Electrochemotherapy for the treatment of primary basal cell carcinoma; A randomised control trial comparing electrochemotherapy and surgery with five year follow up.

Basal cell carcinoma (BCC) are the commonest cutaneous malignancy and incidence continues to increase. There is a need to expand the therapeutic toolbox to increase options for patients that are unsuitable for or unwilling to undergo the current therapies. Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief pulsed electrical field and combined with low dose chemotherapeutics to ablate malignancies. It is a simple technique causing minimal damage to the surrounding healthy tissue and has the potential to avoid the need for complex reconstruction. ECT is an established treatment for skin metastases but its role as a primary treatment modality is not demonstrated. A prospective randomised control trial evaluating ECT against the gold standard of treatment, Surgery, was performed for patients with primary BCC and patients followed for 5 years. All lesions treated with ECT (n = 69) responded although 8/69 (12%) needed a second treatment to ensure a complete response. All surgical lesions (n = 48) showed histological evidence of complete excision with 2/48 (4%) undergoing a second excision. At 5 years, in the surgical arm there was no evidence of recurrence in 39/40 (97.5%) lesions with 1/40 (2.5%) confirmed recurrence. In the ECT arm there was no evidence of recurrence in 42/48 lesions (87.5%). There was 5 confirmed recurrences. These groups show statistical equivalence in this non inferiority study design (p = 0.33). ECT is an effective and durable treatment option for primary BCC and should be considered as part of the armamentarium of options available.

Non-viral immune electrogene therapy induces potent antitumour responses and has a curative effect in murine colon adenocarcinoma and melanoma cancer models.

Antitumour efficacy of electroporated pEEV, coding for granulocyte-macrophage colony-stimulating factor and the B7-1 costimulatory immune molecule (pEEVGmCSF-b7.1) in growing solid tumours, was investigated and compared with a standard plasmid. Application of pEEVGmCSF-b7.1 led to complete tumour regression in 66% of CT26-treated tumours and 100% in the B16F10-treated tumours at day 150 post-treatment. pEEVGmCSF-b7.1 treatment was found to significantly enhance levels of both innate and adaptive immune populations in tumour and systemic sites, which corresponded to significantly increased tissue levels of proinflammatory cytokines including interferon-γ (IFN-γ) and interleukin-12 (IL-12). In contrast, pEEVGmCSF-b7.1 treatment significantly reduced the T-regulatory populations and also the anti-inflammatory cytokine IL-10. Upon further characterisation of functional immune responses, we observed a significant increase in cytotoxic (CD107a+) and IFN-γ-producing natural killer cells and also significantly more in IL-12-producing B cells. Importantly, splenocytes isolated from pEEVGmCSF-b7.1-treated 'cured' mice were tumour-specific and afforded significant protection in a tumour rechallenge model (Winn assay). Our data indicate that electroimmunogene therapy with the non-viral pEEVGmCSF-b7.1 is able to induce potent and durable antitumour immune responses that significantly reduce primary and also secondary tumour growth, and thus represents a solid therapeutic platform for pursuing future clinical trials.

Enhancement of electroporation facilitated immunogene therapy via T-reg depletion.

Regulatory T cells (T-regs) can negatively impact tumor antigen-specific immune responses after infiltration into tumor tissue. However, depletion of T-regs can facilitate enhanced anti-tumor responses, thus augmenting the potential for immunotherapies. Here we focus on treating a highly aggressive form of cancer using a murine melanoma model with a poor prognosis. We utilize a combination of T-reg depletion and immunotherapy plasmid DNA delivered into the B16F10 melanoma tumor model via electroporation. Plasmids encoding murine granulocyte macrophage colony-stimulating factor and human B71 were transfected with electroporation into the tumor and transient elimination of T-regs was achieved with CD25-depleting antibodies (PC61). The combinational treatment effectively depleted T-regs compared to the untreated tumor and significantly reduced lung metastases. The combination treatment was not effective in increasing the survival, but only effective in suppression of metastases. These results indicate the potential for combining T-reg depletion with immunotherapy-based gene electrotransfer to decrease systemic metastasis and potentially enhance survival.

Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management.

Basal Cell Carcinoma (BCC) affecting the ocular region is potentially problematic due to its ability to infiltrate aesthetic and functional structures. Due to the paucity of local tissue, resection frequently requires reconstruction with skin grafts or local flaps. Surgical treatment may not be suitable for patients with multiple co-morbidities. Electrochemotherapy (ECT) is a technique where cells are temporarily permeabilized after exposure to a brief electrical field and when combined with normally impermeant chemotherapy drugs can resolve cutaneous cancers - even those previously recalcitrant to chemotherapy or radiotherapy. Its particular advantage is its speed of application and the minimal damage to the surrounding healthy tissue structures. We present a series of 3 patients with BCCs in the peri-ocular region and significant co-morbidities deemed unsuitable for surgical resection, who underwent ECT. The lesions were all primary BCC ranging in size from 0.5 cm(2) to 1 cm(2). Two lesions were on the upper eyelid and one on the lower eyelid. ECT was performed using an 8-needle electrode and a CE approved electroporation generator with intra-lesional Bleomycin. All lesions responded to treatment. All BCC's completely resolved, with acceptable scarring. No side effects were reported from the Bleomycin or the electric pulses. ECT for peri-ocular BCC is an adjunct to surgical excision in the management of surgically problematic lesions. This technique could provide a useful initial treatment option for patients who are medically unfit or where resection and would be associated with significant morbidity.

The emerging role of viruses in the treatment of solid tumours.

There is increasing optimism for the use of non-pathogenic viruses in the treatment of many cancers. Initial interest in oncolytic virotherapy was based on the observation of an occasional clinical resolution of a lymphoma after a systemic viral infection. In many cancers, by comparison with normal tissues, the competency of the cellular anti-viral mechanism is impaired, thus creating an exploitable difference between the tumour and normal cells, as an unimpeded viral proliferation in cancer cells is eventually cytocidal. In addition to their oncolytic capability, these particular viruses may be engineered to facilitate gene delivery to tumour cells to produce therapeutic effects such as cytokine secretion and anti -tumour immune responses prior to the eventual cytolysis. There is now promising clinical experience with these viral strategies, particularly as part of multimodal studies, and already several clinical trials are in progress. The limitations of standard cancer chemotherapies, including their lack of specificity with consequent collateral toxicity and the development of cross-resistance, do not appear to apply to viral-based therapies. Furthermore, virotherapy frequently restores chemoradiosensitivity to resistant tumours and has also demonstrated efficacy against cancers that historically have a dismal prognosis. While there is cause for optimism, through continued improvements in the efficiency and safety of systemic delivery, through the emergence of alternative viral agents and through favourable clinical experiences, clinical trials as part of multimodal protocols will be necessary to define clinical utility. Significant progress has been made and this is now a major research area with an increasing annual bibliography.