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Human Gene Therapy Sep 2023Interleukin 2 (IL-2) plays a crucial role in T cell growth and survival, enhancing the cytotoxic activity of natural killer and cytotoxic T cells and thus functioning as... (Review)
Review
Interleukin 2 (IL-2) plays a crucial role in T cell growth and survival, enhancing the cytotoxic activity of natural killer and cytotoxic T cells and thus functioning as a versatile master proinflammatory anticancer cytokine. The FDA has approved IL-2 cytokine therapy for the treatment of metastatic melanoma and metastatic renal cell carcinoma. However, IL-2 therapy has significant constraints, including a short serum half-life, low tumor accumulation, and life-threatening toxicities associated with high doses. Oncolytic viruses (OVs) offer a promising option for cancer immunotherapy, selectively targeting and destroying cancer cells while sparing healthy cells. Numerous studies have demonstrated the successful delivery of IL-2 to the tumor microenvironment without compromising safety using OVs such as vaccinia, Sendai, parvo, Newcastle disease, tanapox, and adenoviruses. Additionally, by engineering OVs to coexpress IL-2 with other anticancer transgenes, the immune properties of IL-2 can be further enhanced. Preclinical and clinical studies have shown promising antitumor effects of IL-2-expressing viral vectors, either alone or in combination with other anticancer therapies. This review summarizes the therapeutic potential of IL-2-expressing viral vectors and their antitumor mechanisms of action.
Topics: Animals; Humans; Interleukin-2; Oncolytic Virotherapy; Carcinoma, Renal Cell; Kidney Neoplasms; Cytokines; Oncolytic Viruses; Immunotherapy; Tumor Microenvironment
PubMed: 37578106
DOI: 10.1089/hum.2023.099 -
Nature Protocols May 2024Oncolytic viruses (OVs) represent a novel class of cancer immunotherapy agents that preferentially infect and kill cancer cells and promote protective antitumor... (Review)
Review
Oncolytic viruses (OVs) represent a novel class of cancer immunotherapy agents that preferentially infect and kill cancer cells and promote protective antitumor immunity. Furthermore, OVs can be used in combination with established or upcoming immunotherapeutic agents, especially immune checkpoint inhibitors, to efficiently target a wide range of malignancies. The development of OV-based therapy involves three major steps before clinical evaluation: design, production and preclinical testing. OVs can be designed as natural or engineered strains and subsequently selected for their ability to kill a broad spectrum of cancer cells rather than normal, healthy cells. OV selection is further influenced by multiple factors, such as the availability of a specific viral platform, cancer cell permissivity, the need for genetic engineering to render the virus non-pathogenic and/or more effective and logistical considerations around the use of OVs within the laboratory or clinical setting. Selected OVs are then produced and tested for their anticancer potential by using syngeneic, xenograft or humanized preclinical models wherein immunocompromised and immunocompetent setups are used to elucidate their direct oncolytic ability as well as indirect immunotherapeutic potential in vivo. Finally, OVs demonstrating the desired anticancer potential progress toward translation in patients with cancer. This tutorial provides guidelines for the design, production and preclinical testing of OVs, emphasizing considerations specific to OV technology that determine their clinical utility as cancer immunotherapy agents.
PubMed: 38769145
DOI: 10.1038/s41596-024-00985-1 -
Nature Communications Oct 2023IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known...
IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.
Topics: Animals; Female; Humans; Mice; Brain Neoplasms; Glioma; Isocitrate Dehydrogenase; Methylation; Mutation; Oncolytic Virotherapy; Oncolytic Viruses
PubMed: 37880243
DOI: 10.1038/s41467-023-42545-3 -
Cell Communication and Signaling : CCS Sep 2023Mesenchymal stem cells (MSCs) have attracted considerable interest as a promising approach for cancer treatment due to their ability to undergo tumor-trophic migration.... (Review)
Review
Mesenchymal stem cells (MSCs) have attracted considerable interest as a promising approach for cancer treatment due to their ability to undergo tumor-trophic migration. MSCs possess the unique ability to selectively migrate to tumors, making them an excellent candidate for targeted delivery of oncolytic viruses (OVs) to treat isolated tumors and metastatic malignancies. OVs have attracted attention as a potential treatment for cancer due to their ability to selectively infect and destroy tumor cells while sparing normal cells. In addition, OVs can induce immunogenic cell death and contain curative transgenes in their genome, making them an attractive candidate for cancer treatment in combination with immunotherapies. In combination with MSCs, OVs can modulate the tumor microenvironment and trigger anti-tumor immune responses, making MSC-releasing OVs a promising approach for cancer treatment. This study reviews researches on the use of MSC-released OVs as a novel method for treating cancer. Video Abstract.
Topics: Oncolytic Viruses; Immunotherapy; Immunogenic Cell Death; Mesenchymal Stem Cells; Tumor Microenvironment; Neoplasms
PubMed: 37667271
DOI: 10.1186/s12964-023-01232-y -
Life Science Alliance Jan 2024We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate...
We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activation of melanoma-specific CD8 T cells and increased the efficacy of a tumor cell vaccine using MQ-treated cells even when the B16F10 cells lacked p53. We then designed a novel combination of APR-246 with the TLR-4 agonist, monophosphoryl lipid A, and a CD40 agonist to further enhance these immunogenic effects and demonstrated a significant antitumor response. We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Tumor Suppressor Protein p53; Antigens, Neoplasm; Melanoma
PubMed: 37891002
DOI: 10.26508/lsa.202301999 -
Discover Oncology Oct 2023In the past decade, there has been little progress in the treatment of malignant glioma. Recently, oncolytic virus has made great progress in glioma treatment, and a... (Review)
Review
PURPOSE
In the past decade, there has been little progress in the treatment of malignant glioma. Recently, oncolytic virus has made great progress in glioma treatment, and a number of clinical trials have shown their potential of prolonging the survival time of glioma patients. Our objective is to evaluate effectiveness and safety of oncolytic virus (OV) in malignant glioma treatment.
METHODOLOGY
Based upon PRISMA, we collected relevant published clinical trials by searching medical databases up to January 16, 2023, applying the language restrictions in English and Chinese. We cross-searched the terms: 'glioma', 'glioblastoma', 'oncolytic viruses', 'oncolytic virotherapy' with filter 'clinical trial'. Two researchers independently extracted the data regarding case definitions, published years, trial phase, characteristics of patients, administration of drug, overall survival (OS), and adverse events.
RESULTS
19 published clinical trials in OV treatment of malignant glioma were included in the further systematic review analysis. None of them induced irresistible adverse effects attributing to OV treatment, median overall survival varied from 3.25 to 20.2 months after treatments. According to trials providing patient's detailed molecular diagnosis, we find that the effectiveness of OV treatment has no significant difference in patients with different IDH or MGMT status.
CONCLUSIONS
Current clinical trials have initially shown the potential of oncolytic virotherapy as a new treatment for malignant glioma. Besides development of virus types, the strategy of OV use is an urgent problem to be solved in future clinical application, such as repeated administrations, innovative drug delivery systems, and biomarkers.
PubMed: 37845388
DOI: 10.1007/s12672-023-00769-1 -
Blood Advances Dec 2023Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and...
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.
Topics: Adult; Humans; Lymphoma, Mantle-Cell; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Risk Assessment; Progression-Free Survival
PubMed: 37874912
DOI: 10.1182/bloodadvances.2023010757 -
Molecular Therapy. Oncology Jun 2024Oncolytic virotherapy represents a promising approach in cancer immunotherapy. The primary delivery method for oncolytic viruses (OVs) is intratumoral injection, which... (Review)
Review
Oncolytic virotherapy represents a promising approach in cancer immunotherapy. The primary delivery method for oncolytic viruses (OVs) is intratumoral injection, which apparently limits their clinical application. For patients with advanced cancer with disseminated metastasis, systemic administration is considered the optimal approach. However, the direct delivery of naked viruses through intravenous injection presents challenges, including rapid clearance by the immune system, inadequate accumulation in tumors, and significant side effects. Consequently, the development of drug delivery strategies has led to the emergence of various bio-materials serving as viral vectors, thereby improving the anti-tumor efficacy of oncolytic virotherapy. This review provides an overview of innovative strategies for delivering OVs, with a focus on nanoparticle-based or cell-based delivery systems. Recent pre-clinical and clinical studies are examined to highlight the enhanced efficacy of systemic delivery using these novel platforms. In addition, prevalent challenges in current research are briefly discussed, and potential solutions are proposed.
PubMed: 38845744
DOI: 10.1016/j.omton.2024.200809 -
Stem Cell Research & Therapy Dec 2023Mesenchymal stromal cells (MSCs) show considerable promise in regenerative medicine with superior anti-fibrotic, immunomodulatory, and angiogenic functions. More... (Review)
Review
Mesenchymal stromal cells (MSCs) show considerable promise in regenerative medicine with superior anti-fibrotic, immunomodulatory, and angiogenic functions. More recently, discovered with the tumor tropism, MSCs have been exploited as the basis of targeted cancer therapy. In this scenario, MSCs can directly home to tumor tissues and play anti-tumor properties. In addition, MSCs, MSC-derived exosomes and MSC-derived membranes are often developed as carriers for precisely delivering cytotoxic agents to cancer sites, including chemotherapeutic drugs, therapeutic genes, or oncolytic viruses. However, it has revealed the tumorigenic risk of MSCs as an important component within the tumor microenvironment, hampering the translation of MSC-based cancer therapies into clinical settings. Therefore, in this review, we introduce the specific tumor-tropic ability of MSCs and underlying mechanisms. We also summarize the current application of MSC-based therapeutic approaches in treating gynecologic cancers, mainly including cervical, ovarian, and endometrial cancers. Moreover, we discuss the main challenges that the current MSC-based cancer therapies are facing.
Topics: Humans; Female; Neoplasms; Exosomes; Regenerative Medicine; Mesenchymal Stem Cells; Tumor Microenvironment
PubMed: 38049868
DOI: 10.1186/s13287-023-03585-0 -
Frontiers in Immunology 2023Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple... (Review)
Review
Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple immunotherapy strategies are under development, including CAR-T cells, immune checkpoint inhibitors, oncolytic viruses and dendritic cell vaccines, although these approaches are yet to yield significant clinical benefit. Potential reasons for the lack of success so far include the immunosuppressive tumor microenvironment, the blood-brain barrier, and systemic changes to the immune system driven by both the tumor and its treatment. Furthermore, while T cells are essential effector cells for tumor control, dendritic cells play an equally important role in T cell activation, and emerging evidence suggests the dendritic cell compartment may be deeply compromised in glioblastoma patients. In this review, we describe the immunotherapy approaches currently under development for glioblastoma and the challenges faced, with a particular emphasis on the critical role of the dendritic cell-T cell axis. We suggest a number of strategies that could be used to boost dendritic cell number and function and propose that the use of these in combination with T cell-targeting strategies could lead to successful tumor control.
Topics: Humans; Glioblastoma; T-Lymphocytes; Immunotherapy; Oncolytic Viruses; Dendritic Cells; Tumor Microenvironment
PubMed: 37928547
DOI: 10.3389/fimmu.2023.1261257