Cytokine Modified Dendritic Cells

DCs are extremely efficient APCs that are widely dispersed in tissues and peripheral blood. Because they can be manipulated ex vivo and are perhaps the most specialized APCs they have been considered the prime candidates for cell mediated cancer therapy. A number of clinical trials using DC have been performed for prostate cancer (109-116) as well as other cancers (see ref. 117 for a review of the first 1000 trials). Although melanoma is the most commonly treated cancer using DC immunotherapy, GU cancers, notably, renal and prostate, are also being evaluated (118). Most of these studies involve DC primed with specific polypeptides that will bind MHC Class I or II molecules or with tumor lysates. Tumor derived mRNA transfected into DCs is being used to circumvent the challenge of lack of identity of TAAs. In current clinical trials DCs are most often injected intradermally or subcutaneously and less commonly intravenously or into a lymph node (118). A challenge with current clinical trials is proving efficacy in the patient population that is typically enrolled in phase I studies, advanced disease states typically with large tumor burdens, in whom it may be more difficult to demonstrate clinical and immunological responses (118).

Cytokine modified DCs have been used less extensively but have the advantage of not requiring knowledge of specific tumor antigens. As mentioned above (see Section 3.1.) a significant challenge in prostate cancer immunotherapy is the lack of well-characterized tumor antigens. Because specific cytokines promote intensive antitumor cytotoxicity and can also promote a specific CTL response, potentially obviating the need to provide specific exogenous TAAs (see Section 2.3.), we undertook studies with IL-12 modified DCs using the 178-2 BMA metastatic mouse prostate cancer preclinical model (119) using tumor lysates generated either in situ or ex vivo. We relied on the generation of tumor lysate in situ by delivering adenoviral vector mediated IL-12 gene transduced DCs directly into orthotopic tumors. We compared this novel approach with DC targeting with subcutaneous delivery of adenoviral vector mediated IL-12 transduced DCs that were pulsed with tumor lysates prior to injection. Direct in situ delivery of IL-12 transduced DCs was moderately more effective than the subcutaneous route of administration based on enhanced local growth suppression, reductions in spontaneous metastatic activities and, importantly, a significant increase in the survival of animals. Our results also demonstrated an overlap in cellular mechanisms underlying the therapeutic responses in that both protocols had comparable increases in NK activity and CTL responses.

Clinically, cytokine modified DCs might be used in several situations. The most common delivery method for DCs in clinical trials has been intradermal or subcutaneous and it is conceivable that tumor lysates derived from radical prostatectomy specimens could be used in these protocols in men at high risk of recurrence. It has been shown that migration to lymph nodes of intradermal administered DCs is inefficient if the cells are immature (120), thus cytokine modified could acquire better homing to sites where they would be more effective. It would be informative to evaluate RTVP-1 in this regard since we have shown that this secreted molecule can enhance DCs migration to tumor sites (71). Our studies also suggest that cytokine modified DCs could be injected intra-tumorally and used in a neoadjuvant approach preradical prostatectomy or as an adjuvant to radiation therapy. Intratumoral delivery could also be used independently or potentially in combination with other systemic chemo- or immuno-therapy agents or with other in situ gene therapy protocols in either the neo-adjuvant or adjuvant setting. Overall, numerous studies confirm that opportunities exist for cytokine modified DCs to be used clinically in prostate cancer, however, one challenge may be the considerable financial and logistic support required for their isolation and preparation (121).

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