TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy.
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ABSTRACT:
SUBMITTER: Qiu H
PROVIDER: S-EPMC8446424 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.
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Project description:More than 40 years ago, we discovered that novel transplantation antigens can be induced in vivo or in vitro by treating murine leukemia with dacarbazine. Years later, this phenomenon that we called "Chemical Xenogenization" (CX) and more recently, "Drug-Induced Xenogenization" (DIX), was reproduced by Thierry Boon with a mutagenic/carcinogenic compound (i.e. N-methyl-N'-nitro-N-nitrosoguanidine). In both cases, the molecular bases of DIX rely on mutagenesis induced by methyl adducts to oxygen-6 of DNA guanine. In the present review we illustrate the main DIX-related immune-pharmacodynamic properties of triazene compounds of clinical use (i.e. dacarbazine and temozolomide).In recent years, tumor immunotherapy has come back to the stage with the discovery of immune checkpoint inhibitors (ICpI) that show an extraordinary immune-enhancing activity. Here we illustrate the salient biochemical features of some of the most interesting ICpI and the up-to-day status of their clinical use. Moreover, we illustrate the literature showing the direct relationship between somatic mutation burden and susceptibility of cancer cells to host's immune responses.When DIX was discovered, we were not able to satisfactorily exploit the possible presence of triazene-induced neoantigens in malignant cells since no device was available to adequately enhance host's immune responses in clinical settings. Today, ICpI show unprecedented efficacy in terms of survival times, especially when elevated mutation load is associated with cancer cells. Therefore, in the future, mutation-dependent neoantigens obtained by appropriate pharmacological intervention appear to disclose a novel approach for enhancing the therapeutic efficacy of ICpI in cancer patients.
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Project description:Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of immune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been effective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are unresponsive to current endocrine therapies.
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Project description:To date, clinical trials of various vaccine therapies using autologous tumor antigens or tumor-associated/specific antigen peptide with adjuvants have been performed to treat patients with high-grade gliomas (HGG). Furthermore, immune checkpoint pathway-targeted therapies including anti- programmed cell death 1 (PD-1) antibody have been remarkably effective in other neoplasms, and various clinical trials with anti-PD-1 antibody in patients with HGG have started to date. It is possible that up-regulation of immune checkpoint molecules in tumor tissues after vaccine therapy may be one of the mechanisms of vaccine failure. Multiple preclinical studies indicate that combination therapy with vaccination and immune checkpoint blockade is effective for the treatment of malignant tumors including HGG. Thus, immunotherapy, especially combination therapy with vaccine and immune checkpoint inhibitors, may be a promising strategy for treatment of patients with HGG.
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Project description:One of the most important steps forward in the management of cancer was the discovery of immunotherapy. It has become an essential pillar in the treatment paradigm of cancer patients. Unfortunately, despite the various options presented with immune checkpoint inhibitors (ICIs), the benefit is still limited to select patients and the vast majority of these patients gain either minimal benefit or eventually progress, leaving an unmet need for the development of novel therapeutic agents and strategies. Lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor protein, is a molecule found on the surface of activated T-cells. It plays a major role in negatively regulating T-cell function thereby providing tumors with an immune escape in the tumor microenvironment (TME). Given its importance in regulating the immune system, LAG-3 has been considered as a promising target in oncology and precision medicine. To date, two LAG-3-directed agents (eftilagimod alpha and relatlimab) have been approved in combination with programmed death-1 (PD-1) inhibitors in the setting of advanced solid tumors. In this review, we discuss the structure of LAG-3, its mechanism of action, and its interaction with its ligands. We also shed light on the emerging treatments targeting LAG-3 for the treatment of solid tumors.
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Project description:Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusions: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed.
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Project description:The coronavirus disease 2019 (COVID-19) is currently representing a global health threat especially for fragile individuals, such as cancer patients. It was demonstrated that cancer patients have an increased risk of developing a worse symptomatology upon severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2) infection, often leading to hospitalization and intensive care. The consequences of this pandemic for oncology are really heavy, as the entire healthcare system got reorganized. Both oncologists and cancer patients are experiencing rescheduling of treatments and disruptions of appointments with a concurrent surge of fear and stress. In this review all the up-to-date findings, concerning the association between COVID-19 and cancer, are reported. A remaining very debated question regards the use of an innovative class of anti-cancer molecules, the immune checkpoint inhibitors (ICIs), given their modulating effects on the immune system. For that reason, administration of ICIs to cancer patients represents a question mark during this pandemic, as its correlation with COVID-19-associated risks is still under investigation. Based on the mechanisms of action of ICIs and the current evidence, we suggest that ICIs not only can be safely administered to cancer patients, but they might even be beneficial in COVID-19-positive cancer patients, by exerting an immune-stimulating action.
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Project description:BackgroundInter-individual differences in response to immune checkpoint inhibitors (ICI) remain a major challenge in cancer treatment. The composition of the gut microbiome has been associated with differential ICI outcome, but the underlying molecular mechanisms remain unclear, and therapeutic modulation challenging.MethodsWe established an in vivo model to treat C57Bl/6j mice with the type-I interferon (IFN-I)-modulating, bacterial-derived metabolite desaminotyrosine (DAT) to improve ICI therapy. Broad spectrum antibiotics were used to mimic gut microbial dysbiosis and associated ICI resistance. We utilized genetic mouse models to address the role of host IFN-I in DAT-modulated antitumour immunity. Changes in gut microbiota were assessed using 16S-rRNA sequencing analyses.FindingsWe found that oral supplementation of mice with the microbial metabolite DAT delays tumour growth and promotes ICI immunotherapy with anti-CTLA-4 or anti-PD-1. DAT-enhanced antitumour immunity was associated with more activated T cells and natural killer cells in the tumour microenvironment and was dependent on host IFN-I signalling. Consistent with this, DAT potently enhanced expansion of antigen-specific T cells following vaccination with an IFN-I-inducing adjuvant. DAT supplementation in mice compensated for the negative effects of broad-spectrum antibiotic-induced dysbiosis on anti-CTLA-4-mediated antitumour immunity. Oral administration of DAT altered the gut microbial composition in mice with increased abundance of bacterial taxa that are associated with beneficial response to ICI immunotherapy.InterpretationWe introduce the therapeutic use of an IFN-I-modulating bacterial-derived metabolite to overcome resistance to ICI. This approach is a promising strategy particularly for patients with a history of broad-spectrum antibiotic use and associated loss of gut microbial diversity.FundingMelanoma Research Alliance, Deutsche Forschungsgemeinschaft, German Cancer Aid, Wilhelm Sander Foundation, Novartis Foundation.
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Project description:In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naïve and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.
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