Subcutaneous checkpoint inhibition is equivalent to systemic delivery when combined with nelitolimod delivered via pressure-enabled drug delivery for depletion of intrahepatic myeloid-derived suppressor cells and control of liver metastases

BackgroundToll-like receptor 9 (TLR9) agonists induce inflammatory responses that promote the killing of infectious micro-organisms, cancer cells and develop adaptive immune responses. Their ability as immunomodulators to enhance the activity of checkpoint inhibitors (CPI) in treating liver tumors i...

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Vydáno v:	Journal for immunotherapy of cancer Ročník 12; číslo 7; s. e008837
Hlavní autoři:	Ghosh, Chandra C, Cournoyer, Lauren, Liu, Yujia, Ballarin, Alizee, Layman, Ilan B, LaPorte, Jason, Morrissey, Molly, Fraser, Kayla, Perati, Shriya, Cox, Bryan F, Yakirevich, Evgeny, Treaba, Diana O, Murtha, Timothy D, Guha, Prajna, Katz, Steven C, Davar, Diwakar
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England BMJ Publishing Group Ltd 22.07.2024 BMJ Publishing Group LTD BMJ Publishing Group
Témata:	Animals Antigen presentation Bioluminescence Cell Line, Tumor Clinical/Translational Cancer Immunotherapy Costs Drug Delivery Systems Drug dosages Humans Immune Checkpoint Inhibitor Immune checkpoint inhibitors Immune Checkpoint Inhibitors - administration & dosage Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Inflammation Liver Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - secondary Melanoma Metastasis Mice Mice, Inbred C57BL Myeloid-derived suppressor cell - MDSC Myeloid-Derived Suppressor Cells - drug effects Myeloid-Derived Suppressor Cells - immunology Myeloid-Derived Suppressor Cells - metabolism Original Research Patient satisfaction Toll-like receptor - TLR Tumor microenvironment - TME Tumors Myeloid-derived suppressor cell - MDSC Toll-like receptor - TLR Immune Checkpoint Inhibitor Tumor microenvironment - TME
ISSN:	2051-1426, 2051-1426
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Popis
Shrnutí:	BackgroundToll-like receptor 9 (TLR9) agonists induce inflammatory responses that promote the killing of infectious micro-organisms, cancer cells and develop adaptive immune responses. Their ability as immunomodulators to enhance the activity of checkpoint inhibitors (CPI) in treating liver tumors is limited in part by the distinctive biology of intrahepatic myeloid-derived suppressor cells (MDSC) and challenges with tumor-specific therapeutic delivery. We have shown that the regional delivery of type C TLR9 agonist via pressure-enabled drug delivery (PEDD) system improves delivery to the tumor, enhances depletion of MDSCs and overall, stimulates the immune system in combination with or without CPI. Currently, CPIs are delivered intravenously, although there is a growing interest in its subcutaneous (SQ) administration. We compared nelitolimod formerly known as SD-101 administered using PEDD in combination with systemic (Sys) or SQ CPI in murine liver metastases (LM).MethodsThe LM model was developed by injecting MC38-Luc cells via the spleen of 8–12 week old male C57/BL6 mice followed by splenectomy. After a week, fluorescently labeled nelitolimod (10 µg/mouse) was delivered via PEDD and co-administered anti-programmed cell death-1 (α-PD-1) either via Sys or SQ. Tumor burden was monitored by in vivo imaging system. Serum cytokine levels were analyzed by Luminex. Tissues were harvested on Day 3 (D3) or Day 10 (D10) post-PEDD to enrich CD45+ cells and were analyzed via NanoString targeted transcriptomics (D3) or flow cytometry (FC, D10) to interrogate immune cell populations (D10). For NanoString analysis, the innate immune panels were selected, and for FC, MDSCs (CD11b+Gr1+), B cells (B220+), dendritic cells (DC, CD11c+), T (CD3+) cells, and M1-like macrophages (F4/80+CD38+Egr2−) were quantified.ResultsNelitolimod delivered via PEDD resulted in changes in innate and adaptive immune cells within LM, including depletion of liver MDSC and increased M1-like macrophages in the liver, which are supportive of antitumor immunity. While CPI monotherapy failed to control tumor progression, nelitolimod and CPI combination improved LM control, survival and antitumor immunity beyond the nelitolimod monotherapy effect, irrespective of CPI delivery route.ConclusionThe SQ route of CPI delivery was equivalent to Sys in combination with nelitolimod, suggesting SQ-CPI may be a rational choice in combination with PEDD of nelitolimod for liver tumor treatment.
Bibliografie:	Original research ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 CCG, YL, AB, JL, MM, KF, BFC, PG, SCK are employee of Trisalus Life Sciences. LC, IBL, SP, EY, DOT, TM have no conflict of interest. Conflict of interests of DD are: Grants/Research Support (institutional): Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK. Consultant: ACM Bio, Ascendis Pharma, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics. CE Speakers’ Bureau: Castle Biosciences. Intellectual Property: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, December 11, 2020 US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021. SCK and DD are joint senior authors. Supplement: Additional supplemental material is published online only. To view, please visit the journal online (https://doi.org/10.1136/jitc-2024-008837). Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
ISSN:	2051-1426 2051-1426
DOI:	10.1136/jitc-2024-008837