Chimeric antigen receptor (CAR) T-cell is rapidly emerging as a promising new therapy for cancer. Although it can induce rapid clinical responses, it is also associated with cytokine release syndrome (CRS), the most commonly observed toxicity, which in some cases can lead to life-threatening multi-organ failure. To ameliorate these problems we developed a novel chimeric T-cell therapy platform, the ARTEMIS™ platform, which functionally matches the potency of CAR T-cells, but dramatically reduces the release of cytokines upon killing of target-positive tumor cells. Herein, we describe the first-in-human clinical study of anti-CD19-ARTEMIS, ET190L1-ARTEMISTM, in relapsed and refractory (r/r) B-cell lymphoma.
This dose escalating study is a single-center clinical study to evaluate the safety and efficacy of ET190L1-ARTEMIS T cells in patients with r/r CD19+ non-Hodgkin lymphoma, including diffused large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic lymphoma, and splenic marginal zone lymphoma. All patients received conditioning chemotherapy of cyclophosphamide and fludarabine followed by a single infusion of ET190L1-ARTEMISTM T cells at the dose of 1x106, 3x106, and 6x106 ARTEMIS+ T cells per kilogram respectively. The primary endpoint is safety and estimation of the maximum tolerated dose of ET190L1-ARTEMISTM T cells. Secondary objectives include ARTEMIS T-cell engraftment and response assessment by Lugano criteria.
Manufacturing was successful for all patients. As of July 18, 2018, 21 patients received autologous ET190L1-ARTEMIS T cells, 3 were infused with 1 × 106 (low dose), 13 received 3 × 106 (medium dose) and 5 received 6 × 106 (high dose) ARTEMIS+ T cells/kg. Expansion of ARTEMIS T cells after infusion was observed in all patients by qPCR and flow cytometry using anti-idiotype antibody. No dose-limiting toxicities and no greater than Grade 2 drug-related adverse events (AEs) were observed. Inflammatory-related cytokines in blood including IL-2, IL-4, IL-6, IL-8, IL-10, IFNgamma, TNFalpha, and GM-CSF were below detection level in most time points post infusion. AEs consisted of transient fever (38 ~ 39.2°C) from 1 to 4 days post infusion in 9 patients, transient grade 1 skin rash (1 × 106/kgcohort) in one patient. All of these AEs were limited and spontaneously resolved, except in 3 patients where symptomatic treatment for fever was given. No hypotension or any other clinical signs of CRS or neurotoxicity were observed. No anti-IL6 drug was given nor any hospitalization for AEs were needed. One patient with a large lymphoma mass on the right side of the neck experienced transient hand-tremor and unilateral tongue numbness on the right side, possibly due to the rapid shrinkage of tumor nodules around the neck (Table 1). Efficacy assessment was planned at 1, 2, 3, 6, 9, 12 18 and 24 months post infusion.
All subjects (n=21) completed 1st month efficacy assessment: 11/21 (52%) responders, with 6/11 (55%) complete remission (CR) and 5/11 (45%) partial remission (PR). Of the 11 responders at 1 month, 8 completed 3rd month efficacy assessment, with 6/6 CRs maintained CR and 2/2 PRs had disease progression. Of the 11 responders at 1 month, 6 completed 6th month efficacy assessment, with 5/6 CRs maintained CR and 1/6 CRs releapsed. Of the 2 SDs at 1 month, 1 progressed at 4.5 month (Table 2). The median follow up time is 3 months and the range of follow up time is 1-8 months.
The interim results show that ET190L1-ARTEMISTM T cell therapy is safe and demonstrated promising efficacy in r/r B-cell lymphoma patients at the current dose and schedule, including 11/21 responders and excellent safety profile, with no CRS and neurotoxicity observed. The durability of these efficacy and safety results will be assessed in longer follow up. Clinical trial information: NCT02658929
Long: Eureka Therapeutics, Inc.: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Rizzieri:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nejadnik:Eureka Therapeutics, Inc.: Employment. Zhu:Beijing Cancer Hospital: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership.