An image-guided immunotherapy and hyperthermia delivery device to overcome barriers to tumor immunity for advanced hepatocellular carcinoma

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ABSTRACT Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths in the US. Immunotherapy is a promising new treatment approach for HCC, but there are numerous barriers to immunotherapy in HCC. Local intratumoral injection of immunotherapies is a logical solution to overcoming these barriers, particularly given the fact that local immune activation can drive systemic tumor immunity. However, there are substantial gaps in knowledge regarding the intratumoral delivery of immunotherapies. When delivered through conventional needles, injected medications track along the needle path and leak out into the surrounding normal tissue. Not only does this minimize treatment efficacy due to diminished on-target delivery, but it also increases systemic toxicities. Moreover, even with local deposition of immunotherapies, persistent microenvironmental barriers can inhibit the generation of tumor immunity. This application will evaluate a novel intratumoral drug delivery system with an adjustable, electrically insulating sleeve specifically designed for intratumoral delivery of immunotherapies (ImFusion system). In addition to the controlled delivery of injected drugs, ImFusion also allows for radiofrequency-mediated intratumoral hyperthermia generation. Preliminary data show that the ImFusion system results in a substantial improvement in intratumoral drug delivery relative to conventional needles, and that its hyperthermia capabilities can “prime” the tumor microenvironment for immune activation. Our central hypothesis is not only that our ImFusion needle design will improve i.t. drug delivery, but also that the hyperthermia-mediated alterations to tumor vascularity will countervail immunologic barriers and augment i.t. immunotherapy efficacy. Accordingly, the overall objectives of this proposal are to understand how 1) variations in injection technique and thermal dose influence i.t. drug deposition, 2) hyperthermia affects tumor vascularity and immune microenvironments, and 3) hyperthermia complements i.t. immunotherapy in a syngeneic rat model of HCC. We will test our hypothesis in the following specific aims: 1) Define the influence of injection technique and hyperthermia on i.t. delivery; 2) Determine the tumor microenvironmental ramifications of hyperthermia as a function of thermal dose and time; and 3) Characterize the local and abscopal effects of hyperthermia when combined with i.t. immunotherapy. The proposal is innovative because it pursues a multimodality image-guided approach to maximize tumor immunity. In doing so, the paradigm of hyperthermia as a locoregional therapy is replaced with the paradigm of hyperthermia as an “immune primer.” The proposed research is significant because it is expected to have a broad translational impact on the efficacy of immunotherapy for patients with advanced HCC.