Anti-tumor therapy with macroencapsulated endostatin producer cells

Abstract

BackgroundTheracyte is a polytetrafluoroethylene membrane macroencapsulation system designed to induce neovascularization at the tissue interface, protecting the cells from host's immune rejection, thereby circumventing the problem of limited half-life and variation in circulating levels. Endostatin is a potent inhibitor of angiogenesis and tumor growth. Continuous delivery of endostatin improves the efficacy and potency of the antitumoral therapy. The purpose of this study was to determine whether recombinant fibroblasts expressing endostatin encapsulated in Theracyte immunoisolation devices can be used for delivery of this therapeutic protein for treatment of mice bearing B16F10 melanoma and Ehrlich tumors.ResultsMice were inoculated subcutaneously with melanoma (B16F10 cells) or Ehrlich tumor cells at the foot pads. Treatment began when tumor thickness had reached 0.5 mm, by subcutaneous implantation of 107 recombinant encapsulated or non-encapsulated endostatin producer cells. Similar melanoma growth inhibition was obtained for mice treated with encapsulated or non-encapsulated endostatin-expressing cells. The treatment of mice bearing melanoma tumor with encapsulated endostatin-expressing cells was decreased by 50.0%, whereas a decrease of 56.7% in tumor thickness was obtained for mice treated with non-encapsulated cells. Treatment of Ehrlich tumor-bearing mice with non-encapsulated endostatin-expressing cells reduced tumor thickness by 52.4%, whereas lower tumor growth inhibition was obtained for mice treated with encapsulated endostatin-expressing cells: 24.2%. Encapsulated endostatin-secreting fibroblasts failed to survive until the end of the treatment. However, endostatin release from the devices to the surrounding tissues was confirmed by immunostaining. Decrease in vascular structures, functional vessels and extension of the vascular area were observed in melanoma microenvironments.ConclusionsThis study indicates that immunoisolation devices containing endostatin-expressing cells are effective for the inhibition of the growth of melanoma and Ehrlich tumors.Macroencapsulation of engineered cells is therefore a reliable platform for the refinement of innovative therapeutic strategies against tumors.

Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting

“…Endostatin has been studied in phase I and II clinical trials for patients with metastatic cancer and has shown low efficacy, however, a new more stable version of endostatin has re‐entered the clinic and is now used in certain countries for the treatment of lung and gastric cancer [94]. Recently, an immunoisolation device that contains endostatin‐expressing cells was used effectively for the treatment of melanoma and Ehrlich tumors in mice [98]. This suggests that the macroencapsulation of engineered cells that produce endostatin may be innovate therapeutic strategy for treatment of malignancies (Table 1).…”

Biomedical polymers: synthesis, properties, and applications

“…As of now, therapeutic approaches mediated by cells that mainly belong to the native and adaptive immune systems have been developed for treating cancers [589,590]. Cell therapy has achieved significant progress; however, challenges remain to demonstrate their clinical treatment efficacy and acceptable toxicity [591].…”

Encapsulated Cell Grafts to Treat Cellular Deficiencies and Dysfunction

“…131 Recombinant fibroblasts expressing endostatin and encapsulated in PTFE capsules (Theracyte ™ ) suppressed melanoma in mice. 132 Melanomas were also suppressed when mouse myoblasts that were engineered to express angiostatin were encapsulated in alginate-PLL-alginate beads and grafted in tumor-bearing mice. 15 Combinatorial cell therapy has improved outcomes by attacking multiple targets.…”