The induction of immune responses to murine malignant mesothelioma by IL‐2 gene transfer

Abstract

Summary Stable IL-2 transfectanl clones have been derived frotn two non-immunogenic murine malignant tnesothelioma (MM) cell lines to investigate the induction of protective antitumour immunity to MM. AC29-IL-2 transfectant clones grew at a slower rate in vivo than the parental cell line or a transfectant control clone but all inoculated mice developed tumours despite the continued ability of the tumour cells to express IL-2. Tumour development after inoculation of ABl-IL 2 transfectants varied, the degree of in vivo inhibition (40-100%) being directly related to the rate of IL-2 secretion of the transfectants. When mice which had rejected the ABl-lL-2 transfectants were challenged with parental ABl cells, a proportion (16-709'f) of mice from each group remained tumour free at least 45 days after challenge (naive mice developed tumours within 26 days). The inhtbttion of growth ofthe initial inoculum of ABl-IL-2 transfectants was independent of CD4-' and CD8+ cells, consistent with the demonstration of non-specific cytotoxic activity by splenocytes from mice inoculated with the IL-2 transfectants. These data suggest that IL-2 expression by MM cells is capable of generating in vivo immunity to the tumour. This immunity may be relatively weak or may be subject to downregulation so that consistent rejection of unmodified tumour cells is not achieved. Genetic modification with combinations of genes, including lL-2 and B7-1. will be necessary for reliable generation of protective immunity to MM.

The immune anti-tumor effects of GM-CSF and B7-1 gene transfection are enhanced by surgical debulking of tumor

“…7,10,11,21 As control transfectants, tumor cells were transfected with the phb -Apr-neo vector alone and maintained as described above.…”

“…3,4 More recent treatment strategies for solid tumors such as MM, particularly gene therapy and immunotherapy, have shown some promise in both human 5,6 and murine studies. Several cytokines, including IL -2, 7,8 GM -CSF, 9 B7 -1, 10,11 IL -12, 12 IFN -, 13,14 and IFN - 15 have demonstrated significant antitumor effects. However, the delivery of these cytokines has been problematic, which has limited the use of these cytokines in clinical practice, hence the need for gene therapy approaches that aim to improve cytokine delivery.…”

Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: Persistent transgene expression despite antibody generation

“…MM is an untreatable tumor that is considered to be an ideal target disease for gene therapy approaches, particularly when seen in the context of a progressive increase in the incidence of this tumor worldwide. 18,19 Evidence that MM may be susceptible to immunotherapeutic approaches has come from a number of laboratories worldwide, and we have good evidence that the production of cytokines within MM deposits induces strong anti-MM immunity. We selected the IL-2 gene for our initial experiments because it had powerful effects in our animal model 19 and its effects in human cancer clinical trials have been well-described.…”

“…18,19 Evidence that MM may be susceptible to immunotherapeutic approaches has come from a number of laboratories worldwide, and we have good evidence that the production of cytokines within MM deposits induces strong anti-MM immunity. We selected the IL-2 gene for our initial experiments because it had powerful effects in our animal model 19 and its effects in human cancer clinical trials have been well-described. 2,20 -24 Our initial task was to evaluate the toxicity of this VV-cytokine construct.…”

“…16 There are also limited data from humans with MM supporting the concept that under some circumstances this disease may be susceptible to immunological approaches, such as the relationship between tumor-infiltrating lymphocyte proportions and prognosis, 17 partial responsiveness to the systemic immunomodulatory agent interferon-␣, 18 rare transient spontaneous regressions associated with lymphocytic infiltration (our unpublished observations), and our recently demonstrated association between MM regression and mononuclear cell infiltration in patients undergoing continuous intralesional infusion of recombinant granulocyte-macrophage colony-stimulating factor. 4 IL-2 had powerful anti-MM effects in our animal studies using cytokine gene transfer approaches in MM; 19 on that basis, this cytokine was chosen for our initial human clinical study.…”