Abstract
Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient–response rates. None of the current delivery strategies, including local administration aiming to avoid systemic toxicities, can sustainably supply drugs over the course of weeks; adjustment of drug dose, either to lower systemic toxicities or to augment therapeutic response, is not possible. Herein, we develop an implantable miniaturized device using electrode-embedded optical fibers with both local delivery and measurement capabilities over the course of a few weeks. The combination of local immune checkpoint blockade antibodies delivery via this device with photodynamic therapy elicits a sustained anti-tumor immunity in multiple tumor models. Our device uses tumor impedance measurement for timely presentation of treatment outcomes, and allows modifications to the delivered drugs and their concentrations, rendering this device potentially useful for on-demand delivery of potent immunotherapeutics without exacerbating toxicities.
Highlights
Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient–response rates
Immune checkpoint blockade (ICB) antibodies against cytotoxic T–lymphocyte–associated protein 4 (CTLA-4) or programmed cell death 1 (PD-1) have demonstrated that reactivating anti-tumor immune responses can lead towards tumor regression[1,2], and these ICB antibodies have been approved by the United States Food and Drug Administration (FDA) for the treatment of a broad range of tumors[3,4,5,6,7]
Tubing was inserted into the chip to connect to the inner channel of the fiber, which allowed for on-demand reloading of drugs (e.g., ICB antibodies) into the optical fiber
Summary
Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient–response rates. The modified antibodies can bind to normal collagen-containing tissues (e.g., connective tissues, artery walls), which may limit their efficacy and dose Another local administration strategy involves implanting degradable scaffolds or hydrogels loaded with immunotherapeutics, such as cytokines or ICB antibodies, to control the localization and activation of dendritic cells[25,26] or T cells[27,28,29]. This strategy shows superior efficacy to bolus injections, but a mechanism for dosage adjustment, either to lower systemic toxicities or to augment therapeutic responses, is largely lacking. We envision that localized delivery could be realized with an implantable miniaturized device with both delivery and measurement capabilities, preferably lasting for weeks at a time, because durable anti-tumor immunity requires prolonged drug retention[36]
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