Sustained Intratumoral Administration of Agonist CD40 Antibody Overcomes Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

Abstract

Agonist CD40 monoclonal antibodies (mAb) is a promising immunotherapeutic agent for cold‐to‐hot tumor immune microenvironment (TIME) conversion. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer known as an immune desert, and therefore urgently needs more effective treatment. Conventional systemic treatment fails to effectively penetrate the characteristic dense tumor stroma. Here, it is shown that sustained low‐dose intratumoral delivery of CD40 mAb via the nanofluidic drug‐eluting seed (NDES) can modulate the TIME to reduce tumor burden in murine models. NDES achieves tumor reduction at a fourfold lower dosage than systemic treatment while avoiding treatment‐related adverse events. Further, abscopal responses are shown where intratumoral treatment yields growth inhibition in distant untreated tumors. Overall, the NDES is presented as a viable approach to penetrate the PDAC immune barrier in a minimally invasive and effective manner, for the overarching goal of transforming treatment.

Intratumoral nanofluidic system enhanced tumor biodistribution of PD‐L1 antibody in triple‐negative breast cancer

“…A single dose of 100 μg αPD‐L1‐AF700 was given via IP or bolus IT injection. αPD‐L1‐AF700 loaded NDES devices with release rates of ~7.6 ± 1.5 μg per day (cumulative release over 14 days of 105.8 ± 20.5 μg) 45,46 were implanted intratumorally in a one‐time minimally invasive procedure. Seven days post‐administration, we evaluated αPD‐L1‐AF700 distribution and retention within the tumor using immunofluorescence imaging.…”

“…A single dose of 100 μg αPD-L1-AF700 was given via IP or bolus IT injection. αPD-L1-AF700 loaded NDES devices with release rates of $7.6 ± 1.5 μg per day (cumulative release over 14 days of 105.8 ± 20.5 μg) 45,46 were implanted intratumorally in a one-time minimally invasive procedure.…”

“…44 We posit that liver accumulation contributed to toxicities and adverse effects in systemic-treated mice. 43,45,46 Here, we collected liver, lung, kidney, spleen, and inguinal lymph node (LN) from radiated and non-radiated 4T1 and EMT6 mice at designated time points to assess αPD-L1-AF700 presence via ex vivo IVIS imaging (Figures S6-S11). Radiance values of each organ were presented in bar graphs for visualization of αPDL1-AF700 biodistribution from three different delivery routes over 14 days (Figures S12 and S13).…”

“…[39][40][41] To resolve challenges related to repeated IT injections, as well as to enhance antitumor immune response and reduce the risk of systemic toxicity, we developed a long-term sustained local drug release platform. [42][43][44][45][46] Our IT drug delivery platform, termed the nanofluidic drug-eluting seed (NDES), leverages a Si-SiC-based nanochannel membrane for continuous, controlled therapeutic release. 47,48 In a previous study, we demonstrated that sustained release of αCD40 and αPD-L1 mAbs via the NDES significantly reduced 4T1 murine TNBC tumor burden, induced CD8+ T cells tumor infiltration, and most importantly, avoided TRAE compared to systemic delivery.…”

“…To resolve challenges related to repeated IT injections, as well as to enhance antitumor immune response and reduce the risk of systemic toxicity, we developed a long‐term sustained local drug release platform 42–46 . Our IT drug delivery platform, termed the nanofluidic drug‐eluting seed (NDES), leverages a Si‐SiC‐based nanochannel membrane for continuous, controlled therapeutic release 47,48 .…”