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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 -
Mathematical Biosciences and... May 2024Resistance to treatment poses a major challenge for cancer therapy, and oncoviral treatment encounters the issue of viral resistance as well. In this investigation, we...
Resistance to treatment poses a major challenge for cancer therapy, and oncoviral treatment encounters the issue of viral resistance as well. In this investigation, we introduce deterministic differential equation models to explore the effect of resistance on oncolytic viral therapy. Specifically, we classify tumor cells into resistant, sensitive, or infected with respect to oncolytic viruses for our analysis. Immune cells can eliminate both tumor cells and viruses. Our research shows that the introduction of immune cells into the tumor-virus interaction prevents all tumor cells from becoming resistant in the absence of conversion from resistance to sensitivity, given that the proliferation rate of immune cells exceeds their death rate. The inclusion of immune cells leads to an additional virus-free equilibrium when the immune cell recruitment rate is sufficiently high. The total tumor burden at this virus-free equilibrium is smaller than that at the virus-free and immune-free equilibrium. Therefore, immune cells are capable of reducing the tumor load under the condition of sufficient immune strength. Numerical investigations reveal that the virus transmission rate and parameters related to the immune response significantly impact treatment outcomes. However, monotherapy alone is insufficient for eradicating tumor cells, necessitating the implementation of additional therapies. Further numerical simulation shows that combination therapy with chimeric antigen receptor (CAR T-cell) therapy can enhance the success of treatment.
Topics: Oncolytic Virotherapy; Humans; Neoplasms; Oncolytic Viruses; Computer Simulation; Animals; Tumor Burden; Cell Proliferation
PubMed: 38872564
DOI: 10.3934/mbe.2024261 -
Stem Cells Translational Medicine Jun 2024Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a...
Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable.
PubMed: 38864209
DOI: 10.1093/stcltm/szae039 -
IET Nanobiotechnology 2024Pancreatic cancer is a leading cause of cancer-related deaths worldwide. Conventional therapies often provide limited success, necessitating the need for novel...
Pancreatic cancer is a leading cause of cancer-related deaths worldwide. Conventional therapies often provide limited success, necessitating the need for novel therapeutic strategies. Oncolytic viruses (OVs) are a class of viruses that specifically target and kill cancer cells while leaving normal cells unharmed. These viruses have shown promise in the treatment of various cancers, including pancreatic cancer. However, their use in clinical settings has been limited by several factors. Their inability to efficiently infect and kill tumor cells. To overcome this limitation, a cell membrane-coated oncolytic virus was developed. However, the necessity of homologous and nonhomologous tumor cell membranes for their function has not yet been proven. This novel virus displayed increased infectivity and killing activity against tumor cells compared to nonhomologous tumor cell membranes and noncoated viruses. We believe that the homologous tumor cell membranes-coated OVs can enhance the therapeutic potential for pancreatic cancer therapy.
Topics: Pancreatic Neoplasms; Humans; Oncolytic Virotherapy; Cell Membrane; Oncolytic Viruses; Cell Line, Tumor; Animals
PubMed: 38863971
DOI: 10.1049/2024/9970665 -
Scientific Reports Jun 2024LHPP has been shown to be a new tumor suppressor, and has a tendency to be under-expressed in a variety of cancers. Oncolytic virotheray is a promising therapeutics for...
LHPP has been shown to be a new tumor suppressor, and has a tendency to be under-expressed in a variety of cancers. Oncolytic virotheray is a promising therapeutics for lung cancer in recent decade years. Here we successfully constructed a new recombinant oncolytic adenovirus GD55-LHPP and investigated the effect of GD55-LHPP on the growth of lung cancer cells in vitro and in vivo. The results showed that LHPP had lower expression in either lung cancer cells or clinical lung cancer tissues compared with normal cells or tissues, and GD55-LHPP effectively mediated LHPP expression in lung cancer cells. GD55-LHPP could effectively inhibit the proliferation of lung cancer cell lines and rarely affected normal cell growth. Mechanically, the oncolytic adenovirus GD55-LHPP was able to induce stronger apoptosis of lung cancer cells compared with GD55 through the activation of caspase signal pathway. Notably, GD55-LHPP also activated autophagy-related signal pathway. Further, GD55-LHPP efficiently inhibited tumor growth in lung cancer xenograft in mice and prolonged animal survival rate compared with the control GD55 or PBS. In conclusion, the novel construct GD55-LHPP provides a valuable strategy for lung cancer-targeted therapy and develop the role of tumor suppress gene LHPP in lung cancer gene therapy.
Topics: Lung Neoplasms; Humans; Animals; Oncolytic Virotherapy; Adenoviridae; Oncolytic Viruses; Mice; Cell Line, Tumor; Xenograft Model Antitumor Assays; Apoptosis; Cell Proliferation; Mice, Nude; Female; Autophagy
PubMed: 38849383
DOI: 10.1038/s41598-024-63325-z -
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 -
Frontiers in Immunology 2024Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a...
Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.
Topics: Dendritic Cells; Animals; Paclitaxel; Adenoviridae; Mice; Oncolytic Viruses; Oncolytic Virotherapy; Combined Modality Therapy; Cell Line, Tumor; Humans; Mice, Inbred C57BL; Cancer Vaccines; Immunotherapy; Granulocyte-Macrophage Colony-Stimulating Factor; Female; Tumor Microenvironment
PubMed: 38835775
DOI: 10.3389/fimmu.2024.1355566