Detailed Cancer Ablation

Cancer Ablation

Rethinking Breast Cancer Therapy with an Injectable Polymer

The last 100 years has revolutionized the way we treat breast cancer – from radical mastectomies in the early 1900s to immunotherapies a century later. Yet, the basic approach to cancer treatment – surgery, radiation and chemotherapy, has remained largely unchanged. The more stubborn the tumor, the longer and more frequent the interventions, a perpetuating cycle that wears the body down. Modern drugs are able to reduce this indiscriminate killing of tumor cells by recognizing a single target molecule or mobilizing the patient’s immune system1. However, even in the best possible treatment scenarios a subset of the cancers will recur, increasing the cost of treatment without any guarantee of success. The more complex the procedures the greater the need for patient monitoring, a particularly challenging issue for those who do not live close to hospitals. There is an urgency to reimagine, redesign and restructure existing treatments to maximize therapeutic benefit without wearing the body down and without stretching resources to an unacceptable level. There is a compelling opportunity to maximize the benefit-to-risk ratio for the treatment of early-stage disease breast cancer.

Even if the majority of a tumor is drug-responsive, the survival of small drug-resistant subpopulations could be responsible for tumor recurrences. These residual cells escape therapy, enter a residual stage and eventually recur.

We have identified a natural, phase-changing polymer, ethyl cellulose, which we use as a scaffold to increase the efficacy, effectiveness and efficiency of breast cancer treatment. Ethyl cellulose is a freely flowing fluid in its soluble form; however, it undergoes a phase change into a biodegradable polymer gel in aqueous media encapsulating the solvent within a hydrophobic shell. We have shown that ethyl cellulose dissolved in ethanol changes from an inert polymer into an active therapeutic that has a local ablation effect. Ethanol disrupts tumor cells; ethanol mediated cell injury also releases tumor associated antigens to prime the immune system. However, this is only part of the solution. In cold tumors, immune cells on the periphery are unable to infiltrate the tumor. High metabolic activity and insufficient perfusion of tumors leads to the acidification of the tumor microenvironment, which can in turn inhibit T cell infiltration and activity. A neutralizing agent can be loaded into the polymer to reverse this effect. Chemotherapy drugs have also been used in polymers to increase bioavailability and decrease off-target effects. Certain chemotherapy drugs when delivered at low doses have the capability to suppress regulatory T cells. We have shown that local delivery of the ethanol infused polymer, systemic delivery of cyclophosphamide and oral delivery of sodium bicarbonate and this combination approach elicit a therapeutic effect that is T cell mediated; cured mice resist tumor rechallenge, indicating production of immune memory. The ethanol-polymer formulation reduces circulating myeloid derived suppressor cells (MDSCs), and recovers tumor response to immunotherapy, resulting in increased overall survival compared to the drug alone. This injectable therapeutic is relevant to populations where treatment is not accessible, and it can be used as an adjunct to boost existing treatments with checkpoint inhibitors.

Typically, when abnormal cells form in the body, the immune system is capable of identifying and killing these cells. T cells are associated with this type of response, and high densities of tumor infiltrating T cells are indicative of a good prognosis for breast cancers In addition, CD8 positive T cells can form antigen specific cytotoxic responses to tumor cells under the right conditions. The CD8+ cells are known to be the key effector cells in anti-tumor immunity and are also associated with a good prognosis. However, the immune system can be suppressed, and cancer can grow unchecked and metastasize without this immune regulation. As the cancer cells replicate and undergo metabolic changes, they create their own immunosuppressive environment that is characterized by high levels of lactic acid and hypoxia. Regulatory T cells, known as Tregs, and Myeloid derived suppressor cells, help the tumor grow, by further suppressing anti-tumor immunity. In this acidic and immunosuppressive environment, the CD8 cells undergo anergy and become exhausted, and once this change occurs it is hard to reverse.

ECE sensitizes 4T1 tumors to checkpoint blockade therapy. (A) Average tumor growth and (B) Kaplan–Meier survival curves of mice receiving either saline, ECE, CPI, or ECE + CPI, n = 10. * p < 0.05, ** p < 0.01, *** p < 0.001.

BiCyclA therapy reduced 4T1-luc tumor burden both locally and systemically. (A) Study timeline schematic for treatment of orthotopic 4T1-luc tumors. (B) Representative IVIS images from each treatment group with 4T1-luc tumors. (C) Representative whole-lung H&E and corresponding metastatic mask showing metastatic lesions in the lungs. (D) Average tumor volume over time. (E) Metastatic burden, or percent of lung area occupied by metastatic lesions, for each treatment group. Black bar represents average. (F) Survival rates for mice bearing 4T1-Luc tumors, n = 10. (G) Number of mice out of 10 per treatment group with no detectable metastases or primary tumor at day 60. Scale bar equals 5 mm in images.

When used in the clinic, ECE injection will occur under ultrasound guidance to ensure correct needle placement and observe the flow of injectate. (A) A representative schematic of how the injection will occur in the clinic. (B) A B-mode image of 10% ECE captured with the Clarius handheld ultrasound system. 1 ml of solution was injected manually. The needle is indicated by the red arrow while the injectate depot is circled in green.