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Current Issues in Molecular Biology Jun 2024The recent success of cancer immunotherapies, such as immune checkpoint inhibitor (ICIs), monoclonal antibodies (mAbs), cancer vaccines, and adoptive cellular therapies... (Review)
Review
The recent success of cancer immunotherapies, such as immune checkpoint inhibitor (ICIs), monoclonal antibodies (mAbs), cancer vaccines, and adoptive cellular therapies (ACTs), has revolutionized traditional cancer treatment. However, these immunotherapeutic modalities have variable efficacies, and many of them exhibit adverse effects. Oncolytic viral Immunotherapy (OViT), whereby viruses are used to directly or indirectly induce anti-cancer immune responses, is emerging as a novel immunotherapy for treating patients with different types of cancer. The herpes simplex virus type-1 (HSV-1) possesses many characteristics that inform its use as an effective OViT agents and remains a leading candidate. Its recent clinical success resulted in the Food and Drug Administration (FDA) approval of Talimogene laherparevec (T-VEC or Imlygic) in 2015 for the treatment of advanced melanoma. In this review, we discuss recent advances in the development of oncolytic HSV-1-based OViTs, their anti-tumor mechanism of action, and efficacy data from recent clinical trials. We envision this knowledge may be used to inform the rational design and application of future oHSV in cancer treatment.
PubMed: 38921005
DOI: 10.3390/cimb46060334 -
Expert Opinion on Biological Therapy Jun 2024Advanced hepatocellular carcinoma (HCC) represents a significant global health burden, whose treatment has been recently revolutionized by the advent of biologic... (Review)
Review
INTRODUCTION
Advanced hepatocellular carcinoma (HCC) represents a significant global health burden, whose treatment has been recently revolutionized by the advent of biologic treatments. Despite that, innovative therapeutic regimens and approaches, especially immune-based, remain to be explored aiming at extending the therapeutic benefits to a wider population of patients.
AREAS COVERED
This review comprehensively discusses the evolving landscape of biological treatment modalities for advanced HCC, including immune checkpoint inhibitors, antiangiogenic monoclonal antibodies, tumor-targeting monoclonal antibodies either naked or drug-conjugated, therapeutic vaccines, oncolytic viruses, adoptive cell therapies, and cytokine-based therapies. Key clinical trials and preclinical studies are examined, highlighting the actual or potential impact of these interventions in reshaping treatment paradigms for HCC.
EXPERT OPINION
Tailored and rational combination strategies, leveraging the synergistic effects of different modalities, represent a promising approach to maximize treatment efficacy in advanced HCC, which should aim at conversion endpoints to increase the fraction of patients eligible for curative approaches. The identification of predictive biomarkers holds the key to optimizing patient selection and improving therapeutic outcomes.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Biological Products; Animals; Biological Therapy; Immunotherapy; Immune Checkpoint Inhibitors
PubMed: 38913107
DOI: 10.1080/14712598.2024.2363234 -
Biochimica Et Biophysica Acta. General... Jun 2024Despite advances in cancer therapies, glioblastoma (GBM) remains the most resistant and recurrent tumor in the central nervous system. GBM tumor microenvironment (TME)... (Review)
Review
Despite advances in cancer therapies, glioblastoma (GBM) remains the most resistant and recurrent tumor in the central nervous system. GBM tumor microenvironment (TME) is a highly dynamic landscape consistent with alteration in tumor infiltration cells, playing a critical role in tumor progression and invasion. In addition, glioma stem cells (GSCs) with self-renewal capability promote tumor recurrence and induce therapy resistance, which all have complicated eradication of GBM with existing therapies. Oncolytic virotherapy is a promising field of therapy that can kill tumor cells in a targeted manner. Manipulated oncolytic viruses (OVs) improve cancer immunotherapy by directly lysis tumor cells, infiltrating antitumor cells, inducing immunogenic cell death, and sensitizing immune-resistant TME to an immune-responsive hot state. Importantly, OVs can target stemness-driven GBM progression. In this review, we will discuss how OVs as a therapeutic option target GBM, especially the GSC subpopulation, and induce immunogenicity to remodel the TME, which subsequently enhances immunotherapies' efficiency.
PubMed: 38901497
DOI: 10.1016/j.bbagen.2024.130662 -
Oral Oncology Aug 2024
Topics: Humans; Mouth Neoplasms; Oncolytic Virotherapy; Carcinoma, Squamous Cell; Virus Replication; Oncolytic Viruses
PubMed: 38901367
DOI: 10.1016/j.oraloncology.2024.106897 -
Bulletin of Mathematical Biology Jun 2024Virotherapy treatment is a new and promising target therapy that selectively attacks cancer cells without harming normal cells. Mathematical models of oncolytic viruses...
Virotherapy treatment is a new and promising target therapy that selectively attacks cancer cells without harming normal cells. Mathematical models of oncolytic viruses have shown predator-prey like oscillatory patterns as result of an underlying Hopf bifurcation. In a spatial context, these oscillations can lead to different spatio-temporal phenomena such as hollow-ring patterns, target patterns, and dispersed patterns. In this paper we continue the systematic analysis of these spatial oscillations and discuss their relevance in the clinical context. We consider a bifurcation analysis of a spatially explicit reaction-diffusion model to find the above mentioned spatio-temporal virus infection patterns. The desired pattern for tumor eradication is the hollow ring pattern and we find exact conditions for its occurrence. Moreover, we derive the minimal speed of travelling invasion waves for the cancer and for the oncolytic virus. Our numerical simulations in 2-D reveal complex spatial interactions of the virus infection and a new phenomenon of a periodic peak splitting. An effect that we cannot explain with our current methods.
Topics: Oncolytic Virotherapy; Oncolytic Viruses; Mathematical Concepts; Models, Biological; Humans; Neoplasms; Computer Simulation
PubMed: 38896363
DOI: 10.1007/s11538-024-01322-z -
Current Treatment Options in Oncology Jun 2024Malignant gliomas are common central nervous system tumors that pose a significant clinical challenge due to the lack of effective treatments. Glioblastoma (GBM), a... (Review)
Review
Malignant gliomas are common central nervous system tumors that pose a significant clinical challenge due to the lack of effective treatments. Glioblastoma (GBM), a grade 4 malignant glioma, is the most prevalent primary malignant brain tumor and is associated with poor prognosis. Current clinical trials are exploring various strategies to combat GBM, with oncolytic viruses (OVs) appearing particularly promising. In addition to ongoing and recently completed clinical trials, one OV (Teserpaturev, Delytact®) received provisional approval for GBM treatment in Japan. OVs are designed to selectively target and eliminate cancer cells while promoting changes in the tumor microenvironment that can trigger and support long-lasting anti-tumor immunity. OVs offer the potential to remodel the tumor microenvironment and reverse systemic immune exhaustion. Additionally, an increasing number of OVs are armed with immunomodulatory payloads or combined with immunotherapy approaches in an effort to promote anti-tumor responses in a tumor-targeted manner. Recently completed oncolytic virotherapy trials can guide the way for future treatment individualization through patient preselection, enhancing the likelihood of achieving the highest possible clinical success. These trials also offer valuable insight into the numerous challenges inherent in malignant glioma treatment, some of which OVs can help overcome.
PubMed: 38896326
DOI: 10.1007/s11864-024-01211-6 -
Frontiers in Immunology 2024Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects....
INTRODUCTION
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs.
METHODS
This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells.
RESULTS AND DISCUSSION
Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates.
CONCLUSION
These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.
Topics: Animals; Interleukin-12; Mice; Oncolytic Virotherapy; Oncolytic Viruses; Transgenes; Virus Replication; Cell Line, Tumor; Immunotherapy; Humans; Simplexvirus; Dendritic Cells; Female
PubMed: 38895115
DOI: 10.3389/fimmu.2024.1375413 -
Cancers May 2024Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional... (Review)
Review
Locoregionally advanced and metastatic melanoma represent a challenging clinical problem, but in the era of immune checkpoint blockade and intralesional and infusional therapies, more options are available for use. Isolated limb infusion (ILI) was first introduced in the 1990s for the management of advanced melanoma, followed by the utilization of isolated extremity perfusion (ILP). Following this, intralesional oncolytic viruses, xanthene dyes, and cytokines were introduced for the management of in-transit metastases as well as unresectable, advanced melanoma. In 2015, the Food and Drug Administration (FDA) approved the first oncolytic intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of advanced melanoma. Additionally, immune checkpoint inhibition has demonstrated efficacy in the management of advanced melanomas, and this improvement in outcomes has been extrapolated to aid in the management of in-transit metastatic disease. Finally, percutaneous hepatic perfusion (PHP), also approved by the FDA, has been reported to have a significant impact on the treatment of hepatic disease in uveal melanoma. While some of these treatments have less utility due to inferior outcomes as well as higher toxicity profiles, there are selective patient profiles for which these therapies carry a role. This review highlights intralesional and infusional therapies for the management of metastatic melanoma.
PubMed: 38893078
DOI: 10.3390/cancers16111957 -
International Journal of Molecular... May 2024FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory...
FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou-Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC.
Topics: Humans; Colorectal Neoplasms; Cell Line, Tumor; Fluorouracil; Oncolytic Virotherapy; MicroRNAs; Oncolytic Viruses; Antineoplastic Combined Chemotherapy Protocols; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Enterovirus B, Human; Combined Modality Therapy; Irinotecan
PubMed: 38891807
DOI: 10.3390/ijms25115618 -
Journal For Immunotherapy of Cancer Jun 2024The purpose of this commentary is to highlight the high occurrence of clinical pseudoprogression and delayed responses that have been observed to date with the locally...
The purpose of this commentary is to highlight the high occurrence of clinical pseudoprogression and delayed responses that have been observed to date with the locally injected oncolytic adenovirus, AdAPT-001, currently in a Phase 1/2 clinical trial (NCT04673942) for the treatment of treatment-refractory tumors. Not surprisingly, these have led to confusion about response assessment and whether to continue patients on treatment. AdAPT-001 carries a transforming growth factor (TGF)-beta trap (TGF-β), which sequesters TGF-β, a cytokine that potently regulates inflammation, fibrosis, and immunosuppression in cancer. Pseudoprogression (PsP) or progression prior to response or stabilization, has been widely recognized with radiotherapy for primary brain tumors and immune checkpoint inhibitors (ICIs). PsP has also been described and documented in the context of oncolytic virotherapy but perhaps to a lesser extent. However, repeated intratumoral injections with these immunostimulatory agents may induce a more intense immune response and release more antigenic epitopes than with ICIs, for example, which are strictly T-cell directed rather than also tumor-directed like AdAPT-001.
Topics: Humans; Disease Progression; Oncolytic Virotherapy; Oncolytic Viruses; Neoplasms; Adenoviridae
PubMed: 38886116
DOI: 10.1136/jitc-2024-008809