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

Abstract

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.

Immunotherapy of Pediatric Solid Tumors: Treatments at a Crossroads, with an Emphasis on Antibodies

“…Novel T-cell platforms targeting multiple antigens highlight the potential to overcome antigen loss in pediatric solid tumors. The firstin-human trial evaluating tumor-specific T cells targeting Wilms tumor gene 1 and survivin showed safe administration and a 73% response rate in 15 pediatric patients with relapsed/refractory solid tumors (13). Gamma-delta (gd) T cells constitute another viable cell product given their T cell-like properties, lack of MHC restriction, presence of CD16, and ability to mediate antibody-dependent cellular cytotoxicity (ADCC).…”

Robust Production of Merkel Cell Polyomavirus Oncogene Specific T Cells From Healthy Donors for Adoptive Transfer

“…An alternative immunotherapeutic strategy would be to transfer allogeneic MCPyV-specific T cells derived from an HLA matched healthy donor using peptide libraries of the viral oncoproteins. ACT with peptide library-pulsed ex vivo expanded virus or tumor antigen-specific T cells has been used with success in multiple clinical trials to treat viral infections, EBV-driven lymphomas, and solid tumors (15)(16)(17). MCPyV TAg specific CD4 + , but not CD8 + , T cells have been found in healthy donors and have not been evaluated for ACT (12,(18)(19)(20).…”

Frontiers in cancer immunotherapy—a symposium report

“…Bollard is hopeful that T cell–based therapies will find clinical applications in solid tumors, which have not been as amenable as hematological tumors. In a phase I study in heavily pretreated patients with solid tumors, autologous multiantigen‐specific T cell treatment was safe, with some patients experiencing prolonged disease stabilization 39 …”