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Electrochemotherapy is an established treatment modality in which chemotherapeutics are delivered systemically or locally in combination with local electrical pulses. Pulsing parameters are optimized to induce the reversible formation of pores in the cell membrane, leaving cells intact and healthy. Osmotic gradients during poration result in the rapid uptake of extracellular components, which results in enhanced chemotherapeutic uptake, between 5 to 2,000-fold depending on the hydrophobicity of the drug used. Complete local response rates for dermal lesions exceed 80%. Treatment is suitable for use in proximity to vasculature and offers superior cosmetic results in comparison to surgery when used in areas such as the eyelid or mouth. Recent advances have, however, been able to replace cytotoxic chemotherapeutic agents with calcium with no decrease in efficacy. The nature of cell death induced is believed to be acute, but to date has not been clearly characterized. Using Flou-4 to track the duration of elevated intracellular calcium concentrations, we have shown that elevated calcium levels persist for hours following treatment. Cell death occurs in 60-80% of cells treated in vitro within 8 hours of treatment. Cells surviving this initial insult show no detectable loss in survival or growth potential and appear otherwise unaffected. Necrotic cell death provides a significant source of damage-associated molecular patterns and may aid the generation of anticancer immune responses. Using cocultured macrophages, we have been able to show that treatment can indirectly boost cytotoxic T-cell responses via tumor-associated macrophages. The elucidation of cell death during treatment is critical for the effective optimization of clinical treatment parameters, which has hitherto been determined empirically. Other advances, such as the use of high-frequency electroporation, are transforming the clinical delivery. It is foreseeable that the requirement of surgical theaters may be avoided with the development of a pain-free treatment in the absence of cytotoxic drugs. Note:This abstract was not presented at the conference. Citation Format: Liam Friel Tremble, Cynthia Heffron, Patrick Forde. Calcium electroporation offers an effective local treatment with immunogenic cell death and the potential for systemic remission in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B63.

Tumor interstitial pressure is a fundamental feature of cancer biology. Elevation in tumor pressure affects the efficacy of cancer treatment. It causes heterogenous intratumoral distribution of drugs and macromolecules. It also causes the development of hypoxia within tumor bulk, leading to reduced efficacy of therapeutic drugs and radiotherapy. Tumor pressure has been associated with increased metastatic potential and poor prognosis in some tumors. The formation of increased pressure in solid tumors is multifactorial. Factors known to affect tumor pressure include hyperpermeable tortuous tumor vasculatures, the lack of functional intratumoral lymphatic vessels, abnormal tumor microenvironment, and the solid stress exerted by proliferating tumor cells. Reducing this pressure is known to enhance the uptake and homogenous distribution of many therapies. Pharmacologic and biologic agents have been shown to reduce tumor pressure. These include antiangiogenic therapy, vasodilatory agents, antilymphogenic therapy, and proteolytic enzymes. Physical manipulation has been shown to cause reduction in tumor pressure. These include irradiation, hyperbaric oxygen therapy, hyper- or hypothermic therapy, and photodynamic therapy. This review explores the methods to reduce tumor pressure that may open up new avenues in cancer treatment. Cancer Res; 74(10); 2655–62. ©2014 AACR.

Regulatory T cells (TRegs) constrain anti-tumour immunity and remain the most significant obstacle to successful immunotherapy of cancer. The immunosuppressive influence of these cells can be abrogated by depletion strategies, modulation of T cell plasticity and inhibition of function or migration. A novel and attractive strategy for inhibiting TReg function is RNA interference directed against their crucial transcription factor, FOXP3. RNA interference (RNAi) is still in its infancy as a therapeutic modality but holds great promise in terms of specificity and potency. Foremost within the TReg microRNA signature is micro-RNA 31 (miR-31) which specifically silences FOXP3, abolishing the suppressor capability of these cells. Translation of this promising therapeutic into the clinic hinges on surmounting an obstacle common to all gene therapy strategies - delivery. Cognisant of the dangers of off-target effects, our aim was to mediate cell-specific delivery of RNA interference. This would greatly enhance the clinical utility of this treatment modality. To achieve this objective we used a lentiviral vector, pseudotyped with mutated measles virus glycoproteins bearing an antibody single chain fragment variable. This strategy circumvents the native tropism of the measles virus potentially allowing for cell-specific RNA interference. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5645. doi:1538-7445.AM2012-5645