Search Results (842)

Melanoma represents a worldwide public health problem due to its high incidence and mortality rates. Despite the advances in melanoma therapy, not all patients respond to single or combined therapy because of primary or acquired resistance to the anti-tumor agents. Recently, positive results have been reported since the specific monoclonal antibodies, such as Ipilimumab (Ipi) and Nivolumab (Niv), were included in therapeutic protocols as immune checkpoint inhibitors. The evolution of neoplastic diseases and the therapeutic approaches in cancer involve several biological processes, including apoptosis, DNA progression through cell cycle phases, the release of pro-inflammatory cytokines, and changes in the expression of melanoma genes. Therefore, the potential modulation of these processes and associated molecules, due to single or combined treatments with oncolytic drugs like Carboplatin and Paclitaxel, checkpoint inhibitors such as Ipi and Niv, or natural bioactive compounds like Resveratrol or Quercetin, could represent a great benefit in melanoma treatment, contributing to the decrease or even reversal of the drug resistance in melanoma cells. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, marked by late diagnosis, limited responsiveness to conventional therapies, and an immunosuppressive tumor microenvironment. While immunotherapy has transformed treatment paradigms in several cancers, its efficacy in PDAC has been minimal. Oncolytic viruses and therapeutic cancer vaccines have emerged as promising immunotherapeutic strategies designed to stimulate robust, tumor-specific immune responses and reshape the immune landscape. However, despite encouraging preclinical data, clinical translation in PDAC has been largely disappointing. This review critically evaluates the design, delivery, and efficacy of oncolytic virotherapy and cancer vaccines in PDAC, examining barriers such as stromal desmoplasia, immune exclusion, and tumor heterogeneity. We also explore combination strategies integrating checkpoint inhibitors, chemotherapy, radiotherapy, and stromal modulation to overcome resistance. Ultimately, the viability of these approaches hinges on a clearer understanding of their mechanistic limitations and the refinement of delivery platforms. These factors will determine whether oncolytic viruses and cancer vaccines can be successfully repositioned within the therapeutic arsenal or warrant reevaluation in the evolving landscape of PDAC treatment. Full article

The overall survival rate of brain malignancies such as glioblastoma is currently a little under two years, at most, and treatment options for malignant brain tumors have demonstrated limited efficacy. The current standard of care to treat brain cancer includes surgical resection, radiation, and chemotherapy. Historically, an observed interaction between malignancies and concurrent viral infection has shown therapeutic potential that can perhaps be better leveraged in brain cancer with the technological advances that we have today. We aim to discuss a variety of viral vector designs to harness their oncolytic potential and explore how some of these ideas have performed in clinical trials. In our review, three major viral candidates that have gained traction in this field of research—Herpes simplex virus-1, adenovirus, and poliovirus—are highlighted. How the field has manipulated aspects of their virology and combined these viral platforms with other immune modulating strategies to treat both adult and pediatric tumors is also surveyed. Finally, the work exploring the possibility of other neurotropic viral candidates has been elaborated. More insight into the biological interactions between tumor, brain, and body is needed to address this particularly difficult clinical challenge. While there is still no clear, effective treatment for brain malignancies, the utilization of oncolytic viruses shows potential both as a treatment and as a tool to better understand the immune microenvironment of this pathology. Full article

A three year old male neutered mixed breed dog presented with a mass on the right carpus and accompanying lameness. A Jamshidi bone biopsy was performed, and histopathology results were consistent with a sarcoma. The dog received oncolytic virotherapy (OV) with vesicular stomatitis virus (VSV) as part of a clinical trial in dogs with osteosarcoma (OSA). Ten days after VSV treatment, the affected limb was amputated, and histopathology was consistent with intramedullary HSA. Considering the new diagnosis, standard doxorubicin chemotherapy was prescribed. With this combination of therapies, the dog had an extended survival of more than seven years and remains alive at the time of writing. This is the first case report documenting OV given in conjunction with the standard of care for canine appendicular HSA. Full article

Pediatric oral rhabdomyosarcoma (RMS) is a rare and aggressive cancer of the head and neck, characterized by a complex and mostly immunosuppressive tumor–immune microenvironment. Unlike adult cancers, pediatric RMS typically exhibits a “cold” immune profile, characterized by minimal T-cell infiltration, a low mutational burden, and resistance to immune checkpoint blockade. The tumor’s location in the oral cavity adds difficulty to treatment because of anatomical and functional limitations. Additionally, the presence of fusion oncogenes, such as PAX3:FOXO1, hampers immunogenicity and treatment response by disrupting antigen presentation and reducing immune cell infiltration. Advances in immuno-oncology have introduced new strategies, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) therapies, cancer vaccines, and oncolytic viruses. However, these approaches face specific challenges in the pediatric population due to developmental immune factors. This narrative review highlights recent findings on the immunobiology of pediatric oral RMS, focusing on tumor–immune interactions and their impact on disease progression and treatment resistance. We reviewed the cellular components of the TIME, the mechanisms of immune evasion, and the expression of immune checkpoints, including PD-L1 and B7-H3. Emerging immunotherapies, including CAR-T, CAR-NK, and CAR-CIK cell therapies; checkpoint inhibitors; oncolytic viruses; and cancer vaccines, are discussed, with an emphasis on their current limitations and potential to transform the pediatric RMS immune landscape. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), comprising approximately 20% of newly diagnosed BC cases. The poor prognosis, high recurrence rates, and inefficacy of hormone-based therapies make TNBC one of the greatest challenges in contemporary oncology. The unique immunological features of TNBC, including relatively high tumor mutational burden, abundance of tumor-infiltrating lymphocytes, and elevated PD-L1 expression, offer a wide range of opportunities for immunotherapeutic approaches, of which the most progressive and promising are neoantigen-driven ones. This review examines the current landscape of neoantigen-based therapeutic approaches in TNBC treatment, spanning from discovery methodologies to clinical applications. We provide a critical analysis of the tumor microenvironment (TME) in TNBC, highlighting the balance between its immunoactivating (CD8+ T-cells, dendritic cells) and immunosuppressive (regulatory T-cells, M2 macrophages) components as the key determinant of therapeutic success, as well as reviewing the emerging approaches to TME reprogramming and recruiting in favor of better outcomes. We also present state-of the-art methods in neoantigen identification and prioritization, covering the landscape of technological platforms and prediction algorithms, addressing the existing accuracy limitations along with emerging computational solutions, and comprehensively discussing the TNBC neoantigen spectrum. Our analysis shows the strong domination of patient-specific (“private”) neoantigens over shared variants in the TNBC, with TP53 as the only gene with recurrent variants. Finally, we extensively cover neoantigen-recruiting therapeutic modalities including adoptive cell therapies, personalized vaccine platforms (peptide-based, mRNA/DNA vaccines, dendritic cell vaccines), and oncolytic viruses-based approaches. Our study of current clinical trials demonstrates the substantial gap between early proof-of-concept experiments and further applicability of neoantigen-driven therapies. The major challenges hampering the success of such methods include neoantigen prediction inaccuracy rates, high manufacturing costs, and time consumption. Promising ways to overcome these difficulties include the development of combinational strategies, TME modeling and modifying, and improvement of the therapy delivery properties, along with the optimization of production workflows and cost-effectiveness of vaccine development. Full article

The unique ability of oncolytic viruses (OVs) to replicate in and destroy malignant cells while leaving healthy cells intact and activating the host immune response makes them powerful targeted anti-cancer therapeutic agents. Vesicular stomatitis virus (VSV) only causes mild and asymptomatic infection, lacks pre-existing immunity, can be genetically engineered for enhanced efficiency and improved safety, and has a broad cell tropism. VSV can facilitate targeted delivery of immunostimulatory cytokines for an enhanced immune response against cancer cells, thus decreasing the possible toxicity frequently observed as a result of systemic delivery. In this study, the oncolytic potency of the two rVSV versions, rVSV-dM51-GFP, delivering green fluorescent protein (GFP), and rVSV-dM51-mIL12-mGMCSF, delivering mouse interleukin-12 (mIL-12) and granulocyte-macrophage colony-stimulating factor (mGMCSF), was compared on the four murine cancer cell lines of different origin and healthy mesenchymal stem cells (MSCs) at 24 h post-infection by flow cytometry. Lewis lung carcinoma (LL/2) cells were demonstrated to be more susceptible to the lytic effects of both rVSV versions compared to melanoma (B16-F10) cells. Detection of expression levels of antiviral and pro-apoptotic genes in response to the rVSV-dM51-GFP infection by quantitative PCR (qPCR) showed lower levels of IFIT, RIG-I, and N-cadherin and higher levels of IFNβ and p53 in LL/2 cells. Subsequently, C57BL/6 mice, infused subcutaneously with the LL/2 cells, were injected intratumorally with the rVSV-dM51-mIL12-mGMCSF 7 days later to assess the synergistic effect of rVSV and immunostimulatory factors. The in vivo study demonstrated that treatment with two rVSV-dM51-mIL12-mGMCSF doses 3 days apart resulted in a tumor growth inhibition index (TGII) of over 50%. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

Oncolytic virus (OV) immunotherapy, particularly with oncolytic herpes simplex virus (oHSV), has become a promising new strategy in cancer treatment. This field has achieved significant clinical milestones, highlighted by the FDA approval of Talimogene laherparepvec (T-VEC) for melanoma in 2015 and the approval of Teserpaturev/G47Δ for malignant glioma in Japan in 2021. This review synthesizes the key preclinical and clinical advancements in oHSV therapy over the last decade, critically analyzing the core challenges in target selection, genetic modification, administration routes, and targeted delivery. Key findings indicate that arming oHSV with immunomodulatory transgenes, such as cytokines and antibodies, and combining it with immune checkpoint inhibitors are critical strategies for enhancing therapeutic efficacy. Future research will focus on precision engineering using CRISPR/Cas9, the development of novel delivery vehicles like nanoparticles and mesenchymal stem cells (MSCs), and biomarker-guided personalized medicine, aiming to provide safer and more effective solutions for refractory cancers. This review synthesizes oHSV advances and analyzes novel delivery and gene-editing strategies. Full article

Oncolytic herpes simplex virus (oHSV) is a promising cancer immunotherapy that induces tumor cell lysis and stimulates anti-tumor immunity. Our previous single-cell RNA sequencing analysis of oHSV-treated medulloblastoma tumors revealed expansion and activation of tumor-infiltrating dendritic cells (DCs), and direct oHSV infection of DCs within the brain. While the therapeutic effects of oHSVs have been primarily attributed to tumor cell infection, we hypothesize that direct infection of DCs also contributes to therapeutic efficacy by promoting DC maturation and immune activation. Although the oHSV infection in DCs was abortive, it led to increased expression of major histocompatibility complex (MHC) class I/II and co-stimulatory molecules. oHSV-infected DCs activated naïve CD4⁺ and CD8⁺ T cells, inducing expression of CD69 and CD25. These primed T cells exhibited enhanced cytotoxicity against CT-2A glioma cells. Adoptive transfer of oHSV-infected DCs via subcutaneous injection near inguinal lymph nodes delayed tumor growth in a syngeneic CT-2A glioma model, independent of tumor viral replication and lysis. Mechanistically, our in vitro studies demonstrate that oHSV can directly infect and functionally activate DCs, enabling them to prime effective anti-tumor T cell responses. This study highlights the anti-tumor potential of leveraging oHSV-infected DCs to augment viroimmunotherapy as a cancer therapeutic. Full article

Glioblastoma (GBM) is an aggressive brain tumor characterized by an immunosuppressive tumor microenvironment (TME), which contributes to treatment resistance and disease progression. Background: Tumor-associated macrophages (TAMs), comprising both resident microglia and bone marrow–derived macrophages, play a central role in supporting tumor growth, angiogenesis, and immune evasion. Most TAMs adopt an M2-like immunosuppressive phenotype, making them a promising target for immunomodulatory strategies in GBM. Method: According to PRISMA guidelines, we conducted a systematic literature review and recruited eligible studies focused on therapeutic approaches targeting TAMs in GBM, emphasizing mechanisms of action, efficacy, and challenges. Data extraction focused on therapeutic classes, outcomes, and TAM-related biomarkers. Results: We identified 30 studies meeting the inclusion criteria. These therapies are categorized into three main strategies: inhibition of TAM recruitment, enhancement of TAM-mediated phagocytosis, and reprogramming of TAMs. Combination strategies, including TAM-targeting with checkpoint inhibitors, nanoparticles, and oncolytic viruses, show synergistic effects in preclinical models. Conclusions: Targeting TAMs represents a multifaceted strategy for GBM treatment. Current evidence underscores the need for combination approaches integrating TAM modulation with existing standard-of-care therapies. Clinical translation remains limited due to challenges such as TAM heterogeneity, plasticity, immunosuppressive therapies, and restricted drug delivery across the blood–brain barrier. Future directions should highlight personalized treatments based on detailed TME profiling. Combining TAM-targeted therapies with agents modulating metabolic or immune pathways, and leveraging advanced delivery systems and spatial transcriptomics may improve efficacy. Full article

Objectives: Despite advancements in molecular-targeted therapies and immune checkpoint inhibitors, the survival rate of patients with advanced lung cancer remains unsatisfactory. Therefore, new and effective treatment strategies are urgently needed. Both mesenchymal-epithelial transition (MET) inhibitors and oncolytic viruses exhibit immunomodulatory properties along with direct antitumor effects. Materials and Methods: The antitumor effects of a combination therapy using MDRVV, a modified vaccinia virus for oncolytic virus therapy, and tepotinib, a MET inhibitor, were evaluated in vitro and in vivo using lung cancer models. Results: The combination therapy demonstrated additive cytotoxic effects on various lung cancer cell lines in vitro and significantly suppressed tumor growth in an immunocompetent mouse model. MDRVV triggered immunogenic cell death, evidenced by the release of adenosine triphosphate (ATP) and high-mobility group box-1 (HMGB-1). Additionally, the combination therapy enhanced CD4+ and CD+ T-cell infiltration more effectively than either agent alone. MDRVV exhibited antitumor effects not only in the inoculated tumors but also in distant tumors, with the most pronounced effect observed when combined with tepotinib. Conclusions: These findings suggest that combining a MET inhibitor with oncolytic vaccinia virus represents a promising and effective strategy for improving lung cancer treatment by targeting both tumor cells and the tumor microenvironment. Full article

Despite advances in immunotherapy with checkpoint inhibitors, a significant proportion of patients with head and neck squamous cell carcinoma (HNSCC) do not respond to treatment or eventually develop resistance. This review focuses on novel therapeutic strategies currently under investigation for HNSCC, moving beyond the established paradigms of EGFR inhibition and PD-1/PD-L1 blockade. We explore emerging targets and drug classes, including next-generation immunotherapies, targeted therapies directed at specific molecular alterations, epigenetic modifiers, agents targeting the tumor microenvironment, and innovative approaches like cell-based therapies and oncolytic viruses. We discuss the preclinical rationale and clinical data (where available) for these novel approaches, highlighting the challenges and opportunities in translating these discoveries into improved outcomes for patients with HNSCC. Full article

Chimeric antigen receptor (CAR)-T-cell therapy has revolutionised haematological cancer treatment. However, its application in solid tumours remains significantly limited by the immunosuppressive tumour microenvironment (TME), poor antigen specificity, and physical barriers to infiltration. This review explores a compelling question: can CAR-T cells be adapted to overcome immunosuppression in solid tumours effectively? We provide an in-depth analysis of the immunological, metabolic, and structural challenges posed by the TME and critically evaluate emerging engineering strategies designed to enhance CAR-T cells’ persistence, targeting, and function. These include metabolic reprogramming, hypoxia-responsive constructs, checkpoint-resistant designs, and innovative delivery techniques such as locoregional administration and nanotechnology-assisted targeting. We highlight promising preclinical and early clinical studies demonstrating that armoured CAR-T cells secreting cytokines like interleukin (IL)-12 and IL-18 can reprogram the TME, restoring antitumour immunity. Moreover, we examine synergistic combination therapies that integrate CAR-T cells with immune checkpoint inhibitors, radiotherapy, oncolytic viruses, and epigenetic modulators. Special attention is given to personalised strategies, such as bispecific targeting and precision delivery to tumour-associated vasculature or stromal elements, which are showing encouraging results in overcoming resistance mechanisms. This review aims not only to synthesise current advancements but also to ignite optimism in the potential of CAR-T-cell therapy to breach the immunological fortress of solid tumours. As we enter a new era of synthetic immunology, this evolving landscape offers hope for durable remissions and novel treatment paradigms. For clinicians, researchers, and biotech innovators, this paper provides a roadmap toward transforming a therapeutic dream into clinical reality. Full article