Injectable Ablation Technique for Cancer Treatment Across Clinical Settings

Cancer treatment regimens often include surgery, radiation, and chemotherapy. Though the World Health Organization (WHO) Essential Medicines List includes many globally accessible chemotherapies, surgery and radiation are inaccessible to 90% of patients in low- and middle-income countries (LMICs) due to lack of infrastructure, medical specialists, and funds. Novel treatment options, such as immune checkpoint inhibitors (ICIs), are increasing in use in high income countries (HICs), but can be prohibitively expensive for patients, especially in LMICs. Further, even when accessible in HICs, ICI therapies are not always effective. Breast cancers are especially non-responsive to ICIs. There is a compelling need to advance and/or enhance therapies in both HICs and LMICs. We have developed a novel ablation therapy that encases ethanol in a polymer local destruction of tumors. This proposal shows how we can adapt this for both scenarios as described in greater detail below.Ablation, the chemical or thermal destruction of tissue, is an alternative or adjunct to surgery and radiation because it is less expensive, less time intensive and minimally invasive. In HICs ablation is mainly used for local tumor control, but it can also induce immunomodulation that aids systemic response. When used in combination with chemotherapy or ICI therapy, it can target local and systemic responses. However, LMICs, which often lack access to surgery, also lack access to thermal ablation methods such as radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation due to cost, reliability of electricity. Further, they often lack trained physicians and personnel to maintain equipment. Even in HICs, thermal ablation is not always accessible or possible due to tumor location, exclusion criteria, or cost. Overall, to achieve clinical translation of this therapy it is essential to understand both: 1) the effect of delivery parameters on distribution and necrosis and 2) the potential for combination of novel ablative therapies with chemotherapy and ICI therapy to inform treatment and practice. Ethanol ablation is portable and low-cost, allowing it to overcome treatment barriers in LMICs. However, ethanol ablation has limited treatment efficacy due to poor ethanol localization and off-target leakage. Incorporating ethyl-cellulose (EC), an ethanol-soluble, water-insoluble polymer, to ethanol help mitigate these limitations. EC-ethanol (ECE) transitions from liquid to fibrous gel upon injection into tissue (in-situ gelation). This acts to sequester ethanol, reduces off-target leakage and, overall, can improve ablation efficacy. ECE has the potential to create a more predictable distribution of ablation, therefore I investigated the impact of key components affecting the delivery and therapeutic effect of ECE (Aim 1) and investigate the biological impact of ECE in combination with current clinical treatment paradigms and as a novel drug delivery agent (Aim 2). Pursuit of these aims was intended to elucidate the efficacy, safety, and predictability of ECE ablation for use in cancer treatment and inform eventual clinical translation of this technology. The outcome should demonstrate that ECE is safe for human use and exhibits pharmacological activity, bringing this technology steps closer to investigation in clinical trials. Research in this dissertation pursued a thorough understanding of key factors governing the therapeutic effects of ECE with goal of informing translation of ECE to a clinical setting. I assessed the effect of formulation and delivery parameters on the resultant distribution or leakage and on necrosis. This can lead to algorithms enabling clinicians to select optimal tools and delivery methods to maximize treatment efficacy. Further, adoption of ECE in the clinical setting cannot be achieved without a clear understanding of the healing response to ablation and the safety of the procedure. Thus, time course analysis of the wound healing response and treatment safety compared to traditional ethanol ablation is necessary. To assess these key components, we need a method for assessment that allows for real time visualization of the ablation. For optimization we can us a high resolution more expensive technology, such as computed tomography, with the intent of adapting methods for more accessible technologies like ultrasound in the future. I developed a method for utilizing CT and investigated delivery parameters in both small and large animal models. In addition to investigating larger scale models to inform clinical translation (Aim 1), I also assessed these key determinants of injections success in small animal models to inform the biological mechanisms of injection efficacy (Aim 2). This led to investigating the synergy of ECE with ICI therapy and modification of the ECE formulation as a cytotoxic drug carrier. In particular, ECE ablation has potential for synergy with combination therapeutics, specifically immunotherapies and chemotherapeutic agents. This could have high potential for impact in HICs where implementation of immunotherapies and intensive chemotherapy regimens is more common and accessible. ECE exposes tumor antigens to T cells, evoking an immune-stimulatory response. I hypothesized that ECE can prime “cold” tumors to enhance response to ICI, for which many breast cancers are non-responsive. Previous work demonstrated that low- dose cyclophosphamide enhances the therapeutic effect of ECE. Therefore the combination of ECE ablation and low-dose cyclophosphamide was a logical choice to investigate a neoadjuvant therapy to enhance response to ICIs in non-responsive tumors. I hypothesized that the in-situ gelation of EC can be implemented to improve intra-tumoral drug delivery. Ethanol is know for its cytotoxic effects on cells. vehicle compared to many inert polymer vehicles. Combining ECE with chemotherapy (often, small drug molecules) as a local treatment could synergize apoptotic and necrotic cell death induced by the drugs and ethanol, respectively, a therapeutic process absent in traditional drug carriers. Thus, I focused upon effect of ECE on small molecule transport, drug uptake and distribution throughout the body over time, and also assessed safety and efficacy of this novel combination treatment. The goal of this dissertation research was to improve efficacy, safety, and predictability of ECE ablation. I aimed to optimize delivery of ECE, working to understand the effects of salient injection parameters on distribution and necrosis. I also investigated ECE ablation in combination with chemotherapies or ICIs, helping to lay the groundwork for clinical translation, and informing the foundation for local and systemic treatment responses. To achieve this goal, I completed two parallel aims. Aim 1 focused on delivery of ECE, specifically development of real-time assessment methods, infusion parameter assessment at preclinical and clinical scales, and investigation of resultant necrosis and the wound healing response. Aim 2 focused on investigating the utility, efficacy, and safety of the ECE formulation as a cytotoxic drug carrier, and examined the synergy of ECE with ICIs.