Encapsulated Cells Expressing a Chemotherapeutic Activating Enzyme Allow the Targeting of Subtoxic Chemotherapy and Are Safe and Efficacious: Data from Two Clinical Trials in Pancreatic Cancer

Abstract

Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more.

Update on cellular encapsulation

“…When the cells were encapsulated and transplanted into pancreatic tumors, growth arrest and in one case complete tumor eradication occurred over the 3‐week study period with minimal immune reaction to the capsules . The approach was later adapted to allogeneic cells and tested in patients with pancreatic cancer, which resulted in improved 1‐year survival rates . Encapsulated genetically engineered Chinese hamster ovary cells expressing human endostatin have effectively inhibited tumor angiogenesis in mice .…”

“…85 The approach was later adapted to allogeneic cells and tested in patients with pancreatic cancer, which resulted in improved 1-year survival rates. 160,161 Encapsulated genetically engineered Chinese hamster ovary cells expressing human endostatin have effectively inhibited tumor angiogenesis in mice. 162 Similarly, alginate encapsulated human mesenchymal stem cells modified to express endostatin inhibited angiogenesis and reduced the size of glioblastoma tumors in a mouse model over 22 days.…”

Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes

“…Main clinical trials published and for which we have sufficient data are detailed in Table 3 . Main indication is PDAC at an advanced stage (locally advanced and/or metastatic) with phases 1 and 2 trials and one phase 3 [ 101 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. Three types of strategies have been conducted: in situ gene therapy product injection (by means of EUS), vaccination (intradermal or subcutaneous route) and oncolytic virus administration.…”

Gene Therapy for Pancreatic Diseases: Current Status

“…In addition to pancreatic malignancies, ongoing studies are aimed to establish effective gene therapies for pancreatitis, pancreatic pain, and diabetes mellitus. Based on the several completed ( Table 1 ) and ongoing clinical trials [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ] ( Table 2 ), gene therapy offers a promising avenue as a safe and efficient approach [ 51 ].…”