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Biotech / Medical : Provectus Pharmaceuticals Inc. -- Ignore unavailable to you. Want to Upgrade?


To: pincus who wrote (12248)7/19/2013 2:51:22 PM
From: Bradpalm1  Respond to of 13111
 
Very interesting discussion....

Intralesional (IL) therapies for melanoma have been undertaken for over forty years with a variety of agents including cytokines, pathogens and various pharmaceutical drugs. Some of these agents, such as intralesional IL-2 therapy, were found to be effective for inducing local disease control [14]. However, few intralesional agents have induced a systemic response evidenced by the regression of bystander, untreated lesions. Bacillus Calmette-Guérin (BCG) is the most extensively studied of these agents. BCG has been used since the 1970s for local control of melanoma and is able to induce regression of untreated lesions in 15–20% of patients [15][19].

Recently, PV-10 has been used as an IL therapy for malignancies including melanoma. In initial clinical testing, PV-10 therapy induced regression of both uninjected as well as injected melanoma lesions [10]. Intralesional BCG has been associated with patient fatalities due to anaphylactic hypersensitivity reactions that have not been reported with PV-10 [20][24]. In mice, it has been shown that repeated injections of high dose BCG by the s.c route led to mortality [25], indicating that PV-10 may be safer than BCG for intralesional therapy. In this study, we verified that IL PV-10 resulted in regression of untreated bystander lesions in breast cancer and melanoma mouse models. In both models, IL PV-10 was associated with enhanced tumor-specific interferon-? secretion. These results confirm that IL PV-10 can induce a systemic anti-tumor immune response that can mediate the regression of untreated lesions.

The mechanism by which PV-10 induces systemic immunity is currently unknown. Our studies have shown that direct injection into a tumor lesion is required for the systemic effects of PV-10 as injection of PV-10 into the flank had no effect on distant lung lesions (not shown). After IL injection, PV-10 has been shown to accumulate in the lysosomes of tumor cells resulting in tumor necrosis [11]. It is possible that tumor ablation by PV-10 leads to the release of large amounts of tumor debris that is taken up by antigen-presenting cells such as DCs. The effect of PV-10 on DCs and immune cell infiltration into treated tumor lesions is currently being explored.

While IL-PV-10 therapy alone is capable of inducing an effective systemic anti-tumor immune response, combination of IL PV-10 with other forms of immunotherapy may lead to enhanced responses. It has been shown that tumor ablation in combination with anti-CTLA-4 antibody leads to enhanced anti-tumor immunity in the B16 model [26]. We have shown that direct intratumoral injection with CpG can enhance anti-tumor effects mediated by DC vaccinations [5]. In our study, we demonstrated that systemic anti-tumor immunity in untreated tumor-bearing mice could be mediated by the adoptive transfer of T cells isolated from PV-10 treated mice. As our group has extensive experience with adoptive T cell therapy for the treatment of metastatic melanoma [27], [28], our results support the hypothesis that PV-10 treatment may be combined with adoptive cell therapy to boost the immune response in patients subsequently undergoing adoptive cell therapy.

These studies have demonstrated that intralesional PV-10, in addition to reducing the growth of a directly injected tumor, leads to the induction of a robust anti-tumor T cell response and supports the use of PV-10 to induce systemic anti-tumor immunity for the treatment of metastatic melanoma and breast cancer.

plosone.org



To: pincus who wrote (12248)7/19/2013 4:49:06 PM
From: NTTG1 Recommendation

Recommended By
Pogeu Mahone

  Read Replies (2) | Respond to of 13111
 
Based on?