scholarly journals Current Advances in Immunotherapy for Glioblastoma

2021 ◽  
Vol 23 (2) ◽  
Author(s):  
Abigail L. Mende ◽  
Jessica D. Schulte ◽  
Hideho Okada ◽  
Jennifer L. Clarke
Keyword(s):  
Immune Response ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Adaptive Immune Response ◽  
Complex Nature ◽  
Treatment Regimens ◽  
Cell Dysfunction ◽  
Immune Mediated ◽  
Recent Developments ◽  
T Cell Dysfunction

Abstract Purpose of Review This review seeks to inform oncology clinicians and researchers about the development of novel immunotherapies for the treatment of glioblastoma. An enumeration of ongoing and recently completed clinical trials will be discussed with special attention given to current technologies implemented to overcome central nervous system–specific challenges including barriers to the peripheral immune system, impaired antigen presentation, and T cell dysfunction. Recent Findings The success of immunotherapy in other solid cancers has served as a catalyst to explore its application in glioblastoma, which has limited response to other treatments. Recent developments include multi-antigen vaccines that seek to overcome the heterogeneity of glioblastoma, as well as immune checkpoint inhibitors, which could amplify the adaptive immune response and may have promise in combinatorial approaches. Additionally, oncolytic and retroviruses have opened the door to a plethora of combinatorial approaches aiming to leverage their immunogenicity and/or ability to carry therapeutic transgenes. Summary Treatment of glioblastoma remains a serious challenge both with regard to immune-based as well as other therapeutic strategies. The disease has proven to be highly resistant to treatment due to a combination of tumor heterogeneity, adaptive expansion of resistant cellular subclones, evasion of immune surveillance, and manipulation of various signaling pathways involved in tumor progression and immune response. Immunotherapeutics that are efficacious in other cancer types have unfortunately not enjoyed the same success in glioblastoma, illustrating the challenging and complex nature of this disease and demonstrating the need for development of multimodal treatment regimens utilizing the synergistic qualities of immune-mediated therapies.

scholarly journals Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction in Nonhuman Primate TB Granulomas

mBio ◽  
2021 ◽  
Author(s):  
Bindu Singh ◽  
Dhiraj K. Singh ◽  
Shashank R. Ganatra ◽  
Ruby A. Escobedo ◽  
Shabaana Khader ◽  
...  
Keyword(s):  
T Cell ◽  
Adaptive Immunity ◽  
Nonhuman Primate ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Dysfunction ◽  
First Response ◽  
T Cell Stimulation ◽  
T Cell Dysfunction

Myeloid cells are immunocytes of innate origin that orchestrate the first response toward pathogens via immune surveillance (uptake and killing), antigen presentation, and initiation of adaptive immunity by T cell stimulation. However, MDSCs are a subset of innate immunocytes that deviate to an immunoregulatory phenotype.

scholarly journals Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer

2018 ◽  
Vol Volume 11 ◽  
pp. 6505-6524 ◽  
Author(s):  
Ewelina Grywalska ◽  
Marcin Pasiarski ◽  
Stanisław Góźdź ◽  
Jacek Roliński
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

scholarly journals Immune metabolism in PD-1 blockade-based cancer immunotherapy

2020 ◽  
Vol 33 (1) ◽  
pp. 17-26
Author(s):  
Alok Kumar ◽  
Kenji Chamoto
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Cell ◽  
Metabolic Regulation ◽  
Immune Cell ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming the unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address these issues. Cancer cells render their microenvironment immunosuppressive, driving T-cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T-cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T-cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T-cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers in cancer immunotherapy with immune checkpoint inhibitors.

scholarly journals Immune-Mediated Control of a Dormant Neurotropic RNA Virus Infection

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Katelyn D. Miller ◽  
Christine M. Matullo ◽  
Katelynn A. Milora ◽  
Riley M. Williams ◽  
Kevin J. O’Regan ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein Synthesis ◽  
Measles Virus ◽  
Viral Infections ◽  
Acute Infection ◽  
Adaptive Immune Response ◽  
Viral Control ◽  
Cns Disease ◽  
Adaptive Immune ◽  
Immune Mediated

ABSTRACTGenomic material from many neurotropic RNA viruses (e.g., measles virus [MV], West Nile virus [WNV], Sindbis virus [SV], rabies virus [RV], and influenza A virus [IAV]) remains detectable in the mouse brain parenchyma long after resolution of the acute infection. The presence of these RNAs in the absence of overt central nervous system (CNS) disease has led to the suggestion that they are viral remnants, with little or no potential to reactivate. Here we show that MV RNA remains detectable in permissive mouse neurons long after challenge with MV and, moreover, that immunosuppression can cause RNA and protein synthesis to rebound, triggering neuropathogenesis months after acute viral control. Robust recrudescence of viral transcription and protein synthesis occurs after experimental depletion of cells of the adaptive immune response and is associated with a loss of T resident memory (Trm) lymphocytes within the brain. The disease associated with loss of immune control is distinct from that seen during the acute infection: immune cell-depleted, long-term-infected mice display severe gait and motor problems, in contrast to the wasting and lethal disease that occur during acute infection of immunodeficient hosts. These results illuminate the potential consequences of noncytolytic, immune-mediated viral control in the CNS and demonstrate that what were once considered “resolved” RNA viral infections may, in fact, induce diseases later in life that are distinct from those caused by acute infection.IMPORTANCEViral infections of neurons are often not cytopathic; thus, once-infected neurons survive, and viral RNAs can be detected long after apparent viral control. These RNAs are generally considered viral fossils, unlikely to contribute to central nervous system (CNS) disease. Using a mouse model of measles virus (MV) neuronal infection, we show that MV RNA is maintained in the CNS of infected mice long after acute control and in the absence of overt disease. Viral replication is suppressed by the adaptive immune response; when these immune cells are depleted, viral protein synthesis recurs, inducing a CNS disease that is distinct from that observed during acute infection. The studies presented here provide the basis for understanding how persistent RNA infections in the CNS are controlled by the host immune response, as well as the pathogenic consequences of noncytolytic viral control.

scholarly journals Peroral Ciprofloxacin Therapy Impairs the Generation of a Protective Immune Response in a Mouse Model for Salmonella enterica Serovar Typhimurium Diarrhea, while Parenteral Ceftriaxone Therapy Does Not

2012 ◽  
Vol 56 (5) ◽  
pp. 2295-2304 ◽  
Author(s):  
Kathrin Endt ◽  
Lisa Maier ◽  
Rina Käppeli ◽  
Manja Barthel ◽  
Benjamin Misselwitz ◽  
...  
Keyword(s):  
Immune Response ◽  
Mouse Model ◽  
Antibiotic Treatment ◽  
Salmonella Enterica ◽  
Adaptive Immune Response ◽  
Content Type ◽  
Fecal Shedding ◽  
Treatment Regimens ◽  
Adaptive Immune ◽  
Serovar Typhimurium

ABSTRACTNontyphoidalSalmonella(NTS) species cause self-limiting diarrhea and sometimes severe disease. Antibiotic treatment is considered only in severe cases and immune-compromised patients. The beneficial effects of antibiotic therapy and the consequences for adaptive immune responses are not well understood. We used a mouse model forSalmonelladiarrhea to assess the effects ofper ostreatment with ciprofloxacin (15 mg/kg of body weight intragastrically 2 times/day, 5 days) or parenteral ceftriaxone (50 mg/kg intraperitoneally, 5 days), two common drugs used in human patients. The therapeutic and adverse effects were assessed with respect to generation of a protective adaptive immune response, fecal pathogen excretion, and the emergence of nonsymptomatic excreters. In the mouse model, both therapies reduced disease severity and reduced the level of fecal shedding. In line with clinical data, in most animals, a rebound of pathogen gut colonization/fecal shedding was observed 2 to 12 days after the end of the treatment. Yet, levels of pathogen shedding and frequency of appearance of nonsymptomatic excreters did not differ from those for untreated controls. Moreover, mice treated intraperitoneally with ceftriaxone developed an adaptive immunity protecting the mice from enteropathy in wild-typeSalmonella entericaserovar Typhimurium challenge infections. In contrast, the mice treated intragastrically with ciprofloxacin were not protected. Thus, antibiotic treatment regimens can disrupt the adaptive immune response, but treatment regimens may be optimized in order to preserve the generation of protective immunity. It might be of interest to determine whether this also pertains to human patients. In this case, the mouse model might be a tool for further mechanistic studies.

scholarly journals Immune Therapy Resistance and Immune Escape of Tumors

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 551
Author(s):  
Barbara Seliger ◽  
Chiara Massa
Keyword(s):  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Immune Therapy ◽  
Immune Surveillance ◽  
Therapy Resistance ◽  
The Novel ◽  
Major Goal ◽  
Immune Mediated ◽  
Tumor Clearance

Immune therapy approaches such as checkpoint inhibitors or adoptive cell therapy represent promising therapeutic options for cancer patients, but their efficacy is still limited, since patients frequently develop innate or acquired resistances to these therapies. Thus, one major goal is to increase the efficiency of immunotherapies by overcoming tumor-induced immune suppression, which then allows for immune-mediated tumor clearance. Innate resistance to immunotherapies could be caused by a low immunogenicity of the tumor itself as well as an immune suppressive microenvironment composed of cellular, physical, or soluble factors leading to escape from immune surveillance and disease progression. So far, a number of strategies causing resistance to immunotherapy have been described in various clinical trials, which broadly overlap with the immunoediting processes of cancers. This review summarizes the novel insights in the development of resistances to immune therapy as well as different approaches that could be employed to overcome them.

scholarly journals Mi-2β-targeted inhibition induces immunotherapy response in melanoma

2020 ◽  
Author(s):  
Bo Zhu ◽  
Zhengyu Wang ◽  
Licheng Yao ◽  
Xingyu Lin ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Underlying Mechanism ◽  
Adaptive Immune ◽  
Melanoma Patients ◽  
Ifn Γ ◽  
Targeted Inhibition

Abstract Recent development of some new immune checkpoint inhibitors has been particularly successfully in melanoma, but the majority of melanoma patients exhibit resistance. Understanding and targeting the potential underlying mechanism/targets, especially the tumor-intrinsic modulators to convert resistant melanomas to immunotherapy sensitivity will potentially provide a significant improvement in patient outcome. Here, Mi-2β, a chromatin remodeling enzyme was identified as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, targeting Mi-2β induced the adaptive immune response by transcriptionally enhancing expression of a set of IFN-γ-responsive genes including CXCL9, CXCL10 and IRF1. Finally, we developed a Mi-2β-targeted inhibitor Z36-MP5, which specifically and effectively induced a response to immune checkpoint blockades in otherwise resistant melanomas. Our work provides a new insight into the epigenetic regulation in adaptive immune response, and highlights a viable strategy to improve immunotherapies in melanoma.

scholarly journals Adaptive Antitumor Immune Response Stimulated by Bio-nanoparticle Based Vaccine and Checkpoint Blockade

2021 ◽  
Author(s):  
Xuewei Bai ◽  
Yanmei Zhou ◽  
Yuki Yokota ◽  
Yoshihiro Matsumoto ◽  
Bo Zhai ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Control Group ◽  
Lymphoid Structures

Abstract Background: Interactions between tumor and microenvironment determines the response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors. Aspartate beta-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods: Orthotopic TNBC and subcutaneous HCC murine models were established. Immunohistochemistry, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based vaccine targeting ASPH was administrated to BALB/c mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In the control group, autocrine CXCL13-CXCR5 axis promoted cancer development and progression. Inhibition between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis. In contrast, combination therapy significantly suppressed primary hepatic or mammary tumor growth with distant pulmonary metastases in TNBC. An adaptive immune response was attributed to expansion of activated CD4+ Th1/CD8+ CTLs with enhanced effector function and high titers of ASPH-specific antibody. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), which secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, the presence of TLSs predicts sensitivity to immune checkpoint inhibitor blockade. Conclusions: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH combined with an immune checkpoint inhibitor represents a new approach for TNBC and HCC.

scholarly journals Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 504-513
Author(s):  
Kelly Walkovich ◽  
James A. Connelly
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Immune Dysregulation ◽  
Inborn Errors ◽  
T Cell Therapy ◽  
Adaptive Immune

Abstract As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI—decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival—offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.

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