Small molecule drugs and biological macromolecules are currently being investigated as therapies for various types of disorders such as cancer and infectious disease. Generally, these agents are systemically administered. However, many immunomodulatory agents are active primarily on specific immune cells such as dendritic cells or T cells. The purpose of this study was to evaluate the efficacy of the novel delivery platform, DPX, for targeted delivery of immunomodulatory agents to the lymph node. As the lymph node is the primary site for priming and activation of immune cells, this approach may improve delivery over systemic administration resulting in increased drug efficacy, the use of less drug, and reduced off-target toxicity. To evaluate the efficacy of the DPX platform for lymph node-targeted drug delivery, we used the C57Bl/6 murine model. DPX formulation of small molecule dyes allowed us to visualize the kinetics of lymph node-specific delivery by visual assessments and by flow cytometry. DPX-dye formulations demonstrated a controlled and sustained uptake of molecules from the site of injection, travelling to the regional lymph node, without significant systemic exposure. To test impacts on tumor directed immune responses, the HPV16 E7 expressing C3 tumor model was used. Novel formulations were tested in conjunction with DPX-FP (a C3 tumor-specific antigen HPV16 E749-57 conjugated to a T helper epitope). DPX-mediated delivery of low doses of cyclophosphamide (CPA) were delivered subcutaneously as a single injection. This low dose of CPA has shown to act as an immunomodulatory agent when delivered systemically over a week. Using DPX to deliver CPA resulted in a significant reduction in the number of lymph node cells. This was evident after a single administration, showing equivalent therapeutic benefit was achieved with significantly less active agent. This was observed irrespective of whether CPA was administered alone or with DPX-FP. We also evaluated DPX delivery of the checkpoint inhibitor anti-CTLA-4. We found that administration in DPX was equivalent to systemic administration by intraperitoneal injection in terms of overall survival of tumor-bearing mice and in the proportion of CD3+ T cells bound by anti-CTLA-4, with fewer administrations of antibody. This demonstrates maintenance of biological functionality of macromolecules in the DPX platform. In conclusion, DPX holds promise in terms of lymph node-targeted delivery of functional agents. This delivery is facilitated by a sustained uptake from the site of injection and can offer reduced dosing and off-target toxicity as compared to systemic delivery. Many approaches to targeted therapies have failed to provide a therapeutic index commensurate with their promise through systemic delivery, with a challenge in achieving selectivity for the target cell type. Here, we show the DPX drug delivery platform has the potential to overcome this challenge and thereby increase the efficacy of immune and cancer therapies.
Citation Format: Heather Torrey, Ava Vila-Leahey, Yuchen Cen, Danielle MacKay, Alecia MacKay, Leanne Lucas, Brittany Myers, Arthvan Sharma, Douglas Vieira, Andrea Penwell, Rajkannan Rajagopalan, Marianne Stanford. DPX™ platform for drug delivery: Evaluation of lymph node-targeted delivery of immunomodulatory agents in DPX [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6257.