Next-Generation Autologous T-Cell Therapy Shows Promising Activity in Lymphoma

Article

New findings from a phase 1 trial support the role of antibody-coupled T-cell receptor (ACTR) therapy, the latest entry in the era of T-cell therapies for patients with lymphoma. The next-generation autologous T-cell–based agent may address the limitations of current chimeric antigen receptor (CAR) T-cell therapies, including the risk of severe toxicities and primary tumor resistance.

Matthew S. McKinney, MD, of the Division of Hematologic Malignancies and Cellular Therapy at Duke, presented preliminary results from the ATTCK-20-2 study at the American Society of Hematology's 59th Annual Meeting & Exposition, December 9 to 12, 2017, in Atlanta, GA.

ACTR087 is the first T-cell therapy in development that uses ACTR technology. Patient-derived T-cells are genetically modified to express the ACTR protein, a chimeric protein that combines components of proteins found on T-cells and natural killer (NK) cells. When coadministered with a tumor-specific antibody such as rituximab, the NK cell component binds tumor antigen, while the T-cell component exerts cytotoxic effects.

Unlike CAR T therapy, which is engineered for a specific tumor antigen, the ACTR drug product can target multiple tumor antigens via the coadministration of tumor-specific antibodies. Furthermore, antibody dosing can be adjusted to optimize the therapeutic index of ACTR T-cells.

Phase 1 ATTCK-20-2 study
The multicenter phase 1 ATTCK-20-2 study is designed to assess the safety and antitumor activity of ACTR087 in combination with rituximab in patients with relapsed/refractory CD20+ B-cell lymphoma. Eligible patients received prior treatment with an anti-CD20 monoclonal antibody for diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, or other subtypes.

The treatment process begins with leukapheresis to collect the patient's T-cells for ACTR087 manufacturing. During the manufacturing period, patients are able to undergo chemotherapy at the investigator's discretion, if necessary for disease control.

Once the ACTR087 drug product is available, patients receive 3 days of lympho-depleting chemotherapy with fludarabine and cyclophosphamide, followed by 2 days of rest. Patients then receive 1 cycle of rituximab on day -1, followed by infusion of ACTR087 on day 0. Beginning on day 21, patients receive maintenance rituximab every 3 weeks. Patients undergo radiologic assessment every 6 weeks to monitor treatment response.

The ATTCK-20-2 study protocol includes 3 dosing cohorts of ACTR+ T-cells:

  • Dose cohort 1: 0.5 x 106 cells/kg
  • Dose cohort 2: 1.5 x 106 cells/kg
  • Dose cohort 3: 5.0 x 106 cells/kg

To date, the trial has enrolled 7 patients in dose cohort 1 and 10 patients in dose cohort 2. The median patient ages in cohorts 1 and 2 were 64 years and 45 years, respectively. Most patients had DLBCL (86% and 70%, respectively), were heavily pretreated with 3 or more prior regimens (86% and 90%, respectively), and were refractory to their immediate prior therapy (86% and 80%, respectively).

Successful T-cell expansion and early responses
ACTR087 was successfully manufactured for all patients who underwent leukapheresis, with no manufacturing failures. On average, 26% of the T-cells in the drug product were ACTR+ T-cells.

All patients showed evidence of ACTR+ T-cell expansion, which persisted with continued rituximab treatment. The duration of persistence was at least 28 days for most patients, with some ACTR+ T-cells identified 350 days post-infusion. The median peak expansion was higher in dose cohort 2 than in dose cohort 1, suggesting a dose-dependent increase in ACTR+ T-cell expansion.

Serum levels of cytokines and inflammatory markers such as C-reactive protein, tumor necrosis factor, interleukin (IL)-6, and IL-10 showed similar patterns of dose-dependent T-cell activity.

Clinical responses included 2 durable complete responses in dose cohort 1 and 3 partial responses, 1 in dose cohort 1 and 2 in dose cohort 2. In dose cohort 2, 3 patients had not yet undergone their first radiographic assessment of disease response.

Manageable safety profile
In the safety analysis, the dose-limiting toxicity (DLT) in dose cohort 1 was grade 4 thrombocytopenia. The most common grade 3 or higher adverse events (AEs) in this cohort were neutropenia (100%), leukopenia (71%), lymphopenia (43%), and thrombocytopenia (29%). AEs potentially related to ACTR087 included grade 2 squamous cell carcinoma of the skin, grade 2 dyspnea, and grade 2 dysphagia, all of which occurred in the same patient.

Safety results in dose cohort 2 suggest a dose-dependent increase in treatment toxicity. The DLT in this cohort was grade 4 thrombocytopenia persisting for longer than 28 days. Grade 3 or higher AEs included neutropenia (40%), thrombocytopenia (30%), bacteremia (10%), and increased transaminase (10%). The AEs related to ACTR087 included grade 4 cytokine release syndrome in 2 patients, and 1 case each of grade 5 neurotoxicity, grade 4 sepsis, and grade 1 pyrexia.

"These data clearly demonstrate proof of concept that ACTR can be safely combined with a therapeutic antibody to yield anti-tumor activity," McKinney said. "The ACTR construct continues to be evaluated in other clinical studies, and the next steps include maximizing the therapeutic index through titration of antibody dose and schedule," he concluded.

Source: Akard LP, Jaglowski S, Devine SM, et al. 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. Presented at: American Society of Hematology 59th Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 580.