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Frontiers in Immunology 2023Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. Despite two decades of... (Review)
Review
Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. Despite two decades of relentless pursuit in exploring novel therapeutic approaches for GBM, there is limited progress in improving patients' survival outcomes. Numerous obstacles impede the effective treatment of GBM, including the immunosuppressive tumor microenvironment (TME), the blood-brain barrier, and extensive heterogeneity. Despite these challenges, immunotherapies are emerging as a promising avenue that may offer new hope for the treatment of gliomas. There are four main types of immunotherapies for gliomas, immune checkpoint blockades, chimeric antigen receptor T-cell therapies, vaccines, and oncolytic viruses. In addition, gene therapy, bispecific antibody therapy, and combine therapy are also briefly introduced in this review. The significant role of TME in the process of immunotherapies has been emphasized in many studies. Although immunotherapy is a promising treatment for gliomas, enormous effort is required to overcome the existing barriers to its success. Owing to the rapid development and increasing attention paid to immunotherapies for gliomas, this article aims to review the recent advances in immunotherapies for gliomas.
Topics: Humans; Immunotherapy; Glioma; Glioblastoma; Immunotherapy, Adoptive; Radioimmunotherapy; Tumor Microenvironment
PubMed: 37744349
DOI: 10.3389/fimmu.2023.1255611 -
Current Oncology Reports Aug 2023Head and neck cancer (HNC) comprises a group of malignancies, amongst which squamous cell carcinoma accounts for more than 90% of the cases. HNC has been related to... (Review)
Review
PURPOSEOF REVIEW
Head and neck cancer (HNC) comprises a group of malignancies, amongst which squamous cell carcinoma accounts for more than 90% of the cases. HNC has been related to tobacco use, alcohol consumption, human papillomavirus, Epstein-Barr virus, air pollution, and previous local radiotherapy. HNC has been associated with substantial morbidity and mortality. This review aims to summarize the recent findings regarding immunotherapy in HNC.
RECENT FINDINGS
The recent introduction of immunotherapy, with the use of programmed death 1 (PD-1) inhibitors pembrolizumab and nivolumab, which have been FDA approved for the treatment of metastatic or recurrent head and neck squamous cell carcinoma, has changed the field in metastatic or recurrent disease. There are many ongoing trials regarding the use of novel immunotherapeutic agents, such as durvalumab, atezolizumab, avelumab, tremelimumab, and monalizumab. In this review, we focus on the therapeutic potential of novel immunotherapy treatment modalities, such as combinations of newer immune-checkpoint inhibitors; the use of tumor vaccines such as human papillomavirus-targeted vaccines; the potential use of oncolytic viruses; as well as the latest advances regarding adoptive cellular immunotherapy. As novel treatment options are still emerging, a more personalized approach to metastatic or recurrent HNC therapy should be followed. Moreover, the role of the microbiome in immunotherapy, the limitations of immunotherapy, and the various diagnostic, prognostic, and predictive biomarkers based on genetics and the tumor microenvironment are synopsized.
Topics: Humans; Epstein-Barr Virus Infections; Neoplasm Recurrence, Local; Herpesvirus 4, Human; Head and Neck Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37213060
DOI: 10.1007/s11912-023-01425-1 -
Nature Communications Jul 2023The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in...
The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.
Topics: Male; Mice; Animals; Glioblastoma; Oncolytic Viruses; Tumor-Associated Macrophages; Phagocytosis; Cholesterol; Tumor Microenvironment
PubMed: 37474548
DOI: 10.1038/s41467-023-39683-z -
Current Treatment Options in Oncology Jul 2023Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths worldwide and its associated mortality rate is expected to rise within the next decade. The... (Review)
Review
Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths worldwide and its associated mortality rate is expected to rise within the next decade. The incidence rate of hepatocellular carcinoma varies significantly across countries and the latter can be attributed to the differences in risk factors that are prevalent across different countries. Some of the risk factors associated with hepatocellular carcinoma include hepatitis B and C infections, non-alcoholic fatty liver disease, and alcoholic liver disease. Regardless of the underlying aetiology, the end result is liver fibrosis and cirrhosis that ultimately progress into carcinoma. The treatment and management of hepatocellular carcinoma is complicated by treatment resistance and high tumor recurrence rates. Early stages of hepatocellular carcinoma are treated with liver resection and other forms of surgical therapy. Advanced stages of hepatocellular carcinoma can be treated with chemotherapy, immunotherapy, and the use of oncolytic viruses and these treatment options can be combined with nanotechnology to improve efficacy and reduce side effects. Moreover, chemotherapy and immunotherapy can be combined to further improve treatment efficacy and overcome resistance. Despite the treatment options available, the high mortality rates provide evidence that current treatment options for advanced-stage hepatocellular carcinoma are not achieving the desired therapeutic goals. Various clinical trials are ongoing to improve treatment efficacy, reduce recurrence rates, and ultimately prolong survival. This narrative review aims to provide an update on our current knowledge and future direction of research on hepatocellular carcinoma.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic; Neoplasm Recurrence, Local; Risk Factors
PubMed: 37103744
DOI: 10.1007/s11864-023-01098-9 -
Human Gene Therapy Sep 2023The use of oncolytic viruses has become an attractive tool in the clinics for the treatment of various tumor types. Such viruses are genetically modified to... (Review)
Review
The use of oncolytic viruses has become an attractive tool in the clinics for the treatment of various tumor types. Such viruses are genetically modified to conditionally replicate in malignant cells while unharming healthy cells. This platform offers a highly specific tumor killing with exceptional safety profiles. However, the use of oncolytic viruses as sole oncolytic platforms has not achieved full tumor clearance in murine models and in the clinics. In fact, the formation of anti-tumor immune responses is attributed to the effectiveness of oncolytic viruses. In this review, we will discuss the various strategies that scientists have employed to enhance the anti-tumor immune responses driven by oncolytic viruses. Moreover, focus will be drawn into personalizing such anti-tumor responses by the addition of tumor-associated peptides.
Topics: Animals; Mice; Oncolytic Virotherapy; Oncolytic Viruses
PubMed: 37698876
DOI: 10.1089/hum.2023.122 -
Nature Nov 2023Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma...
Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM). Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV). In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).
Topics: Humans; Brain Neoplasms; Glioblastoma; Nestin; Oncolytic Virotherapy; Oncolytic Viruses; Reproducibility of Results; Survival Analysis; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment; Herpesvirus 1, Human
PubMed: 37853118
DOI: 10.1038/s41586-023-06623-2 -
International Journal of Molecular... Nov 2023This Special Issue highlights multiple facets of virus engineering, ranging from the dissection of the biological properties of individual viral functions in the context...
This Special Issue highlights multiple facets of virus engineering, ranging from the dissection of the biological properties of individual viral functions in the context of safe genomic backbones, virus genetic modification for applications in gene therapy, oncolytic virotherapy and vaccine production, to the hurdles presented by quality control and the delivery of viruses for their final applications and finally to the simulation, prediction and validation of virus evolution [...].
Topics: Humans; Oncolytic Viruses; Oncolytic Virotherapy; Genetic Therapy; Neoplasms; Genetic Engineering
PubMed: 38069111
DOI: 10.3390/ijms242316788 -
International Journal of Molecular... Oct 2023Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients... (Review)
Review
Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.
Topics: Humans; Glioblastoma; Immune Checkpoint Inhibitors; Cancer Vaccines; Neoplasm Recurrence, Local; Glioma; Immunotherapy; Immunotherapy, Adoptive; Brain Neoplasms; Tumor Microenvironment
PubMed: 37894718
DOI: 10.3390/ijms242015037 -
Advanced Materials (Deerfield Beach,... Jul 2023Despite the superior tumor lytic efficacy of oncolytic viruses (OVs), their systemic delivery still faces the challenges of limited circulating periods, poor tumor...
Despite the superior tumor lytic efficacy of oncolytic viruses (OVs), their systemic delivery still faces the challenges of limited circulating periods, poor tumor tropism, and spontaneous antiviral immune responses. Herein, a virus-concealed tumor-targeting strategy enabling OVs' delivery toward lung metastasis via systemic administration is described. The OVs can actively infect, be internalized, and cloak into tumor cells. Then the tumor cells are subsequently treated with liquid-nitrogen-shocking to eliminate the pathogenicity. Such a Trojan Horse-like vehicle avoids virus neutralization and clearance in the bloodstream and facilitates tumor-targeted delivery for more than 110-fold virus enrichment in the tumor metastasis. In addition, this strategy can serve as a tumor vaccine and initiate endogenous adaptive antitumor effects through increasing the memory T cells and modulating the tumor immune microenvironment, including reducing the M2 macrophage, downregulating Treg cells, and priming T cells.
Topics: Humans; Oncolytic Viruses; Oncolytic Virotherapy; Neoplasms; Lung Neoplasms; Cancer Vaccines; Tumor Microenvironment; Immunotherapy
PubMed: 37002917
DOI: 10.1002/adma.202212210 -
The Journal of Experimental Medicine Oct 2023While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and...
While checkpoint blockade immunotherapies have widespread success, they rely on a responsive immune infiltrate; as such, treatments enhancing immune infiltration and preventing immunosuppression are of critical need. We previously generated αPD-1 resistant variants of the murine HNSCC model MEER. While entirely αPD-1 resistant, these tumors regress after single dose of oncolytic vaccinia virus (VV). We then generated a VV-resistant MEER line to dissect the immunologic features of sensitive and resistant tumors. While treatment of both tumor types induced immune infiltration and IFNγ, we found a defining feature of resistance was elevation of immunosuppressive cytokines like TGFβ, which blunted IFNγ signaling, especially in regulatory T cells. We engineered VV to express a genetically encoded TGFβRII inhibitor. Inhibitor-expressing VV produced regressions in resistant tumor models and showed impressive synergy with checkpoint blockade. Importantly, tumor-specific, viral delivery of TGFβ inhibition had no toxicities associated with systemic TGFβ/TGFβR inhibition. Our data suggest that aside from stimulating immune infiltration, oncolytic viruses are attractive means to deliver agents to limit immunosuppression in cancer.
Topics: Animals; Mice; Cell Line, Tumor; Immunosuppressive Agents; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Transforming Growth Factor beta; Tumor Microenvironment; Vaccinia virus
PubMed: 37552475
DOI: 10.1084/jem.20230053