Other Clinical and Preclinical In Situ Cytokine Gene Therapy Approaches

A number of other cytokines have been proposed or used for prostate cancer gene therapy including, IL-2, IL-15, IL-18, and IL-24. In a neo-adjuvant phase I clinical trial of 24 patients with locally advanced prostate cancer, the cDNA for IL-2 was injected into the prostate as a lipid complex (72). It was well tolerated with no evidence of significant toxicity and yielded some evidence of systemic immune activation in the peripheral blood and in the radical prostatectomy specimens. The IL-2 gene has also been inserted into a vaccinia virus that coexpressed the MUC-1 gene, which was then delivered as an intramuscular injection to men with advanced prostate cancer (73). No toxicity was observed and one patient that received three doses had some evidence of systemic immune effects. IL-15 was shown to contribute to the development of NK and antitumor response to prostate cancer in a xenograft model with PC-3 tumors (74). IL-18 may synergize with IL-12 (75) and although it has not been used in gene therapy strategies for prostate cancer the recombinant protein has been used in combination with IL-12 gene therapy in a bladder cancer model (76). The IL-24 gene also known as a melanoma differentiation associated gene 7 (MDA-7) has been used in preclinical studies for prostate cancer gene therapy (77).

Intratumoral injection of the cDNAs for interferon-y, major histocompatability complex (MHC) class II transactivator and an antisense construct for a portion of the Ii gene has demonstrated tumor suppression in the RM-9 subcutaneous prostate cancer model (78). The addition of radiation therapy led to complete tumor regression and CTL activities and the ability to reject tumor challenge in long-term survivors. The IFN-P gene has also evaluated in prostate (79,80), bladder (81), and renal (82) cancer.

Delivery of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene in either a herpesvirus vector (83) or a canarypox vector (84) has been explored in preclinical models. The GM-CSF gene was combined with IFN-a gene for liposomal delivery in a bladder cancer model (85).

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