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.

Figure 1

(A) schematic of placement of capsules in vessels leading to the pancreatic tumor using supraselective angiography with a catheter being inserted into a vessel in the groin, followed by low-dose ifosfamide administration given intravenously (IV); (B) schematic of ifosfamide (prodrug) conversion by encapsulated cells. Ifosfamide (blue arrow) delivered systemically enters the porous capsules and penetrates the encapsulated cells, where it is converted by the cytochrome P450 enzyme to its active form (red arrow). The short-lived activated ifosfamide (white arrow) exits the cells and leaves the capsules to bathe the tumor.

Figure 2

Kaplan–Meier curves describing the survival of patients from the phase 1/2 trial (green boxes), the phase 2 trial (blue triangles) and an age and disease stage matched historic control group receiving the best available standard care (red diamonds).