Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape

Hicks, Kristin C.; Chariou, Paul L.; Ozawa, Yohei; Minnar, Christine M.; Knudson, Karin M.; Meyer, Thomas J.; Bian, Jing; Cam, Margaret C.; Schlom, Jeffrey; Gameiro, Sofia R.

doi:10.1038/s41467-021-25393-x

Cited by 51 publications

(51 citation statements)

References 62 publications

(81 reference statements)

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“…NHS-IL12 in combination with entinostat has been shown to elicit robust antitumor activity against murine PD-L1 + /MHC-I + breast and colorectal tumors through IFN-γ-driven innate and adaptive immune cross-talk. 9 Here we examined the antitumor effects of NHS-IL12 plus entinostat as a potential combination therapy for patients harboring resistance to αPD-1/αPD-L1 therapies associated with defects in antigen presentation and IFN-γ signaling. Our data suggest that the antitumor effects in αPD-1/αPD-L1‒resistant tumor models were attained via epigenetic and IFN-γ-mediated induction of MHC-I/APM, CD8 + T, and NK cell-mediated antitumor immunity, engaging M1-like TAMs and other APCs, and decreasing suppressive cells in the TME.…”

Section: Discussionmentioning

confidence: 99%

“…NHS76 binds to exposed DNA fragments in necrotic areas, allowing delivery of immune stimulatory IL-12 into the tumor microenvironment (TME). 9 10 In the first in-human clinical study in patients with solid malignancies, NHS-IL12 was well tolerated with signs of clinical activity, although no objective responses, suggesting NHS-IL12 may achieve improved efficacy in a combinatorial setting. 11 …”

Section: Introductionmentioning

confidence: 97%

“… 14 15 Entinostat-mediated suppression of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) further supports its use in combination with immunotherapies. 15 16 Preclinically, entinostat was shown to promote tumor necrosis 9 15 and induce potent suppression of MHC-I + tumors in combination with NHS-IL12. 9 Entinostat has been proven safe and well tolerated in multiple clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“… 15 16 Preclinically, entinostat was shown to promote tumor necrosis 9 15 and induce potent suppression of MHC-I + tumors in combination with NHS-IL12. 9 Entinostat has been proven safe and well tolerated in multiple clinical trials. 17 …”

Section: Introductionmentioning

confidence: 99%

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Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies

Minnar

Chariou

Horn

et al. 2022

J Immunother Cancer

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BackgroundImmune checkpoint blockade (ICB) has achieved unprecedented success in treating multiple cancer types. However, clinical benefit remains modest for most patients with solid malignancies due to primary or acquired resistance. Tumor-intrinsic loss of major histocompatibility complex class I (MHC-I) and aberrations in antigen processing machinery (APM) and interferon gamma (IFN-γ) pathways have been shown to play an important role in ICB resistance. While a plethora of combination treatments are being investigated to overcome ICB resistance, there are few identified preclinical models of solid tumors harboring these deficiencies to explore therapeutic interventions that can bypass ICB resistance. Here, we investigated the combination of the epigenetic modulator entinostat and the tumor-targeted immunocytokine NHS-IL12 in three different murine tumor models resistant to αPD-1/αPD-L1 (anti-programmed cell death protein 1/anti-programmed death ligand 1) and harboring MHC-I, APM, and IFN-γ response deficiencies and differing tumor mutational burden (TMB).MethodsEntinostat and NHS-IL12 were administered to mice bearing TC-1/a9 (lung, HPV16 E6/E7+), CMT.64 lung, or RVP3 sarcoma tumors. Antitumor efficacy and survival were monitored. Comprehensive tumor microenvironment (TME) and spleen analysis of immune cells, cytokines, and chemokines was performed. Additionally, whole transcriptomic analysis was carried out on TC-1/a9 tumors. Cancer Genome Atlas (TCGA) datasets were analyzed for translational relevance.ResultsWe demonstrate that the combination of entinostat and NHS-IL12 therapy elicits potent antitumor activity and survival benefit through prolonged activation and tumor infiltration of cytotoxic CD8+T cells, across αPD-1/αPD-L1 refractory tumors irrespective of TMB, including in the IFN-γ signaling-impaired RVP3 tumor model. The combination therapy promoted M1-like macrophages and activated antigen-presenting cells while decreasing M2-like macrophages and regulatory T cells in a tumor-dependent manner. This was associated with increased levels of IFN-γ, IL-12, chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL13 in the TME. Further, the combination therapy synergized to promote MHC-I and APM upregulation, and enrichment of JAK/STAT (janus kinase/signal transducers and activators of transcription), IFN-γ-response and antigen processing-associated pathways. A biomarker signature of the mechanism involved in these studies is associated with patients’ overall survival across multiple tumor types.ConclusionsOur findings provide a rationale for combining the tumor-targeting NHS-IL12 with the histone deacetylase inhibitor entinostat in the clinical setting for patients unresponsive to αPD-1/αPD-L1 and/or with innate deficiencies in tumor MHC-I, APM expression, and IFN-γ signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies

Minnar

Chariou

Horn

et al. 2022

J Immunother Cancer

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“…Other pharmacological agents that block MDSC production including FATP2 inhibitor ( 189 ), the STAT3-specific inhibitor static ( 190 ), and the receptor tyrosine kinase (RTK) inhibitor sunitinib ( 189 ) can be combined with GM-CSF treatment to avoid potential immunosuppressive side effects of long-term GM-CSF treatment. Because GM-CSF suppresses the generation of beneficial M1 macrophages ( 132 ) that can produce the anti-cancer cytokine IL-12 in certain tumor types ( 118 ), IL-12-based therapies ( 191 , 192 ) may represent another promising approach to overcome GM-CSF-mediated activation of suppressive myeloid cells.…”

Section: Future Of Gm-csf-based Anti-cancer Therapies: Challenges And...mentioning

confidence: 99%

GM-CSF: A Double-Edged Sword in Cancer Immunotherapy

et al. 2022

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that drives the generation of myeloid cell subsets including neutrophils, monocytes, macrophages, and dendritic cells in response to stress, infections, and cancers. By modulating the functions of innate immune cells that serve as a bridge to activate adaptive immune responses, GM-CSF globally impacts host immune surveillance under pathologic conditions. As with other soluble mediators of immunity, too much or too little GM-CSF has been found to promote cancer aggressiveness. While too little GM-CSF prevents the appropriate production of innate immune cells and subsequent activation of adaptive anti-cancer immune responses, too much of GM-CSF can exhaust immune cells and promote cancer growth. The consequences of GM-CSF signaling in cancer progression are a function of the levels of GM-CSF, the cancer type, and the tumor microenvironment. In this review, we first discuss the secretion of GM-CSF, signaling downstream of the GM-CSF receptor, and GM-CSF’s role in modulating myeloid cell homeostasis. We then outline GM-CSF’s anti-tumorigenic and pro-tumorigenic effects both on the malignant cells and on the non-malignant immune and other cells in the tumor microenvironment. We provide examples of current clinical and preclinical strategies that harness GM-CSF’s anti-cancer potential while minimizing its deleterious effects. We describe the challenges in achieving the Goldilocks effect during administration of GM-CSF-based therapies to patients with cancer. Finally, we provide insights into how technologies that map the immune microenvironment spatially and temporally may be leveraged to intelligently harness GM-CSF for treatment of malignancies.

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Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

Strobl,

Zucchetta,

Vašíček

et al. 2024

Angewandte Chemie

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Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, toll‐like receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of Lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1'‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1')βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation.

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Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape

Cited by 51 publications

References 62 publications

Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies

Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies

GM-CSF: A Double-Edged Sword in Cancer Immunotherapy

Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

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