How Might CTO1681 Prevent CRS After CAR T-Cell Therapy in DLBCL?

In a conversation with CancerNetwork^® at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition, Jordan Gauthier, MD, MSc, spoke about his work in an ongoing phase 1b/2a clinical trial (NCT05905328) assessing the safety and tolerability of CTO1681 in patients with diffuse large B-cell lymphoma (DLBCL). Investigators also look to determine the preliminary efficacy of CTO1681, an investigational PGE2 and PGI2 agonist, in preventing or reducing the incidence of cytokine release syndrome (CRS) among patients undergoing CAR T-cell therapy for their disease.

According to Gauthier, associate professor in the Clinical Research Division, a member of the Immunotherapy Integrated Research Center, and a member of the Translational Data Science Integrated Research Center at Fred Hutch Cancer Center, CTO1681’s mechanism of action allows it to prevent NF-κB activation, the signaling of which is critical for regulating cytokine production. By reducing the production of a broad range of proinflammatory cytokines, the novel agent may successfully mitigate CRS in patients who receive standard-of-care cellular therapies.

Investigators of the phase 1b/2a trial are enrolling patients scheduled to receive CD19-targeting CAR T-cell therapy who will not receive prophylaxis with tocilizumab (Actemra) or steroids. The phase 1a component is an open-label, dose-escalation study that will assess up to 3 dosing levels of CTO1681; patient enrollment for this portion began in December 2023. Additionally, phase 2a will include a randomized, placebo-controlled design using a recommended phase 2 dose identified in phase 1b.

Transcript:

CTO1681 is a drug that functions as a prostacyclin or prostaglandin agonist, which means it will bind to the PGE2 and PGI2 receptors on the surface of immune cells. By doing so, you will prevent NF-κB activation. It will prevent [this] through different mechanisms, one of them being by preventing its translocation into the nucleus of the cells. We know that NF-κB signaling is very important to regulate cytokine production.

That explains the effect of CTO1681 at reducing the production of a broad range of proinflammatory cytokines.

Reference

Gauthier J, Frigault M, Bertolino A, Howell M, Whalen T. A phase 1b/2a study of CTO1681 for the prevention of cytokine release syndrome in patients with diffuse large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy. Blood. 2025;146(suppl 1):5955. doi:10.1182/blood-2025-5955