ACTR087, Autologous T Lymphocytes Expressing Antibody Coupled T-Cell Receptors (ACTR), Induces Complete Responses in Patients with Relapsed or Refractory CD20-Positive B-Cell Lymphoma, in Combination with Rituximab
Authors: Akard Luke Paul , Jaglowski Samantha , Devine Steven M. , McKinney Matthew S. , Vasconcelles Michael , Huet Heather , Ettenberg Seth , Ranger Ann , Abramson Jeremy S. 
Published: October 2019

Background: Autologous T cells engineered to express the universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res. 2014]. Preclinical findings with ACTR+ T cells, which bind immunoglobulin Fc via CD16V158 and signal via CD3ζ and 4-1BB (ACTR087), demonstrate markedly enhanced target- and antibody-specific tumor cell cytotoxicity, as evidenced by CD20+ B cell lymphoma killing in combination with rituximab, compared with rituximab alone. Preclinical data also demonstrate rituximab dose-dependent effects in combination with ACTR087, suggesting that the therapeutic index of ACTR087 in combination with rituximab may be affected by rituximab dose or schedule and present an advantage over chimeric antigen receptor (CAR) T cell therapies [Huet H, Blood 2016]. Study UT-201501 (ATTCK-20-2) is the first clinical trial of ACTR087 in combination with rituximab in patients with relapsed or refractory CD20+ B cell lymphoma previously treated with rituximab (NCT02776813). We report data from the 7 patients treated with ACTR087 in the first dose level of the ATTCK-20-2 study.

Methods: This is a multicenter Phase 1 dose escalation study. The primary objective is to evaluate the safety of the combination of ACTR087 and rituximab, and the key secondary objective is to evaluate antitumor efficacy. Exploratory objectives include measurement of ACTR T cell persistence, cytokines, and rituximab pharmacokinetics. Eligible patients must have histologically confirmed relapsed/refractory aggressive CD20+ B cell lymphoma of DLBCL, MCL, PBMCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb in combination with anthracycline-containing chemotherapy. In the first dose level, patients received lymphodepleting chemotherapy (cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and ACTR087 (0.5x106 ACTR+ T cells/kg). Up to 7 additional doses of rituximab are then administered, one dose every 3 weeks in the absence of disease progression.

Results: Seven patients received ACTR087 in combination with rituximab at the first dose level. Median age was 64 years (range: 36-71), 57.1% were male, all had ECOG PS 1, 86% were treated with ≥ 3 lines of prior therapy, and 86% were refractory to the immediate prior therapy. ACTR087 was successfully manufactured for all subjects. ACTR+ T cells were detectable in the peripheral blood and demonstrated expansion post-infusion. One patient had a dose-limiting toxicity of grade 4 thrombocytopenia for > 14 days that later resolved. At the first dose level, there were no SAEs or deaths related to ACTR087 and no AEs of special interest, including cytokine-release syndrome, neurotoxicity, or autoimmune events. Cytopenias were the most common ≥ grade 3 AEs (neutropenia n=7, leukopenia n=5). Rituximab pharmacokinetics were not affected by ACTR087 administration. Independently-confirmed objective responses were observed in patients evaluable for response (n=6), including 2 ongoing complete responses (CR) and 1 partial response (PR). One of the CRs continues 6+ months after a single dose of ACTR087.

Conclusions:In the first dose level studied in patients with relapsed/refractory aggressive CD20+ B cell lymphoma, ACTR087 in combination with rituximab induced complete responses with no serious AEs, AEs leading to treatment discontinuation, cytokine-release syndrome, or neurotoxicity. ACTR+ T cells were detectable in all patients and ACTR+ T cells persisted in the presence of continued rituximab administration. These results support the continued dose escalation of ACTR087 in combination with rituximab; dose level 2 enrollment is ongoing and updated data, including correlative biomarkers, will be presented.

Disclosures

Jaglowski: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Pharmacyclics Inc: Research Funding. McKinney: Kite Pharma: Other: advisory comittee. Vasconcelles: Unum Therapeutics Inc: Employment. Huet: Unum Therapeutics Inc: Employment. Ettenberg: Unum Therapeutics Inc.: Employment. Ranger: Unum Therapeutics Inc: Employment. Abramson: Seattle Genetics: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Kite Pharma: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; LAM Therapeutics: Research Funding; Novartis: Consultancy.