Abstract CT125: A Phase 1 study to evaluate the safety and tolerability of a combination autologous CD19 CAR T cell therapy (SYNCAR-001) and orthogonal IL-2 (STK-009) in subjects with relapsed or refractory  CD19 expressing hematologic malignancies (NCT05665062)
Authors: Palomba Maria Lia , Mei Matthew G. , Caimi Paolo F. , Cortese Matthew , Davila Marco , Yadnik Greg , Huang Nestor , Mou David , Oft Martin , Aspuria Paul-Joseph , Mehta-Damani Anita , Ratti Navneet , Rizvi Naiyer , Azrilevich Alex , Reshef Ran 
Published: April 2023

Abstract
Background: Chimeric antigen receptor T cell therapy (CAR T) has demonstrated remarkable clinical efficacy in hematological malignancies. However, compromised T cell effector function, proliferation, and persistence can limit CAR T from reaching their full curative potential. Interleukin-2 (IL-2) is a potent stimulator of T cells, however therapeutic use of IL-2 is limited by systemic toxicity due its pleiotropy. Therefore, to provide a selective IL-2 signal to engineered T cells, we have developed a human orthogonal ligand/receptor system consisting of a half-life extended pegylated IL-2 mutein (STK-009) and a mutated IL-2 Receptor Beta (hoRb) that responds to STK-009 but not wild type IL-2. SYNCAR-001 is an autologous CAR T co-expressing a CD19 CAR and hoRb on the T cell surface. In mouse models of refractory lymphoma, STK-009 treatment led to expansion and activation of SYNCAR-001 cells with a maintenance of stem cell memory and effector T cell phenotypes. When added to SYNCAR-001, STK-009 increased complete response rate and durable responses in a dose dependent manner. In non-human primate studies, STK-009 alone demonstrated no significant biological activity in IL-2 sensitive populations (T cells or NK cells) and was tolerable without toxicity.
Methods: This is a first-in-human, open-label, dose escalation study of combination SYNCAR-001 + STK-009 in adults with relapsed or refractory (r/r) CD19+ hematologic malignancies. The objectives of this study are to evaluate the safety, preliminary efficacy, pharmacokinetics, immunogenicity, and pharmacodynamics of SYNCAR-001 + STK-009. Dose escalation follows a standard 3+3 design with STK-009 being escalated while SYNCAR-001 is held at a single fixed dose. A dose extension will enroll a cohort of patients treated at a selected dose level and indication based on dose escalation findings. SYNCAR-001 is dosed intravenously (IV) once at Day 0 and STK-009 is dosed subcutaneously (SC) over the course of the study. Participants receive a single safety lead-in dose of STK-009 prior to lymphodepletion and subsequent SYNCAR-001 infusion. After SYNCAR-001 initiation, STK-009 is dosed SC weekly for 12 weeks and then monthly for 3 months. Eligible participants include individuals with r/r chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and selected r/r B-cell non-Hodgkin lymphoma (NHL subtypes of large B cell, mantle cell, and indolent lymphoma). Prior CD19 CAR use is excluded. The primary endpoint of safety includes outcomes such as adverse events and dose-limiting toxicities. Secondary endpoints include assessments of response, pharmacokinetics, and immunogenicity. Exploratory endpoints include assessment of immune cell populations, and relevant gene/protein expression, as well as persistence, phenotype, and functionality of SYNCAR-001 in the peripheral blood and/or bone marrow in response to STK-009.
Citation Format: Maria Lia Palomba, Matthew G. Mei, Paolo F. Caimi, Matthew Cortese, Marco Davila, Greg Yadnik, Nestor Huang, David Mou, Martin Oft, Paul-Joseph Aspuria, Anita Mehta-Damani, Navneet Ratti, Naiyer Rizvi, Alex Azrilevich, Ran Reshef. A Phase 1 study to evaluate the safety and tolerability of a combination autologous CD19 CAR T cell therapy (SYNCAR-001) and orthogonal IL-2 (STK-009) in subjects with relapsed or refractory  CD19 expressing hematologic malignancies (NCT05665062) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT125.