Inhibition of established pancreatic cancers following specific active immunotherapy with interleukin-2 gene-transduced tumor cells.
Pancreatic cancer has a poor prognosis even when complete resection can be accomplished. Recent studies have demonstrated that the immune system is capable of mounting effective tumor-specific immune responses even against "nonimmunogenic" tumors. The studies reported herein were conducted to determine if induction of tumor-specific immune responses of inhibiting in vivo pancreatic tumor growth could be achieved through active immunization with pancreatic tumor cells genetically engineered to secrete interleukin-2 (IL-2). A relevant poorly immunogenic subcutaneous model of murine ductal pancreatic cancer was first developed using an implantable tumor cell line Panc02 in C57BL/6 mice. Panc02 cells were then genetically engineered to secrete human IL-2 (Panc02/IL2). The ability of irradiated Panc02/IL2 cells to stimulate an immune response capable of rejecting a subsequent tumor challenge was first demonstrated. Ninety percent of animals vaccinated with irradiated parental Panc02 and subsequently challenged with parental Panc02 cells developed tumors by 48 days (mean tumor volume of 234 mm3) compared to only 40% (P < .05, chi square) of animals vaccinated with irradiated Panc02/IL2 and challenged with parental Panc02 (14 mm3, P < .004, tau test). The therapeutic benefit of active immunization in tumor-bearing animals was then examined. Mice with 3-day-old established subcutaneous tumors were administered a series of 4 weekly vaccinations with irradiated Panc02 or Panc02/IL2 cells. A significant reduction in tumor growth was present in those animals vaccinated with Panc02/IL2 (P < .005, tau test) versus Panc02 or saline. Animals whose established tumors regressed following vaccinations with IL-2-secreting Panc02 cells were found to have long-lasting immunity as demonstrated by rejection of a tumor challenge presented over 140 days following inoculation of the primary tumor. We conclude that an immune response capable of inhibiting established pancreatic tumors can be generated by vaccination with IL-2-secreting tumor cells. Furthermore, long-term immunological memory was established in mice that rejected the original established tumor. These studies provide preclinical evidence to support the use of cytokine gene-transduced tumor cell vaccinations in patients with pancreatic cancer.
Clary
B M
BM
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Coveney
E C
EC
Philip
R
R
Blazer
D G
DG
Morse
M
M
Gilboa
E
E
Lyerly
H K
HK
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D000818:Animals; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000276:immunology / Q000628:therapy; D017690:Cell Transplantation; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D015395:Histocompatibility Antigens Class I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000235:genetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D011994:Recombinant Proteins