First-in-Human Study of ET019003, a Next Generation Anti-CD19 T-Cell Therapy, in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma (r/r DLBCL)

Background:

CD19-targeted CAR-T therapies have shown promising efficacy in treating B-cell malignancies. However, treatment-related toxicities, such as cytokine-release syndrome (CRS) and CAR T-cell-related encephalopathy syndrome (CRES), have been one of the major obstacles limiting the use of CAR-T therapies. How to minimize occurrence and severity of toxicity while maintaining efficacy is a major focus for T-cell therapies in development.

ET019003 is a next generation CD19-targeted T-cell therapy developed by Eureka Therapeutics, built on the proprietary ARTEMIS^TM T-cell platform. The ET019003 construct is optimized with the co-expression of an ET190L1 Antibody-TCR (Xu et al, 2018) and novel co-stimulation molecule. We are conducting a First-in-human (FIH) study of ET019003 T cells in CD19+ r/r DLBCL patients.

Methods:

This FIH study aims to evaluate the safety and efficacy of ET019003 T-cell therapy in CD19+ patients with r/r DLBCL. As of July 2019, six subjects were administered ET019003 T cells. These subjects were pathologically confirmed with DLBCL that is CD19+ (by immunohistochemistry), whose disease have progressed or relapsed after 2-5 lines of prior therapies. All were high-risk patients with rapid tumor progression and heavy tumor burden. Each subject had a Ki67 proliferative index over 60%, 2/6 of the subjects had a Ki67 proliferative index over 90%. Moreover, 5/6 of the subjects had extra-nodal involvement.

Following a 3-day preconditioning treatment with Fludarabine (25mg/m2/day)/ Cyclophosphamide (250mg/m2/day), patients received i.v. infusions of ET019003 T cells at an initial dose of 2-3×10⁶ cells/kg. Additional doses at 3×10⁶ cells/kg were administered at 14 to 30-day intervals. Adverse events were monitored and assessed based on CTCAE 5.0. Clinical responses were assessed based on Lugano 2014 criteria.

Results:

As of July 2019, six subjects have received at least one ET019003 T-cell infusion, and four subjects have received two or more ET019003 T-cell infusions. No Grade 2 or higher CRS was observed in the six subjects. One subject developed convulsions and cognitive disturbance. This subject had lymphoma invasion in the central nervous system before ET019003 T-cell therapy. The subject was treated with glucocorticoid and the symptoms resolved within 24 hours. Other adverse events included fever (6/6, 100%), fatigue (3/6, 50%), thrombocytopenia (3/6, 50%), diarrhea (2/6, 33%), and herpes zoster (1/6, 17%).

ET019003 T-cell expansion in vivo (monitored by flow cytometry and qPCR) was observed in all six subjects after first infusion. The absolute peak value of detected ET019003 T cells ranged between 26,000 - 348,240 (median 235,500) per ml of peripheral blood. Tmax (time to reach the absolute peak value) was 6 - 14 days (median 7.5 days). For the four subjects who received multiple ET019003 T-cell infusions, the absolute peak values of detected ET019003 T cells after the second infusion were significantly lower than the absolute peak values achieved after the first infusion. For the two subjects who received three or more infusions of ET019003 T cells, no significant ET019003 T-cell expansion in vivo was observed after the third infusion.

All six subjects completed the evaluation of clinical responses at 1 month after ET019003 T-cell therapy. All subjects responded to ET019003 T cells and achieved either a partial remission (PR) or complete response (CR).

Conclusions:

Preliminary results from six CD19+ r/r DLBCL patients in a FIH study show that ET019003 T-cell therapy is safe with robust in vivo T-cell expansion. The clinical study is on-going and we are monitoring safety as well as duration of response in longer follow-up.

Reference: Xu et al. Nature Cell Discovery, 2018