Abstract B105: ACTR707: a novel T-cell therapy for the treatment of relapsed or refractory CD20+ B cell lymphoma in combination with rituximab
Authors: Motz Greg , Whiteman Kathleen , Shin John , Pai Tapasya , Judge Casey , Barnitz Anthony , Hemphill James , Kim James , Ranger Ann , Huet Heather , McGinness Kathleen , Schultes Birgit , Hodge Geoffrey , Vasconcelles Michael , Ettenberg Seth 
Published: August 2018

Abstract
The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy developed to combine with tumor-targeting antibodies to exert potent antitumor immune responses and tumor cell killing. The ACTR construct is composed of the extracellular domain of CD16 (FCGR3A; high-affinity V158 variant) linked to CD3ζ signaling and costimulatory domains. ACTR-expressing T cells are universal, and can be flexibly paired with desired therapeutic antibodies to target tumor antigens. Unum’s most advanced clinical candidate, ACTR087, is currently in clinical testing in combination with rituximab for the treatment of CD20+ B cell lymphoma (NCT02776813). To expand upon the ACTR platform, over 90 different domain-modified variant ACTRs were generated and evaluated through rigorous in vitro and in vivo testing in combination with a broad range of tumor-targeting antibodies for use in hematologic and solid tumor indications. ACTR T-cell cytotoxicity, cytokine release and proliferation assays, combined with performance in an in vitro repeated stimulation “stress test,” led to the identification of several lead ACTR candidates. The final ACTR candidate was identified on the ability to mediate tumor regressions of aggressive CD20+ lymphomas and HER2+ solid tumors in vivo when combined with rituximab or trastuzumab, respectively. These efforts identified ACTR707, an ACTR construct containing a CD28 costimulatory domain with additional molecular elements. Here we present nonclinical data supporting an ongoing first-in-human phase 1 clinical trial of ACTR707 in combination with rituximab. When combined with rituximab, ACTR707 T cells had potent activation, proliferation, cytokine production, and tumor-directed cytotoxicity in the presence of CD20+ lymphoma cell lines. ACTR707 T-cell in vitro activity was dependent on rituximab and was dose-titratable. ACTR707 T cells had potent antitumor efficacy in vivo in an aggressive Raji lymphoma xenograft model in NSG mice; ACTR707 T cell antitumor activity was ACTR T cell and rituximab dose-dependent, with higher T-cell numbers and antibody concentrations mediating improved responses. Further, ACTR707 in combination with rituximab outperformed a CD19 targeted CAR-T against aggressive Raji tumors in vivo. Taken together, these nonclinical data demonstrate the specificity and versatility of the ACTR707 T-cell therapeutic approach to target diverse cancer antigens and directly supports clinical testing in combination with rituximab. The phase I study, ATTCK-20-03 (NCT03189836), in subjects with relapsed or refractory CD20+ B cell lymphoma is a multicenter, single-arm, open-label dose escalation study evaluating the safety and antilymphoma efficacy of ACTR707 T cells in combination with rituximab. Subjects who meet eligibility requirements with histologically confirmed relapsed or refractory CD20+ B cell lymphoma of one of the following histologic subtypes are eligible: DLBCL, MCL, PMBCL, Gr3b-FL, TH-FL. The study’s primary objective is to assess the safety of the combination and define dose recommendations for further study. Additional study objectives include the assessment of antilymphoma activity, ACTR707 persistence, ACTR707 product characterization, inflammatory laboratory assessments, and rituximab pharmacokinetics. Enrollment is ongoing.
Citation Format: Greg Motz, Kathleen Whiteman, John Shin, Tapasya Pai, Casey Judge, Anthony Barnitz, James Hemphill, James Kim, Ann Ranger, Heather Huet, Kathleen McGinness, Birgit Schultes, Geoffrey Hodge, Michael Vasconcelles, Seth Ettenberg. ACTR707: a novel T-cell therapy for the treatment of relapsed or refractory CD20+ B cell lymphoma in combination with rituximab [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B105.