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  • br Introduction br Immunotherapy has emerged


    1. Introduction
    Immunotherapy has emerged as a robust and durable treatment option for a subset of patients; however, therapeutic efficacy has been limited to tumors with high mutational burdens and T-cell infiltration [1–5]. While immune checkpoints and co-stimulatory molecules have been effective for overcoming the inhibitory mechanisms largely dic-tated by the PD-1/PD-L1 axis, IDO, and regulatory T-cells in the T-cell-inflamed tumor micro-environment (TME), it has become apparent that new strategies may be required to treat non-T-cell-inflamed tumors [5]. For example, local adjuvant therapy can create an innate immune
    response that enhances efficacy [6–8]. The addition of chemotherapy to the protocol can further facilitate reaching the following goals: debulk large tumors, release tumor antigen for cross-presentation and cross-priming, release cancer-suppressive cytokines and retain circulating immune cell populations. Thermally-activated drug delivery particles have the potential to accomplish these goals as ultrasound or other treatment modalities can release the chemotherapy within bulky solid tumors to maximize the local response and minimize off-target effects. We set out to determine whether a single protocol could accomplish these goals and yield a potentially translational therapy.
    Chemotherapeutics have long been the clinical standard for the
    Corresponding author at: Department of Radiology, 3165 Porter Drive, Stanford University, Palo Alto, CA 94304, USA.
    E-mail address: [email protected] (K.W. Ferrara). 1 These two authors contributed equally to this work.
    A. Kheirolomoom, et al.
    treatment of solid tumors, yet the overwhelming majority of patients with metastatic disease do not have durable responses [9,10]. Che-motherapy is generally considered immune suppressive as it is cytotoxic to dividing Necrostatin-1 in lymphoid tissue, however, recent work has de-monstrated that a fraction of these drugs can induce cancer cells to undergo immunogenic cell death (ICD) [11]. ICD mediates tumor im-munity through the spatiotemporal release of soluble factors Necrostatin-1 that re-cruit leukocytes, support antigen processing and presentation, and sti-mulate tumor specific cytotoxic lymphocytes (CTL) [12,13]. The cumulative effect of ICD in response to anti-neoplastic agents has been reported to dramatically alter the composition of the tumor immune infiltrate toward an effector T-cell phenotype, which has a positive prognostic value [14–17]. Specifically, anthracyclines are a class of cytotoxic chemotherapeutics that are known to induce a potent ICD response [18], and as a result are of particular interest for the treatment of non-T-cell-inflamed-tumors. However, the dosing and duration of anthracyclines for treating metastatic cancer is limited due to the acute and cumulative cardiotoxicity incurred to the patient throughout treatment, and can be insufficient for overcoming tumor-mediated immune suppression [19].
    Doxorubicin-loaded liposomes have been employed to deliver a lo-calized dose of drug and circumvent the cardiotoxicity observed with anthracycline administration [20–23]. Previously, we formulated novel temperature-sensitive liposomes (TSL) loaded with a pH-sensitive complex between doxorubicin (Dox) and copper (CuDox) and demon-strated the efficient delivery of drug to a tumor in a murine model of multi-focal murine cancer [24,25]. This CuDox complex confers a highly-stable particle at physiological pH, thus minimizing the con-centration of circulating free Dox [24–26]. The local release of Dox is triggered by insonifying a tumor to mild-hyperthermic temperatures (~42 °C) via ultrasound (US). The incorporation of a toll-like receptor (TLR) 9 agonist, CpG, into a treatment protocol with CuDox-TSL and US (activatable drug delivery, ADD) enhanced the local response, where all directly-treated tumors were eliminated after 3 treatments over a one-week treatment protocol [26]. However, Ochre mutation treatment protocol was insufficient for overcoming tumor-mediated immune suppression in distant solid tumors. Similarly, we have previously shown that local administration of CpG combined with anti-PD-1 (αPD-1) could achieve a complete response in ~70% of mice with multisite disease; however, such a protocol is less effective when a greater tumor burden is present and therefore clinical management will require the incorporation of chemotherapy, surgery, or focal therapy [27].