Interleukin-2 Gene-Modified Allogeneic Tumor Cells for Treatment of Relapsed Neuroblastoma

Publisher Website
Google Scholar
Abstract
Tumor cells that have been genetically modified to express immunostimulatory genes will induce effective antitumor responses in a range of syngeneic animal models. For human applications, transduced autologous tumor cell lines are often difficult or impossible to prepare, so that there are strong incentives for substituting a standardized allogeneic tumor cell line. However, such lines may be inferior immunogens if they differ from host tumors in the antigens they express. We have evaluated the safety, immunostimulatory, and antitumor activity of an interleukin-2-secreting allogeneic neuroblastoma cell line in 12 children with relapsed stage IV neuroblastoma. They received two to four subcutaneous injections of cells in a dose-escalating schedule, up to a maximum of 108 cells per injection. There was induration and pruritus at the injection site, and skin biopsies revealed mild panniculitis with CD3+ cells surrounding scanty residual tumor cells. There was a limited but significant peripheral monocytosis. No patient showed any increase in direct cytotoxic effector function against the immunizing cell line, but 3 patients had a rise in the frequency of neuroblastoma-reactive cytotoxic T lymphocyte precursor cells. One child had > 90% tumor response (PR), 7 had stable disease, and 4 had progressive disease in response to vaccine alone. Although these results offer some encouragement for the continued pursuit of allogeneic vaccine strategies in human cancer, the antitumor immune responses we observed are inferior to those obtained in an earlier immunization study using autologous neuroblastoma cells. Hence, we suggest that this earlier approach remains preferable, its difficulties notwithstanding. When tumor cells are genetically modified to express immunostimulatory molecules, they may generate an immune response that is active against unmodified tumor cells elsewhere in the host. It would be simpler to apply this approach to humans if a standardized tumor cell line could be genetically modified and used for all patients in a study, rather than growing and modifying tumor cells from each individual. We have determined the effects of such allogeneic tumor cells, modified to secrete interleukin-2, in children with relapsed neuroblastoma. Our results show only limited antitumor immunologic activity and suggest that allogeneic lines are likely to prove inferior immunogens compared with autologous tumor cells.