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

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 10(8) 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.

Anti-tumour activity against B16-F10 melanoma with a GM-CSF secreting allogeneic tumour cell vaccine

“…However, early reports of allogeneic vaccines modified to secrete IL-2 have reported a limited response. 20,21 As pre-clinical models for autologous vaccines show GM-CSF to be more potent than IL-2, it would seem logical to expect that this may also extend to allogeneic vaccines. A recent report 22 showed that GM-CSF enhanced the protective ability of autologous tumour vaccine cells modified to express an allogeneic MHC.…”

Immunotherapy for neuroblastoma using syngeneic fibroblasts transfected with IL-2 and IL-12

“…Cytokine adjuvant immunotherapy strategies for neuroblastoma have been investigated clinically with both autologous and allogeneic neuroblastoma tumour cells transduced with IL-2 (Bowman L et al, 1998;Bowman LC et al, 1998). Autologous cells were much more effective in these studies, but the difficulty of establishing cultures of purified primary neuroblastoma tumour cells rapidly has limited the wider exploitation of this approach.…”

Histone H2A-mediated transient cytokine gene delivery induces efficient antitumor responses in murine neuroblastoma

“…Six weeks postimmunization, one patient presented with a partial response, and four patients had stable disease. Subsequently, however, one of the patients with stable disease progressed to a complete tumor response (4). An alternative cytokine that has increasingly been used for cytokine gene therapy is IL-12, based on its ability to activate naïve T cells, thereby facilitating T cell priming in contrast to IL-2, which primarily amplifies and proliferates primed T cells.…”