scholarly journals 765 The first-in-class small molecule TREX1 inhibitor CPI-381 demonstrates type I IFN induction and sensitization of tumors to immune checkpoint blockade

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A800-A800
Author(s):  
Costa Salojin ◽  
Anna Gardberg ◽  
Valerie Vivat ◽  
Lei Cui ◽  
Jeffrey Lauer ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Tumor Growth ◽  
Small Molecule ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I ◽  
Type I Ifn ◽  
Syngeneic Tumor

BackgroundTREX1 is an exonuclease that functions as a negative regulator of innate immunity. TREX1 controls dsDNA sensing in tumor and immune cells by preventing aberrant dsDNA buildup that triggers STING-mediated Type 1 Interferon (IFN) induction leading to priming of the adaptive immune system. Loss of function mutations in TREX1 and genetic ablation of trex1 in mice lead to induction of IFNbeta-driven autoimmunity. Thus, TREX1 is a promising target to elicit IFN-mediated anti-tumor immunity.MethodsTo characterize TREX1 inhibitors we developed cell-based assays utilizing human HCT116 carcinoma and THP-1 monocytic Dual reporter cell lines to monitor IRF activity. Activation of cGAS was assessed by measuring cGAMP levels in B16F10 melanoma cells. The potency of TREX1 inhibitors in primary human dendritic cells (DC)s was analyzed by measuring IFNbeta induction by exogenous dsDNA. Analysis of tumor growth inhibition following TREX1 inhibitor treatment was conducted in mouse syngeneic tumor models. TREX1 activity was assessed by measuring degradation of a custom dsDNA substrate.ResultsWe report here the development of a small molecule TREX1 inhibitor, CPI-381, with nanomolar cellular potency, which translated into a robust induction of IRF reporter activity. We observed a significant increase in cGAMP production in B16F10 cells transfected with DNA in the presence of CPI-381, suggesting that CPI-381-mediated inhibition of TREX1 leads to the activation of dsDNA sensors, such as cGAS. Treatment of THP-1 cells with CPI-381 induced the expression of several key ISG involved in innate immunity. Moreover, inhibition of TREX1 with CPI-381 phenocopied the effect of TREX1 genetic deletion in primary human DCs by upregulating IFNbeta. To evaluate whether TREX1 negatively regulates IFNbeta production in syngeneic tumor models, we knocked down trex1 in B16F10, MB49, MC38, and CT26 murine cells. Accumulation of cytosolic dsDNA resulted in a substantial increase in IFNbeta secretion by all four TREX1-KO cell lines.In vivo efficacy studies with CPI-381 demonstrated reduced tumor growth in the MC38 syngeneic tumor model either alone or in combination with anti-PD1. We observed a reduction of TREX1 activity in CPI-381 treated tumors, confirming an inverse relationship between TREX1 intra-tumor activity and tumor growth, and efficient target engagement after systemic (oral) delivery.ConclusionsWe have developed a first-in-class, potent TREX1 inhibitor demonstrating excellent in vitro and in vivo potency via enhancement of cytosolic dsDNA sensing and induction of IFNbeta in cancer and immune cells. CPI-381-induced tumor-intrinsic TREX1 inhibition elicits antitumor immunity as a single agent and increases response to immune checkpoint blockade via mechanisms downstream of TREX1 that activate type I IFN signaling.Ethics ApprovalAll animal work was approved and conducted under the oversight of the Charles River Accelerator and Development Lab (CRADL, Cambridge, MA) Institutional Animal Care and Use Committee (protocol # 2021-1258).

scholarly journals Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

2021 ◽  
Vol 9 (11) ◽  
pp. e002970
Author(s):  
Yu-Chao Zhu ◽  
Hany M Elsheikha ◽  
Jian-Hua Wang ◽  
Shuai Fang ◽  
Jun-Jun He ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Complete Regression ◽  
Type I

BackgroundIn this study, we hypothesize that the ability of the protozoan Toxoplasma gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint blockade. We examined the synergetic therapeutic activity of attenuated T. gondii RH ΔGRA17 strain and programmed death ligand-1 (PD-L1) treatment on both targeted and distal tumors in mice.MethodsThe effects of administration of T. gondii RH ΔGRA17 strain on the tumor volume and survival rate of mice bearing flank B16-F10, MC38, or LLC tumors were studied. We characterized the effects of ΔGRA17 on tumor biomarkers’ expression, PD-L1 expression, immune cells infiltrating the tumors, and expression of immune-related genes by using immunohistochemistry, immunofluorescence, flow cytometry, NanoString platform, and real-time quantitative PCR, respectively. The role of immune cells in the efficacy of ΔGRA17 plus PD-L1 blockade therapy was determined via depletion of immune cell subtypes.ResultsTreatment with T. gondii ΔGRA17 tachyzoites and anti-PD-L1 therapy significantly extended the survival of mice and suppressed tumor growth in preclinical mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma. Attenuation of the tumor growth was detected in the injected and distant tumors, which was associated with upregulation of innate and adaptive immune pathways. Complete regression of tumors was underpinned by late interferon-gamma-producing CD8+ cytotoxic T cells.ConclusionThe results from these models indicate that intratumoral injection of ΔGRA17 induced a systemic effect, improved mouse immune response, and sensitized immunologically ‘cold’ tumors and rendered them sensitive to immune checkpoint blockade therapy.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

scholarly journals Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

2017 ◽  
Vol 114 (51) ◽  
pp. E10981-E10990 ◽  
Author(s):  
Meredith L. Stone ◽  
Katherine B. Chiappinelli ◽  
Huili Li ◽  
Lauren M. Murphy ◽  
Meghan E. Travers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Histone Deacetylase Inhibitors ◽  
Unmet Need ◽  
Tumor Burden ◽  
Epigenetic Therapy ◽  
Type I ◽  
Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

scholarly journals Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5912
Author(s):  
Angèle Luby ◽  
Marie-Clotilde Alves-Guerra
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Metabolic Stress ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Therapeutic Approaches ◽  
Immunosuppressive Tumor Microenvironment

Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

Sequential and Timely Combination of a Cancer Nanovaccine with Immune Checkpoint Blockade Effectively Inhibits Tumor Growth and Relapse

2020 ◽  
Vol 59 (34) ◽  
pp. 14628-14638
Author(s):  
Yujin Kim ◽  
Sukmo Kang ◽  
Hocheol Shin ◽  
Taewoo Kim ◽  
Byeongjun Yu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals BCG vaccine and COVID-19: implications for infection prophylaxis and cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001119 ◽  
Author(s):  
Madhuri Koti ◽  
Alvaro Morales ◽  
Charles H Graham ◽  
David Robert Siemens
Keyword(s):  
Immune Checkpoint ◽  
Critical Role ◽  
Immune Checkpoint Blockade ◽  
Lessons Learned ◽  
Checkpoint Blockade ◽  
Childhood Vaccination ◽  
Infection Prevalence ◽  
Type I ◽  
Infection Prophylaxis ◽  
Vaccination Programs

The COVID-19 pandemic has killed over 400 000 people globally. Ecological evidence indicates that countries with national universal BCG vaccination programs for tuberculosis (TB) prevention have a much lower incidence of severe COVID-19 and mortality compared with those that do not have such programs. BCG is a century old vaccine used for TB prevention via infant/childhood vaccination in lowto middle-income countries with high infection prevalence rate and is known to reduce all-cause neonatal mortality. BCG remains the standard immunotherapy treatment for patients with high-risk non-muscle invasive bladder cancer globally for more than 44 years. Several trials are, therefore, investigating BCG as a prophylactic against COVID-19 in healthcare workers and the elderly. In this commentary, we discuss the potential mechanisms that may underlie BCG associated heterologous protection with a focus on tertiary lymphoid structure (TLS) organogenesis. Given the significance of TLSs in mucosal immunity, their association with positive prognosis and response to immune checkpoint blockade with a critical role of Type I interferon (IFN-1) in inducing these, we also discuss potentiating TLS formation as a promising approach to enhance anti-tumor immunity. We propose that lessons learned from BCG immunotherapy success could be applied to not only augment such microbe-based therapeutics but also lead to similar adjunctive IFN-1 activating approaches to improve response to immune checkpoint blockade therapy in cancer.

scholarly journals cGAS is essential for the antitumor effect of immune checkpoint blockade

2017 ◽  
Vol 114 (7) ◽  
pp. 1637-1642 ◽  
Author(s):  
Hua Wang ◽  
Shuiqing Hu ◽  
Xiang Chen ◽  
Heping Shi ◽  
Chuo Chen ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Antitumor Effect ◽  
Adaptor Protein ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I Interferons ◽  
Type I ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Cross Presentation

cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment. Consistently, intramuscular delivery of cGAMP inhibited melanoma growth and prolonged the survival of the tumor-bearing mice. The combination of cGAMP and PD-L1 antibody exerted stronger antitumor effects than did either treatment alone. cGAMP treatment activated dendritic cells and enhanced cross-presentation of tumor-associated antigens to CD8 T cells. These results indicate that activation of the cGAS pathway is important for intrinsic antitumor immunity and that cGAMP may be used directly for cancer immunotherapy.

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