Synergy of vaccination and agonist OX40 treatment-toward a mechanism-driven combination of glioma immunotherapy.
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ABSTRACT:
SUBMITTER: Deumelandt K
PROVIDER: S-EPMC5761563 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
Synergy of vaccination and agonist OX40 treatment-toward a mechanism-driven combination of glioma immunotherapy.
Deumelandt Katrin K Platten Michael M Ochs Katharina K
Neuro-oncology 20180101 1
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Project description:BackgroundGlioma immunotherapy is an active area of clinical investigation. Glioma-associated immunosuppression remains an obstacle to efficacious immunotherapy, and combination approaches are likely necessary for durable success. OX40 is a member of the tumor necrosis factor receptor superfamily that is upregulated on activated lymphocytes, ligation of which results in enhanced activity and may be active against cancer. We sought to confirm the efficacy of agonist anti-OX40 immunotherapy against glioma and hypothesized that it is complementary with irradiated whole tumor cell vaccination.MethodsGL261 tumor cells were implanted into the right frontal lobes of syngeneic mice, which were then treated with controls, agonist anti-OX40 monoclonal antibody, vaccination with subcutaneous injection of irradiated granulocyte macrophage colony stimulating factor (GM-CSF)-expressing GL261 cells (GVAX), or vaccination + agonist anti-OX40 therapy. Animals were followed for survival. On day 18, splenocytes were harvested for enzyme-linked immunosorbent spot analyses and brains were harvested for immunohistochemistry and flow cytometry analyses of infiltrating lymphocytes.ResultsCombination immunotherapy with GVAX and systemic agonist anti-OX40 monoclonal antibody improved survival by 14 days over controls (median survival 36 vs 22 days, P < 0.00005). Systemically, T helper cell type 1 (Th1) antitumor immunity was enhanced significantly by combination therapy. In the brain, combination immunotherapy increased the percentage of Th1 CD4+ T lymphocytes and reduced the fraction that were Th2. In the brain, vaccination improved the ratio of CD8+ to FoxP3+ T lymphocytes, while combination immunotherapy reversed intracranial T-lymphocyte exhaustion, reducing their coexpression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as well as PD-1 and lymphocyte-activation gene 3 (LAG-3).ConclusionsAnti-OX40 immunotherapy is active against intracranial glioma and synergizes with GVAX. Vaccination and anti-OX40 immunotherapy are mechanistically complementary, particularly in the glioma microenvironment.
| S-EPMC5761505 | biostudies-literature
Project description:Various cancer vaccines have been developed to generate and amplify antigen-specific T cell responses against malignancy. Among them, in situ vaccination is one of the most practical types as it can trigger immune responses without previous antigen identification. Here we reported a novel in situ vaccine by intratumoral injection of imiquimod and OX40 agonist. In mice bearing hepatic carcinoma, both the injected tumor and the noninjected tumor in the distant lesion of the same mice were suppressed after vaccination. Further studies found that this in situ vaccine triggered systemic tumor-specific responses, with one-fold increase of effector memory T cells properties and stronger toxicity of lymphocytes in spleen. Besides, we found that imiquimod upregulated the expression of OX40 on CD4+ T cells and thus enhanced the effectiveness of OX40 agonist. Five immune-positive-related pathways were activated after vaccination. This in situ vaccine caused little harm to normal organs and provided long-term protection against the same syngeneic tumor rechallenge. Due to its effectiveness, feasibility and safety, this strategy could potentially be applied to various types of late-stage solid tumors and worthy of further clinical research.
| S-EPMC8586665 | biostudies-literature
Project description:Single-agent immunotherapy, including with immune checkpoint inhibition with anti-PD-1 antibody, has not extended survival in patients with malignant glioma. However, PD-1 inhibition may still play a role in combination immunotherapy with multiple agents. In this study, we evaluated anti-PD-1 antibody treatment in combination with multiple approaches, including vaccination and agonist anti-OX40 immunotherapy, as well as triple combination immunotherapy with each of the above agents in a murine glioma model. Treatments were delivered on days 3,6, and 9 after intracranial implantation of glioma cells in the right frontal lobes of the mice. Vaccination consisted of subcutaneous implantation of irradiated GL261 cells engineered to express GM-CSF. We harvested splenocytes and brain tissue 18 days after glioma implantation and analyzed them by ELISPOT and flow cytometry, respectively. Treated mice surviving for 120 days were challenged with implantation of large numbers of GL261 cells and either followed for survival or sacrificed for study of the memory response. Survival was assessed by the Kaplan-Meier method and the log-rank test. Means were compared by the 2-tailed student's t-test. We report that combining anti-PD-1 immunotherapy with either vaccination or agonist anti-OX40 immunotherapy improves survival in GL261-bearing mice compared with any of the above as monotherapy. Triple combination immunotherapy with vaccination, anti-PD-1 antibody, and agonist anti-OX40 antibody results in long-term survival in all mice. Triple combination immunotherapy resulted in an elevated CD4+/CD8 + T lymphocyte ratio amongst tumor-infiltrating lymphocytes as well as a diminished fraction of regulatory T lymphocytes, likely reflective of a more vigorous Th1 antitumor response.
| S-EPMC6492981 | biostudies-literature
Project description:Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient's own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as "checkpoint inhibitors," can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) releases the "brakes" on T cells to boost anti-tumor immunity. Generating optimal "killer" CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.
| S-EPMC4329814 | biostudies-literature
Project description:The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics. However, only a few studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically based real-time microtiter plate readout with a matrix-like heat map of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of extraintestinal pathogenic Escherichia coli (ExPEC) with antibiotic levels blanketing the MIC across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drug-resistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, two different related phages that differed in their burst sizes produced drastically different synograms. Collectively, these data suggest lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria while also synergizing with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments.IMPORTANCE Bacteriophage (phage) therapy is a promising approach to combat the rise of multidrug-resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.
| S-EPMC7407087 | biostudies-literature
Project description:Purpose: Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.Experimental Design: We utilized an anti-PD-1-refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1.Results: The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type I and type II serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells. Combination treatment increased intratumoral CD4+ T-cell proliferation at day 13, but at day 19, both CD4+ and CD8+ T-cell proliferation was significantly reduced compared with untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors, sequential combination was dependent on both CD4+ and CD8+ T cells and completely regressed tumors in approximately 30% of treated animals.Conclusions: These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials. Clin Cancer Res; 23(20); 6165-77. ©2017 AACRSee related commentary by Colombo, p. 5999.
| S-EPMC5641261 | biostudies-literature
Project description:In situ vaccination is a promising strategy to convert the immunosuppressive tumor microenvironment into an immunostimulatory one with limited systemic exposure and side effect. However, sustained clinical benefits require long-term and multidimensional immune activation including innate and adaptive immunity. Here, we develop a probiotic food-grade Lactococcus lactis-based in situ vaccination (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand. Intratumoural delivery of FOLactis contributes to local retention and sustained release of therapeutics to thoroughly modulate key components of the antitumour immune response, such as activation of natural killer cells, cytotoxic T lymphocytes, and conventional-type-1-dendritic cells in the tumors and tumor-draining lymph nodes. In addition, intratumoural administration of FOLactis induces a more robust tumor antigen-specific immune response and superior systemic antitumour efficacy in multiple poorly immune cell-infiltrated and anti-PD1-resistant tumors. Specific depletion of different immune cells reveals that CD8+ T and natural killer cells are crucial to the in situ vaccine-elicited tumor regression. Our results confirm that FOLactis displays an enhanced antitumour immunity and successfully converts the 'cold' tumors to 'hot' tumors.
| S-EPMC9719518 | biostudies-literature
Project description:Despite the growing appreciation that the future of cancer treatment lies in combination therapies, finding the right drugs to combine and the optimal way to combine them remains a nontrivial task. Herein, we introduce the Multi-Objective Optimization of Combination Synergy - Dose Selection (MOOCS-DS) method for using drug synergy as a tool for guiding dose selection for a combination of preselected compounds. This method decouples synergy of potency (SoP) and synergy of efficacy (SoE) and identifies Pareto optimal solutions in a multi-objective synergy space. Using a toy combination therapy model, we explore properties of the MOOCS-DS algorithm, including how optimal dose selection can be influenced by the metric used to define SoP and SoE. We also demonstrate the potential of our approach to guide dose and schedule selection using a model fit to preclinical data of the combination of the PD-1 checkpoint inhibitor pembrolizumab and the anti-angiogenic drug bevacizumab on two lung cancer cell lines. The identification of optimally synergistic combination doses has the potential to inform preclinical experimental design and improve the success rates of combination therapies. Jel classificationDose Finding in Oncology.
| S-EPMC10681518 | biostudies-literature
Project description:PurposeWe hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. Virally encoded IL15Rα-IL15 as the T-cell activating stimulus and a prostaglandin synthesis inhibitor as the anti-immunosuppressant were combined with adoptive transfer of tumor-specific T cells.Experimental designTwo oncolytic poxviruses, vvDD vaccinia virus and myxoma virus, were each engineered to express the fusion protein IL15Rα-IL15 and a fluorescent protein. Viral gene expression (YFP or tdTomato Red) was confirmed in the murine glioma GL261 in vitro and in vivo. GL261 tumors in immunocompetent C57BL/6J mice were treated with vvDD-IL15Rα-YFP vaccinia virus or vMyx-IL15Rα-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T-cell therapy.ResultsvvDD-IL15Rα-YFP and vMyx-IL15Rα-tdTr each infected and killed GL261 cells in vitro. In vivo, NK cells and CD8+ T cells were increased in the tumor due to the expression of IL15Rα-IL15. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15Rα-IL15 expressed by the virus, a source of T cells (whether by prevaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce elimination of gliomas in a majority of mice. vvDD-IL15Rα-YFP occasionally caused ventriculitis-meningitis, but vMyx-IL15Rα-tdTr was safe and effective, causing a strong infiltration of tumor-specific T cells and eliminating gliomas in 83% of treated mice.ConclusionsIL15Rα-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T-cell therapy, rapamycin, and celecoxib.
| S-EPMC7723446 | biostudies-literature
Project description:Recently, cancer immunotherapy has received attention as a viable solution for the treatment of refractory tumors. However, it still has clinical limitations in its treatment efficacy due to inter-patient tumor heterogeneity and immunosuppressive tumor microenvironment (TME). In this study, we demonstrated the triggering of anti-cancer immune responses by a combination of irreversible electroporation (IRE) and a stimulator of interferon genes (STING) agonist. Optimal electrical conditions inducing damage-associated molecular patterns (DAMPs) by immunogenic cell death (ICD) were determined through in vitro 2D and 3D cell experiments. In the in vivo syngeneic lung cancer model, the combination of IRE and STING agonists demonstrated significant tumor growth inhibition. We believe that the combination strategy of IRE and STING agonists has potential for effective cancer immunotherapy.
| S-EPMC7693597 | biostudies-literature