years old (range, 28-83), and the majority of patients with male (n = 23) rather than female (n = 12). Overall, 77% had DLBCL not otherwise specified, and 23% were transformed from follicular or marginal zone lymphoma. This was a high-risk group of patients, and the majority had stage IV disease (n = 22), high-intermediate (n = 10), or high risk (n = 4) IPI scores, were relapsed and refractory (n = 19), and heavily pretreated. The median number of prior lines was 3 (range, 1-10).

Cytokine release syndrome (CRS) occurred in 12 patients overall. Grade 1 CRS occurred in 8 patients (22.9%) and grade 2 in 4 (11.4%), while no cases of grade 3 or worse CRS were observed in the study. The median duration of CRS was 3 days (range, 1-19), and only 5 patients required tocilizumab, although no prophylactic tocilizumab was used. The median time to onset of CRS was 6 days (range, 1-36).

Neurotoxicity occurred in 5 patients total, in which only 2 cases were considered severe as grade 3 or greater.

“Of note is that all 3 were atypical and seen in a setting with fdisease progression and confounding factors, such as sepsis, narcotic use, electrolyte abnormality, or metabolic acidosis,” said Tholouli. “At the same time, there was evidence of no or minimal CAR T expansion in the peripheral blood.”

There was no neurotoxicity observed in patients who achieved a response with robust CAR T expansion. No prophylactic measures were used in this setting, overall demonstrating the superiority of AUTO3 to other CAR T constructs seen and currently approved.

To date, 30 of the 35 patients were evaluable for response. The overall response rate (ORR) was 68%, with CRs in 54%. Among patients who received ≥150 x 106 CD19/22 CAR T cells, which was the recommended phase 2 dose, with preconditioning pembrolizumab the ORR was 71%, and the CR rate was 64%.

The CRs appeared durable, with only 1 patient developing progressive disease after achieving a CR, which was a patient treated with the lowest dose of AUTO3 without the immune checkpoint inhibitor for preconditioning. With a median follow-up of 6 months, 93% of patients achieved a CR and did not have progressive disease.

At this time, the study is currently enrolling patients to an outpatient expansion cohort following the positive results of this study. The primary end point of this cohort is safety, which will be evaluated in terms of grade 3 through 5 toxicities.

_Reference

_{Tholouli E, Ardeshna K, Ramakrishnan A, et al. Phase I alexander study of auto3, the first cd19/22 dual targeting car t cell therapy, with pembrolizumab in patients with r/r dlbcl. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 890MO.}