Abstract
Background: Chimeric antigen receptor (CAR) T-cell therapy has become an established modality in patients with high-risk B-cell malignancies with high rates of durable remission and curative potential. However, up to 95% of patients treated with CAR T-cell therapy develop potentially life-threatening immune-mediated toxicities such as cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). These syndromes interfere with the therapeutic benefit of CAR T-cell therapy resulting in greater length of hospital stay and increased need for interventional and supportive therapies. The current standard-of-care treatment for CRS is tocilizumab and/or corticosteroids, the latter being used for ICANS management. However, these treatments fail to prevent these toxicities. There is therefore a major need for alternative therapies to prevent and treat CAR T-cell therapy related toxicities; mitigation of CRS associated with CAR T-cell therapy would reduce the incidence of hospital admission and length of hospital stay and reduce mortality. More broadly, effective CRS prevention strategies will improve patients access to approved CAR T-cell therapies, and augment the therapeutic index of novel CAR T-cell therapies.
Using in vitro and in vivo models of systemic inflammation, our group demonstrated that the PGE2 and PGI2 agonist CTO1681 downregulates the production of over 20 cytokines directly involved in CRS, ameliorates end-organ responses associated with excessive cytokine production. In addition, CTO1681 does not interfere with CAR T-cell therapy efficacy in vitro or in a CD19+ tumor-bearing mouse model. Based on these promising findings, we hypothesized CTO1681 may successfully mitigate CRS in patients receiving standard-of-care CAR T-cell therapies.
Methods: This Phase 1b/2a clinical trial (NCT05905328) evaluates the safety and tolerability of CTO1681 and aims to determine preliminary effectiveness of CTO1681 in preventing or reducing CRS, as well as preventing or reducing ICANS while investigating the potential impact on the antitumor activity of CAR T-cell therapy. This study is currently enrolling diffuse large B-cell lymphoma (DLBCL) patients scheduled to receive CD19 directed CAR T-cell therapy who will not receive prophylactic treatment with tocilizumab or steroids. Treatment with CTO1681 is initiated one day prior to CAR T-cell therapy and continued TID for 15 days. Phase 1b is an open-label, dose escalation study of up to 3 dosing level cohorts that began enrolling patients in December 2023. Phase 2a is a randomized placebo-controlled study using the recommended Phase 2 dose identified in Phase 1b.
