Feasibility and safety of adoptive immunotherapy with ex vivo-generated autologous, cytotoxic T lymphocytes in patients with solid tumor

Abstract

Background aims. Adoptive T-cell therapy with tumor-specific T cells has emerged as a potentially useful approach for treating patients with advanced malignancies. We have demonstrated previously the feasibility of obtaining large numbers of autologous anti-tumor-specific cytotoxic T lymphocytes (CTL) generated by stimulation of patients’ peripheral blood mononuclear cells with dendritic cells pulsed with apoptotic tumor cells. Methods. Six patients with progressing metastatic solid tumors (one renal cell carcinoma, two ovarian cancers, two extraosseous peripheral neuroectodermal tumors, one soft tissue sarcoma) not eligible for conventional therapies were treated with adoptive immunotherapy. Anti-tumor CTL, proven to be reactive in vitro against patient tumor cells, but not against normal cells, were infused following lymphodepleting chemotherapy administered to favor T-cell proliferation in vivo. Results. Patients received a median of nine CTL infusions (range 2–19). The median number of CTL administered per infusion was 11 × 10⁸ (range 1–55 × 10⁸). No patient experienced acute or late adverse events related to CTL infusion, even when large numbers of cells were given. Post-infusion laboratory investigations demonstrated an increase in the frequency of circulating anti-tumor T-cells and, in patients with a longer follow-up receiving two CTL infusions/year, a stabilization of these values. Conclusions. Our study demonstrates that autologous ex vivo-generated anti-tumor CTL can be administered safely in patients with advanced solid tumors and can improve the immunologic reactivity of recipients against tumor. These preliminary results provide a rationale for evaluating the clinical efficacy of this immunotherapeutic approach in phase I/II studies.

Key Words::

• adoptive T-cell therapy
• autologous tumor cells
• cytotoxic T lymphocytes
• lymphodepletion
• solid tumors

Acknowledgments

This work was partially supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) to DM, NZ, FL and PP; Ministero della Salute (Progetto Oncologia 2006, Ricerca Finalizzata) to FL and RM; Fondazione IRCCS Policlinico San Matteo Pavia Ricerca Corrente to DM, FL and RM and Oncologia Ca’ Granda ONLUS Fondazione.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.