Advancements and challenges: immunotherapy therapy in high-grade glioma - a meta-analysis of randomized clinical trials.

BACKGROUND: High-grade gliomas (HGG) are the most aggressive primary brain tumors with poor prognoses despite conventional treatments. Immunotherapy has emerged as a promising avenue due to its potential to elicit a targeted immune response against tumor cells. OBJECTIVE: This meta-analysis aimed to evaluate the efficacy and safety of various immunotherapeutic strategies, including immune checkpoint inhibitors (ICI), virotherapy, and dendritic cell vaccines (DCV) in treating HGG. METHODS: Following the PRISMA framework, we searched PubMed, Cochrane, and Embase for studies reporting outcomes of HGG patients treated with immunotherapy. Key metrics included overall survival, progression-free survival, and treatment-related adverse events. RESULTS: We reviewed 47 studies, analyzing data from 3674 HGG patients treated with immunotherapy. The mean overall survival for patients treated with ICI was 11.05 months, with virotherapy at 11.79 months and notably longer for DCV at 24.11 months. The mean progression-free survival (PFS) for ICIs was 3.65 months. Virotherapy demonstrated a PFS favoring the control group, indicating minimal impact, while DCV showed substantial PFS improvement with a median of 0.43 times lower hazard compared to controls (95% CI: 29-64%). Adverse events were primarily Grade 1 or 2 for ICI, included a Grade 5 event for virotherapy, and were predominantly Grade 1 or 2 for DCV, indicating a favorable safety profile. CONCLUSION: Immunotherapy holds potential as an effective treatment for HGG, especially DCV. However, results vary significantly with the type of therapy and individual patient profiles. Further randomized controlled trials are necessary to establish robust clinical guidelines and optimize treatment protocols.

Antimetastatic and antitumor activities of oncolytic NDV AMHA1 in a 3D culture model of breast cancer.

Introduction: Newcastle disease virus (NDV) AMHA1 is capable of killing cancer cells by direct replication or induction of apoptosis alongside other pathways. In this study, we report the potent antimetastatic and anticancer activities of NDV AMHA1 in a 3D spheroid model of breast cancer metastasis. Methods: we used two breast cancer cell lines AMJ13 and MCF7 in our metastasis model system. Results: First, we showed that NDV AMHA1 can infect and kill breast cancer cells in proliferating adherent cells and tumor spheroids using different virus doses and studying virus replication kinetics. We showed that NDV can infect and spread within the spheroids that represent metastasis before and after reattachment. Furthermore, we evaluated the ability of NDV to induce apoptosis in cancer spheroids and by virus tracking showed that NDV infection is essential for the elimination of these metastasis spheroids. Discussion: The mechanism by which NDV induces cell killing in the metastasis model is the induction of caspase-3 and P21 and inhibition of Ki67 in cancer cells, but not in normal cells. In conclusion, these results indicate that NDV AMHA1 has the ability to kill breast cancer metastases in suspension or attached, and this is a novel finding of NDV AMHA1 being a possibly efficient therapy against human metastatic breast cancer.

IL-12-mediated toxicity from localized oncolytic virotherapy can be reduced using systemic TNF blockade.

Cytokine therapy represents an attractive option to improve the outcomes of cancer patients. However, the systemic delivery of these agents often leads to severe immune-related toxicities, which can prevent their efficient clinical use. One approach to address this issue is the use of recombinant oncolytic viruses to deliver various cytokines directly to the tumor. This improves the biodistribution of the secreted cytokine-transgenes, both augmenting antitumor immune responses and decreasing systemic toxicities. We have shown recently that a doubly recombinant oncolytic myxoma virus that secretes a soluble version of PD1 as well as an interleukin-12 (IL-12) fusion protein (vPD1/IL-12) can cause potent regression of disseminated cancers. Here we show that, despite the predominant localization of both transgenes within the infected tumor, treatment with vPD1/IL-12 still results in systemic, IL-12-mediated toxicities. Interestingly, these toxicities are independent of interferon-γ and instead appear to be mediated by the interaction of tumor necrosis factor α with tumor necrosis factor receptor 2 on hematopoietic cells. Critically, this unique mechanism allows for vPD1/IL-12-mediated toxicities to be alleviated through the use of US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) blockers such as etanercept.

Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy.

Oncolytic viruses often face challenges in achieving optimal antitumor immunity as standalone therapies. The penton base RGD-integrin interactions play a significant role in wild-type adenovirus-induced innate immune responses. To modify these responses, we present ISC301, a novel oncolytic adenovirus engineered by deleting the natural RGD motifs in the penton base while incorporating artificial RGD motifs in the fiber knobs. ISC301 demonstrated comparable in vitro infectivity, cytotoxic effects, and signaling profiles across various cell types to its parental ICOVIR-5, which retains the penton base RGD motif. In immunodeficient and immunocompetent mouse models, ISC301 exhibited similar in vivo antitumor efficacy to ICOVIR-5. However, ISC301 induced higher intratumoral inflammation through NF-κB activation, leading to increased levels of tumor-infiltrating leukocytes and higher proportion of cytotoxic CD8+ T cells. In addition, ISC301 elicits a heightened pro-inflammatory response in peripheral blood. Importantly, when combined with CAR T cell therapy, ISC301 exhibited superior antitumor efficacy, surpassing monotherapy outcomes. These findings emphasize the impact of adenoviral modifications on antitumor immune responses. The deletion of penton base RGD motifs enhances ISC301's pro-inflammatory profile and boosts CAR T cell therapy efficacy. This study enhances understanding of oncolytic virus engineering strategies, positioning ISC301 as a promising candidate for combined immunotherapeutic approaches in cancer treatment.

Smoldering oncolysis by foamy virus carrying CD19 as a CAR target escapes CAR T detection by genomic modification.

Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δbel2 and oFV-bel2 vectors to test the efficiency and stability of viral/CD19 spread. While both viruses conferred equal CAR T killing in vitro, the oFV-Δbel2 virus acquired G-to-A mutations, whereas oFV-bel2 virus had genome deletions. In subcutaneous tumor models in vivo, CAR T cells led to a significant decrease in oFV-specific bioluminescence, confirming clearance of oFV-infected tumor cells. However, the most effective therapy was with high-dose oFV in the absence of CAR T cells, indicating that CAR T clearance of oFV was detrimental. Moreover, in tumors that escaped CAR T cell treatment, resurgent virus contained deletions within the oFV-CD19 transgene, allowing the virus to escape CAR T elimination. Therefore, oFV represents a slow smoldering type of oncolytic virus, whose chronic spread through tumors generates anti-tumor therapy, which is abolished by CAR T therapy. These results suggest that further development of this oncolytic platform, with additional immunotherapeutic arming, may allow for an effective combination of chronic oncolysis.

Clinical strategies with antibody-drug conjugates as potential modifications for virotherapy.

The ability to selectively target cancer cells makes antibody-drug conjugates (ADCs) promising therapeutic options. They have been tested in clinical trials as a vehicle for tumor-specific delivery of cytotoxic payloads for a range of cancers. However, systemic administration of oncolytic virotherapy is challenging, because only a small portion of injected viruses reach the target. Despite the approval of higher viral doses, most viruses still end up in the liver, potentially causing toxicity in that organ. Integrating ADCs with virotherapy in the form of antibody-virus conjugates or virus-drug conjugates can potentially overcome these challenges and improve therapeutic outcomes.

p53-armed oncolytic virotherapy induces abscopal effect in osteosarcoma by promoting immunogenic cell death.

Osteosarcoma (OS), the most frequent primary malignant tumor of bone in children and adolescents, is refractory to immune checkpoint inhibitors due to its poor antitumor immune response. Chemotherapy and virotherapy induce immunogenic cell death (ICD) and antitumor immune responses, leading to the abscopal effect in untreated tumors. We previously demonstrated the antitumor activity of the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 in human OS cells. Here, we show the therapeutic potential of chemotherapeutic drugs (doxorubicin, cisplatin) and telomerase-specific oncolytic adenoviruses (OBP-301, p53-armed OBP-702) to induce ICD in human OS cells (U2OS, MNNG/HOS, SaOS-2) and murine OS cells (NHOS). OBP-702 induced more profound ICD via the secretion of adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1) compared with chemotherapy and OBP-301 in human OS cells. Murine NHOS cells were also more sensitive to OBP-702 than OBP-301. Subcutaneous NHOS tumor models demonstrated that intratumoral injection of OBP-702 significantly increased the tumor infiltration of cytotoxic CD8+ T cells and induced the abscopal effect against non-treated tumors compared with OBP-301. Our results suggest that OBP-702 is a promising antitumor reagent to induce ICD with secretion of ATP and HMGB1 and the abscopal effect against OS.

Advances in gene therapy for high-grade glioma: a review of the clinical evidence.

INTRODUCTION: High-grade glioma (HGG) is one of the most deadly and difficult cancers to treat. Despite intense research efforts, there has not been a significant breakthrough in treatment outcomes since the early 2000's. Anti-glioma gene therapy has demonstrated promise in preclinical studies and is under investigation in numerous clinical trials. AREAS COVERED: This manuscript reviews the current landscape of clinical trials exploring gene therapy treatment of HGG. Using information from clinicaltrials.gov, all trials initiated within the past 5 years (2018-2023) as well as other important trials were cataloged and reviewed. This review discusses trial details, innovative methodologies, and concurrent pharmacological interventions. The review also delves into the subtypes of gene therapy used, trends over time, and future directions. EXPERT OPINION: Trials are in the early stages (phase I or II), and there are reports of clinical efficacy in published results. Synergistic effects utilizing immunotherapy within or alongside gene therapy are emerging as a promising avenue for future breakthroughs. Considerable heterogeneity exists across trials concerning administration route, vector selection, drug combinations, and intervention timing. Earlier intervention in newly diagnosed HGG and avoidance of corticosteroids may improve efficacy in future trials. The results from ongoing trials demonstrate promising potential for molding the future landscape of HGG care.

miRNA-Mediated Mechanisms in the Generation of Effective and Safe Oncolytic Viruses.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by inhibiting the translation of target transcripts. The expression profiles of miRNAs vary in different tissues and change with the development of diseases, including cancer. This feature has begun to be used for the modification of oncolytic viruses (OVs) in order to increase their selectivity and efficacy. OVs represent a relatively new class of anticancer drugs; they are designed to replicate in cancer tumors and destroy them. These can be natural viruses that can replicate within cancer tumor cells, or recombinant viruses created in laboratories. There are some concerns regarding OVs' toxicity, due to their ability to partially replicate in healthy tissues. In addition, lytic and immunological responses upon OV therapy are not always sufficient, so various OV editing methods are used. This review discusses the latest results of preclinical and clinical studies of OVs, modifications of which are associated with the miRNA-mediated mechanism of gene silencing.

Proliferating Cell Nuclear Antigen in the Era of Oncolytic Virotherapy.

Proliferating cell nuclear antigen (PCNA) is a well-documented accessory protein of DNA repair and replication. It belongs to the sliding clamp family of proteins that encircle DNA and acts as a mobile docking platform for interacting proteins to mount and perform their metabolic tasks. PCNA presence is ubiquitous to all cells, and when located in the nucleus it plays a role in DNA replication and repair, cell cycle control and apoptosis in proliferating cells. It also plays a crucial role in the infectivity of some viruses, such as herpes simplex viruses (HSVs). However, more recently it has been found in the cytoplasm of immune cells such as neutrophils and macrophages where it has been shown to be involved in the development of a pro-inflammatory state. PCNA is also expressed on the surface of certain cancer cells and can play a role in preventing immune cells from killing tumours, as well as being associated with cancer virulence. Given the growing interest in oncolytic viruses (OVs) as a novel cancer therapeutic, this review considers the role of PCNA in healthy, cancerous, and immune cells to gain an understanding of how PCNA targeted therapy and oncolytic virotherapy may interact in the future.

H-1 Parvovirus-Induced Oncolysis and Tumor Microenvironment Immune Modulation in a Novel Heterotypic Spheroid Model of Cutaneous T-Cell Lymphoma.

The rat protoparvovirus H-1 (H-1PV) is an oncolytic virus known for its anticancer properties in laboratory models of various human tumors, including non-Hodgkin lymphomas (NHL) of B-cell origin. However, H-1PV therapeutic potential against hematological malignancies of T-cell origin remains underexplored. The aim of the present study was to conduct a pilot preclinical investigation of H-1PV-mediated oncolytic effects in cutaneous T-cell lymphoma (CTCL), a type of NHL that is urgently calling for innovative therapies. We demonstrated H-1PV productive infection and induction of oncolysis in both classically grown CTCL suspension cultures and in a novel, in vivo-relevant, heterotypic spheroid model, but not in healthy donor controls, including peripheral blood mononuclear cells (PBMCs). H-1PV-mediated oncolysis of CTCL cells was not prevented by Bcl-2 overexpression and was accompanied by increased extracellular ATP release. In CTCL spheroid co-cultures with PBMCs, increased spheroid infiltration with immune cells was detected upon co-culture treatment with the virus. In conclusion, our preclinical data show that H-1PV may hold significant potential as an ingenious viroimmunotherapeutic drug candidate against CTCL.

Newcastle Disease Virus Virotherapy: Unveiling Oncolytic Efficacy and Immunomodulation.

In virotherapy, cancer cells are eradicated via viral infection, replication, and dissemination (oncolysis). BACKGROUND: This study aims to evaluate the oncolytic potential of Newcastle disease virus (NDV) against colon cancer and explore the immune response associated with its therapeutic effects. METHODS: NDV was tested for its oncolytic potential in colon cancer cell lines using MTT assays and apoptosis assessments. Tumor-induced mice were treated with NDV, tumor cell lysate (TCL), or a combination of both. After the euthanasia of murine subjects, an assessment of oncolytic efficacy was performed through flow cytometry analysis of murine blood and tumor tissue, targeting CD83, CD86, CD8, and CD4. An ELISA was also performed to examine interferon-gamma levels, interleukin-4 levels, interleukin-12 levels, and interleukin-10 levels in serum and spleen homogenate. RESULTS: Cell viability was low in HCT116 and HT-29, indicating a cytotoxic effect in the MTT assay. NDV+TCL recorded the highest rate of cell death (56.72%). NDV+TCL had accelerated cell death after 48 h, reaching 58.4%. The flow cytometry analysis of the blood and tumor of mice with induced tumor treated with combined treatment revealed elevated levels of CD83, CD86, CD8, and CD4 (76.3, 66.9, 83.7, and 14.4%, respectively). The ELISA levels of IFN-γ, IL-4, and IL-12 in serum and the spleen homogenate were elevated (107.6 ± 9.25 pg/mL). In contrast, the expression of IL-10 was significantly reduced (1 ± 0.79).

Simultaneous Expression of Different Therapeutic Genes by Infection with Multiple Oncolytic HSV-1 Vectors.

Oncolytic viruses (OVs) are anti-cancer therapeutics combining the selective killing of cancer cells with the triggering of an anti-tumoral immune response. The latter effect can be improved by arming OVs with immunomodulatory factors. Due to the heterogeneity of cancer and the tumor microenvironment, it is anticipated that strategies based on the co-expression of multiple therapeutic molecules that interfere with different features of the target malignancy will be more effective than mono-therapies. Here, we show that (i) the simultaneous expression of different proteins in triple-negative breast cancer (TNBC) cells can be achieved through their infection with a combination of OVs based on herpes simplex virus type 1 (oHSV1), each encoding a single transgene. (ii) The level of expressed proteins is dependent on the number of infectious viral particles utilized to challenge tumor cells. (iii) All recombinant viruses exhibited comparable efficacy in the killing of TNBC cells in single and multiple infections and showed similar kinetics of replication. Overall, our results suggest that a strategy based on co-infection with a panel of oHSV1s may represent a promising combinatorial therapeutic approach for TNBC, as well as for other types of solid tumors, that merits further investigation in more advanced in vitro and in vivo models.

Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors.

Introduction: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy's antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.

Revisiting the standards of cancer detection and therapy alongside their comparison to modern methods.

In accordance with the World Health Organization data, cancer remains at the forefront of fatal diseases. An upward trend in cancer incidence and mortality has been observed globally, emphasizing that efforts in developing detection and treatment methods should continue. The diagnostic path typically begins with learning the medical history of a patient; this is followed by basic blood tests and imaging tests to indicate where cancer may be located to schedule a needle biopsy. Prompt initiation of diagnosis is crucial since delayed cancer detection entails higher costs of treatment and hospitalization. Thus, there is a need for novel cancer detection methods such as liquid biopsy, elastography, synthetic biosensors, fluorescence imaging, and reflectance confocal microscopy. Conventional therapeutic methods, although still common in clinical practice, pose many limitations and are unsatisfactory. Nowadays, there is a dynamic advancement of clinical research and the development of more precise and effective methods such as oncolytic virotherapy, exosome-based therapy, nanotechnology, dendritic cells, chimeric antigen receptors, immune checkpoint inhibitors, natural product-based therapy, tumor-treating fields, and photodynamic therapy. The present paper compares available data on conventional and modern methods of cancer detection and therapy to facilitate an understanding of this rapidly advancing field and its future directions. As evidenced, modern methods are not without drawbacks; there is still a need to develop new detection strategies and therapeutic approaches to improve sensitivity, specificity, safety, and efficacy. Nevertheless, an appropriate route has been taken, as confirmed by the approval of some modern methods by the Food and Drug Administration.

Systemic delivery of oncolytic herpes virus using CAR-T cells enhances targeting of antitumor immuno-virotherapy.

Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.

Translation of oncolytic viruses in sarcoma.

Sarcomas are a rare and highly diverse group of malignancies of mesenchymal origin. While sarcomas are generally considered resistant to immunotherapy, recent studies indicate subtype-specific differences in clinical response to checkpoint inhibitors (CPIs) that are associated with distinct immune phenotypes present in sarcoma subtypes. Oncolytic viruses (OVs) are designed to selectively infect and kill tumor cells and induce intratumoral immune infiltration, enhancing immunogenicity and thereby sensitizing tumors to immunotherapy. Herein we review the accumulated clinical data evaluating OVs in sarcoma. Small numbers of patients with sarcoma were enrolled in early-stage OV trials as part of larger solid tumor cohorts demonstrating safety but providing limited insight into the biological effects due to the low patient numbers and lack of histologic grouping. Several recent studies have investigated talimogene laherparepvec (T-VEC), an approved oncolytic herpes simplex virus (HSV-1), in combination therapy regimens in sarcoma patient cohorts. These studies have shown promising responses in heavily pre-treated and immunotherapy-resistant patients associated with increased intratumoral immune infiltration. As new and more potent OVs enter the clinical arena, prospective evaluation in subtype-specific cohorts with correlative studies to define biomarkers of response will be critical to advancing this promising approach for sarcoma therapy.

Corrigendum: Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors.

[This corrects the article DOI: 10.3389/fimmu.2024.1384623.].

The Role of Natural Killer Cells in Oncolytic Virotherapy: Friends or Foes?

Oncolytic virotherapy (OVT) has emerged as a promising cancer immunotherapy, and is capable of potentiating other immunotherapies due to its capacity to increase tumor immunogenicity and to boost host antitumor immunity. Natural killer (NK) cells are a critical cellular component for mediating the antitumor response, but hold a mixed reputation for their role in mediating the therapeutic efficacy of OVT. This review will discuss the pros and cons of how NK cells impact OVT, and how to harness this knowledge for the development of effective strategies that could modulate NK cells to improve OVT-based therapeutic outcomes.

Oncolytic virotherapy for hepatocellular carcinoma: A potent immunotherapeutic landscape.

Hepatocellular carcinoma (HCC) is a systemic disease with augmented malignant degree, high mortality and poor prognosis. Since the establishment of the immune mechanism of tumor therapy, people have realized that immunotherapy is an effective means for improvement of HCC patient prognosis. Oncolytic virus is a novel immunotherapy drug, which kills tumor cells and exempts normal cells by directly lysing tumor and inducing anti-tumor immune response, and it has been extensively examined as an HCC therapy. This editorial discusses oncolytic viruses for the treatment of HCC, emphasizing viral immunotherapy strategies and clinical applications related to HCC.