Outcome of donor-derived TAA-T cell therapy in patients with high-risk or relapsed acute leukemia post allogeneic BMT.

Patients with hematologic malignancies relapsing after allogeneic blood or marrow transplantation (BMT) have limited response to conventional salvage therapies, with an expected 1-year overall survival (OS) of <20%. We evaluated the safety and clinical outcomes following administration of a novel T-cell therapeutic targeting 3 tumor-associated antigens (TAA-T) in patients with acute leukemia who relapsed or were at high risk of relapse after allogeneic BMT. Lymphocytes obtained from the BMT donor were manufactured to target TAAs WT1, PRAME, and survivin, which are over-expressed and immunogenic in most hematologic malignancies. Patients received TAA-T infusions at doses of 0.5 to 4 × 107/m2. Twenty-three BMT recipients with relapsed/refractory (n = 11) and/or high-risk (n = 12) acute myeloid leukemia (n = 20) and acute lymphoblastic leukemia (n = 3) were infused posttransplant. No patient developed cytokine-release syndrome or neurotoxicity, and only 1 patient developed grade 3 graft-versus-host disease. Of the patients who relapsed post-BMT and received bridging therapy, the majority (n = 9/11) achieved complete hematologic remission before receiving TAA-T. Relapsed patients exhibited a 1-year OS of 36% and 1-year leukemia-free survival of 27.3% post-TAA-T. The poorest prognosis patients (relapsed <6 months after transplant) exhibited a 1-year OS of 42.8% postrelapse (n = 7). Median survival was not reached for high-risk patients who received preemptive TAA-T posttransplant (n = 12). Although as a phase 1 study, concomitant antileukemic therapy was allowed, TAA-T were safe and well tolerated, and sustained remissions in high-risk and relapsed patients were observed. Moreover, adoptively transferred TAA-T detected by T-cell receptor V-ß sequencing persisted up to at least 1 year postinfusion. This trial was registered at clinicaltrials.gov as #NCT02203903.

Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study.

PURPOSE: Tumor-associated antigen cytotoxic T cells (TAA-Ts) represent a new, potentially effective and nontoxic therapeutic approach for patients with relapsed or refractory solid tumors. In this first-in-human trial, we investigated the safety of administering TAA-Ts that target Wilms tumor gene 1, preferentially expressed antigen of melanoma, and survivin to patients with relapsed/refractory solid tumors. MATERIALS AND METHODS: TAA-T products were generated from autologous peripheral blood and infused over three dose levels: 1, 2, and 4 × 107 cells/m2. Patients were eligible for up to eight infusions administered 4 to 7 weeks apart. We assessed dose limiting toxicity during the first 45 days after infusion. Disease response was determined within the context of a phase I trial. RESULTS: There were no dose-limiting toxicities. Of 15 evaluable patients, 11 (73%) with stable disease or better at day 45 postinfusion were defined as responders. Six responders remain without progression at a median of 13.9 months (range, 4.1 to 19.9 months) after initial TAA-Ts. Patients who were treated at the highest dose level showed the best clinical outcomes, with a 6-month progression-free survival of 73% after TAA-T infusion compared with a 38% 6-month progression-free survival with prior therapy. Antigen spreading and a reduction in circulating tumor-associated antigens using digital droplet polymerase chain reaction was observed in patients after TAA-T infusion. CONCLUSION: TAA-Ts safely induced disease stabilization, prolonged time to progression, and were associated with antigen spreading and a reduction in circulating tumor-associated antigen DNA levels in patients with relapsed/refractory solid tumors without lymphodepleting chemotherapy before infusion. TAA-Ts are a promising new treatment approach for patients with solid tumors.