In situ gene therapy for prostate cancer: immunomodulatory approaches

Abstract

The development of effective treatments for prostate cancer is thwarted by the natural history of the disease. The biological and clinical potential of most individual cancers is uncertain. In many cases the disease will not progress to clinical significance but experimental and clinical studies indicate that prostate cancer can and may metastasis early in the course of the disease from relatively small foci (i.e., not necessarily the largest or index cancer). Localised prostate cancer is potentially curable with localised therapies (radical prostatectomy or irradiation therapy). However, there are no curative therapies for metastatic prostate cancer. Gene therapy, especially those approaches with an immunomodulatory component, may provide additional therapeutic options with the potential to affect both localised and systemic disease. We have pioneered the development and application of in situ gene therapy protocols using adenoviral vectors to transduce specific genes that generate cytotoxic activity and/or a systemic antitumour immune response. In addition we have completed initial studies that demonstrate the therapeutic potential of adenoviral vector-mediated gene modified cell-based vaccines. Our review discusses preclinical studies focused on the development of immunostimulatory in situ gene therapy approaches that hopefully will provide novel and effective treatments for localised and metastatic prostate cancer.

Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model

“…19 Since DC are potent professional APC with the capacity to induce tumorspecific CTL activity and potent antitumor effects, we reasoned that IL-12 gene-modified DC may offer an alternative and potentially more potent immuno-gene therapy by providing enhanced APC functions. 21,22 Consistent with other reports, 13,23 we needed a high moi of adenoviral vector to achieve significant IL-12 secretion by DC (see Fig 1). We therefore chose an moi of 3000 as our working condition of infection.…”

In vivo sodium iodide symporter gene therapy of prostate cancer

“…22 In addition, using adenoviral vectors efficient in vivo gene transfer has been demonstrated in numerous tissue types, including prostate tissue. 23 LNCaP tumors injected with Ad5-CMV-NIS accumulated 20.2 ± 11.4% of the total radioiodine dose administered with an average biological half life of 5.6 ± 1.4 h. Further, NIS protein expression in LNCaP cell xenografts was confirmed by Western blot analysis and immunohistochemistry using a mouse monoclonal NIS-specific antibody. Following intraperitoneal injection of a single therapeutic dose of 3 mCi 131 I 4 days after adenovirus-mediated intratumoral NIS gene delivery, LNCaP xenografts showed a clear therapeutic response with an average volume reduction of 84 ± 12%.…”

Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

“…2,17 In parallel with the development of gene therapy, there have been significant advances in the 18 New computer-assisted conformal means of delivering radiation specifically to target tumor tissues such as intensity modulated radiotherapy can provide dose escalation, while keeping the radiotherapy dose below the radiation threshold for adjacent normal tissue. 18 Importantly, there are significant advantages for combining gene therapy with XRT for enhancing the therapeutic index in several malignancies.…”