Intratumoral neoadjuvant immunotherapy based on the BO-112 viral RNA mimetic

Molina, Carmen; Garasa, Saray; Ochoa, M. Carmen; Rodríguez-Ruiz, María E.; Gomis, Gabriel; Cirella, Assunta; Olivera, Irene; Glez-Vaz, Javier; González-Gomariz, José; Luri-Rey, Carlos; Bolaños, Elixabet; Teijeira, Álvaro; Berraondo, Pedro; Quintero, Marisol; Melero, Ignacio

doi:10.1080/2162402x.2023.2197370

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…TAMs (18-20), but not poly(I:C), which has been mainly applied in the form of nanocomplexes through i.t. administration (23)(24)(25)(26). Our results show significant reduction of lung tumors and activation of systemic immunity (CXCL10 and IL-6, but not TNF-a), with no apparent toxicity.…”

Section: Discussionmentioning

confidence: 54%

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Polymeric nanocapsules loaded with poly(I:C) and resiquimod to reprogram tumor-associated macrophages for the treatment of solid tumors

Anfray,

Varela,

Ummarino

et al. 2024

Front. Immunol.

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BackgroundIn the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer. Toll-like receptors (TLRs) ligands, such as poly(I:C) or resiquimod (R848) are able to reprogram TAMs towards M1-like antitumor effector cells. The objective of our work has been to develop and evaluate polymeric nanocapsules (NCs) loaded with poly(I:C)+R848, to improve drug stability and systemic toxicity, and evaluate their targeting and therapeutic activity towards TAMs in the TME of solid tumors.MethodsNCs were developed by the solvent displacement and layer-by-layer methodologies and characterized by dynamic light scattering and nanoparticle tracking analysis. Hyaluronic acid (HA) was chemically functionalized with mannose for the coating of the NCs to target TAMs. NCs loaded with TLR ligands were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry, using primary human monocyte-derived macrophages. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry and multispectral immunophenotyping.ResultsWe have developed polymeric NCs loaded with poly(I:C)+R848. Among a series of 5 lead prototypes, protamine-NCs were selected based on their physicochemical properties (size, charge, stability) and in vitro characterization, showing good biocompatibility on primary macrophages and ability to stimulate their production of T-cell attracting chemokines (CXCL10, CCL5) and to induce M1-like macrophages cytotoxicity towards tumor cells. In mouse tumor models, the intratumoral injection of poly(I:C)+R848-protamine-NCs significantly prevented tumor growth and lung metastasis. In an orthotopic murine lung cancer model, the intravenous administration of poly(I:C)+R848-prot-NCs, coated with an additional layer of HA-mannose to improve TAM-targeting, resulted in good antitumoral efficacy with no apparent systemic toxicity. While no significant alterations were observed in T cell numbers (CD8, CD4 or Treg), TAM-reprogramming in treated mice was confirmed by the relative decrease of interstitial versus alveolar macrophages, having higher CD86 expression but lower CD206 and Arg1 expression in the same cells, in treated mice.ConclusionMannose-HA-protamine-NCs loaded with poly(I:C)+R848 successfully reprogram TAMs in vivo, and reduce tumor progression and metastasis spread in mouse tumors.

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Section: Discussionmentioning

confidence: 54%

“…Similarly, poly(I:C)-nanoparticle based formulations (i.e. BO-112 ® ) or poly-ICLC (Hiltonol ® ), a synthetic analogue of dsRNA which mimics RNA from viruses binding to endosomal TLR3, have shown better stability in vivo versus the free drug, and are being tested in clinical trials (23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Polymeric nanocapsules loaded with poly(I:C) and resiquimod to reprogram tumor-associated macrophages for the treatment of solid tumors

Anfray,

Varela,

Ummarino

et al. 2024

Front. Immunol.

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“…It also decreases Tregs and increases anti-tumor cytokine production. NCT03131765 BO-112 TLR3 RIG-I MDA5 Nanoparticles Intravenous Approved for clinical trials in resectable soft tissue sarcoma A nanoplexed form of poly (I:C) that aims to mimic viral particles loaded with dsRNA of viral features 686 NCT04420975 Rintatolimod (Ampligen) TLR3 dsRNA Intravenous Approved for clinical trials in metastatic PDAC A mismatched, dsRNA molecule. Does not activate MDA5 and RIG-I; Development for the treatment of a variety of chronic diseases and viral disorders, such as chronic fatigue syndrome 687 NCT05927142 NCT00215813 G100 (GLA-SE) TLR4 Lipid A derivative Intratumoural Approved for clinical trials in various cancers, including sarcoma, lymphoma A synthetic lipid A derivative composed of glucopyranosyl lipid-A (GLA) in a stable, oil-in-water emulsion (GLA-SE) NCT02387125 NCT02501473 GSK1795091 TLR4 Lipid A derivative Intravenous Approved for clinical trials in cancers A synthetic analog of bacterial lipid A.…”

Section: Cancer Therapeutic Strategies Targeting Innate Immune Pathwaymentioning

confidence: 99%

Harnessing innate immune pathways for therapeutic advancement in cancer

Hu,

Sun,

Lin

et al. 2024

Sig Transduct Target Ther

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The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor’s innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

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“…16 Among different available cancer immunotherapy tools, intratumoral administration of pathogen-associated molecular patterns or damage-associated molecular patterns stands out in this regard. [21][22][23][24] These microbial molecular patterns are recognized by innate receptors, such as toll-like receptors (TLRs), activating cancer immunity. Polyinosinic:polycytidylic acid (poly(I:C)) is a synthetic molecule that mimics double-stranded RNA.…”

Section: What This Study Addsmentioning

confidence: 99%

Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C

Gomar,

Di Trani,

Bella

et al. 2024

J Immunother Cancer

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BackgroundLymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored.MethodsWe assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination’s efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials.ResultsIntratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included.ConclusionIntratumoral injection of poly(I:C) sensitizes MHClowtumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.

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Intratumoral neoadjuvant immunotherapy based on the BO-112 viral RNA mimetic

Cited by 7 publications

References 26 publications

Polymeric nanocapsules loaded with poly(I:C) and resiquimod to reprogram tumor-associated macrophages for the treatment of solid tumors

Polymeric nanocapsules loaded with poly(I:C) and resiquimod to reprogram tumor-associated macrophages for the treatment of solid tumors

Harnessing innate immune pathways for therapeutic advancement in cancer

Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C

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