-
Signal Transduction and Targeted Therapy Apr 2023Oncolytic viruses (OVs) have attracted growing awareness in the twenty-first century, as they are generally considered to have direct oncolysis and cancer immune... (Review)
Review
Oncolytic viruses (OVs) have attracted growing awareness in the twenty-first century, as they are generally considered to have direct oncolysis and cancer immune effects. With the progress in genetic engineering technology, OVs have been adopted as versatile platforms for developing novel antitumor strategies, used alone or in combination with other therapies. Recent studies have yielded eye-catching results that delineate the promising clinical outcomes that OVs would bring about in the future. In this review, we summarized the basic principles of OVs in terms of their classifications, as well as the recent advances in OV-modification strategies based on their characteristics, biofunctions, and cancer hallmarks. Candidate OVs are expected to be designed as "qualified soldiers" first by improving target fidelity and safety, and then equipped with "cold weapons" for a proper cytocidal effect, "hot weapons" capable of activating cancer immunotherapy, or "auxiliary weapons" by harnessing tactics such as anti-angiogenesis, reversed metabolic reprogramming and decomposing extracellular matrix around tumors. Combinations with other cancer therapeutic agents have also been elaborated to show encouraging antitumor effects. Robust results from clinical trials using OV as a treatment congruously suggested its significance in future application directions and challenges in developing OVs as novel weapons for tactical decisions in cancer treatment.
Topics: Humans; Immunotherapy; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses
PubMed: 37041165
DOI: 10.1038/s41392-023-01407-6 -
Journal For Immunotherapy of Cancer Oct 2020Oncolytic viruses (OVs) are a new class of cancer therapeutics. This review was undertaken to provide insight into the current landscape of OV clinical trials. A PubMed... (Review)
Review
Oncolytic viruses (OVs) are a new class of cancer therapeutics. This review was undertaken to provide insight into the current landscape of OV clinical trials. A PubMed search identified 119 papers from 2000 to 2020 with 97 studies reporting data on 3233 patients. The viruses used, presence of genetic modifications and/or transgene expression, cancer types targeted, inclusion of combination strategies and safety profile were reported. In addition, information on viral bioshedding across the studies, including which tissues or body fluids were evaluated and how virus was detected (eg, PCR, plaque assay or both), is also reported. Finally, the number of studies evaluating antiviral and antitumor humoral and cellular immune responses were noted. We found that adenovirus (n=30) is the most common OV in clinical trials with approximately two-thirds (n=63) using modified or recombinant viral backbones and granulocyte-macrophage colony-stimulating factor (n=24) was the most common transgene. The most common tumors targeted were melanoma (n=1000) and gastrointestinal (GI; n=577) cancers with most using monotherapy OVs given by intratumoral (n=1482) or intravenous (n=1347) delivery. The most common combination included chemotherapy (n=36). Overall, OV treatment-related adverse events were low-grade constitutional and local injection site reactions. Viral shedding was frequently measured although many studies restricted this to blood and tumor tissue and used PCR only. While most studies did report antiviral antibody titers (n=63), only a minority of studies reported viral-specific T cell responses (n=10). Tumor immunity was reported in 48 studies and largely relied on general measures of immune activation (eg, tumor biopsy immunohistochemistry (n=25) and serum cytokine measurement (n=19)) with few evaluating tumor-specific immune responses (n=7). Objective responses were reported in 292 (9%) patients and disease control was achieved in 681 (21.1%) patients, although standard reporting criteria were only used in 53% of the trials. Completed clinical trials not reported in the peer-reviewed literature were not included in this review potentially underestimating the impact of OV treatment. These data provide insight into the current profile of OV clinical trials reporting and identifies potential gaps where further studies are needed to better define the role of OVs, alone and in combination, for patients with cancer.
Topics: Biomedical Research; History, 21st Century; Humans; Immunotherapy; Oncolytic Virotherapy; Oncolytic Viruses
PubMed: 33046622
DOI: 10.1136/jitc-2020-001486 -
Science Translational Medicine Apr 2022Oncolytic viruses (OVs) encoding a variety of transgenes have been evaluated as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)-modified T...
Oncolytic viruses (OVs) encoding a variety of transgenes have been evaluated as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)-modified T cells in the solid tumor microenvironment (TME). Here, using systemically delivered OVs and CAR T cells in immunocompetent mouse models, we have defined a mechanism by which OVs can potentiate CAR T cell efficacy against solid tumor models of melanoma and glioma. We show that stimulation of the native T cell receptor (TCR) with viral or virally encoded epitopes gives rise to enhanced proliferation, CAR-directed antitumor function, and distinct memory phenotypes. In vivo expansion of dual-specific (DS) CAR T cells was leveraged by in vitro preloading with oncolytic vesicular stomatitis virus (VSV) or reovirus, allowing for a further in vivo expansion and reactivation of T cells by homologous boosting. This treatment led to prolonged survival of mice with subcutaneous melanoma and intracranial glioma tumors. Human CD19 CAR T cells could also be expanded in vitro with TCR reactivity against viral or virally encoded antigens and was associated with greater CAR-directed cytokine production. Our data highlight the utility of combining OV and CAR T cell therapy and show that stimulation of the native TCR can be exploited to enhance CAR T cell activity and efficacy in mice.
Topics: Animals; Glioma; Immunotherapy, Adoptive; Melanoma; Mice; Oncolytic Virotherapy; Oncolytic Viruses; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 35417192
DOI: 10.1126/scitranslmed.abn2231 -
Oncoimmunology 2022Resistance remains an obstacle to anti-programmed cell death protein 1 (PD-1) therapy in human cancer. One critical resistance mechanism is the lack of T cell chemotaxis...
Resistance remains an obstacle to anti-programmed cell death protein 1 (PD-1) therapy in human cancer. One critical resistance mechanism is the lack of T cell chemotaxis in the tumor microenvironment (TME). CXCL10-CXCR3 signaling is required for T cell tumor infiltration and tumor immunotherapy. Oncolytic viruses (OVs), including oncolytic adenoviruses (AdVs), induce effective T cell immunity and tumor infiltration. Thus, arming OV with CXCL10 would be an attractive strategy to overcome resistance to anti-PD1 therapy. Here, we successfully constructed a novel recombinant oncolytic adenovirus encoding murine CXCL10, named Adv-CXCL10. Through intratumoural injection, the continuous expression of the functional chemokine CXCL10 in the TME is realized to recruit more CXCR3 T cells into the TME to kill tumor cells, and the recombinant adenovirus shows great power to 'fire up' the TME and enhance the antitumour efficiency of PD-1 antibodies.
Topics: Adenoviridae; Adenoviridae Infections; Animals; Chemokine CXCL10; Chemotaxis; Humans; Mice; Neoplasms; Oncolytic Viruses; Rhabdomyosarcoma, Alveolar; Tumor Microenvironment
PubMed: 36092638
DOI: 10.1080/2162402X.2022.2118210 -
Nature Communications Mar 2020Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and...
Oncolytic viruses offer an in situ vaccination approach to activate tumor-specific T cell responses. However, the upregulation of PD-L1 expression on tumor cells and immune cells leads to tumor resistance to oncolytic immunotherapy. In this study, we generate an engineered oncolytic virus that coexpresses a PD-L1 inhibitor and GM-CSF. We find that the oncolytic virus is able to secrete the PD-L1 inhibitor that systemically binds and inhibits PD-L1 on tumor cells and immune cells. Importantly, the intratumoral injection with the oncolytic virus overcomes PD-L1-mediated immunosuppression during both the priming and effector phases, provokes systemic T cell responses against dominant and subdominant neoantigen epitopes derived from mutations, and leads to an effective rejection of both virus-injected and distant tumors. In summary, this engineered oncolytic virus is able to activate tumor neoantigen-specific T cell responses, providing a potent, individual tumor-specific oncolytic immunotherapy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Genetic Engineering; Granulocyte-Macrophage Colony-Stimulating Factor; HEK293 Cells; Humans; Immunosuppression Therapy; Immunotherapy; Mice; Mice, Inbred C57BL; Oncolytic Virotherapy; Oncolytic Viruses; Recombinant Proteins
PubMed: 32170083
DOI: 10.1038/s41467-020-15229-5 -
Nature Nov 2023Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma...
Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM). Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV). In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).
Topics: Humans; Brain Neoplasms; Glioblastoma; Nestin; Oncolytic Virotherapy; Oncolytic Viruses; Reproducibility of Results; Survival Analysis; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment; Herpesvirus 1, Human
PubMed: 37853118
DOI: 10.1038/s41586-023-06623-2 -
International Journal of Molecular... Nov 2023This Special Issue highlights multiple facets of virus engineering, ranging from the dissection of the biological properties of individual viral functions in the context...
This Special Issue highlights multiple facets of virus engineering, ranging from the dissection of the biological properties of individual viral functions in the context of safe genomic backbones, virus genetic modification for applications in gene therapy, oncolytic virotherapy and vaccine production, to the hurdles presented by quality control and the delivery of viruses for their final applications and finally to the simulation, prediction and validation of virus evolution [...].
Topics: Humans; Oncolytic Viruses; Oncolytic Virotherapy; Genetic Therapy; Neoplasms; Genetic Engineering
PubMed: 38069111
DOI: 10.3390/ijms242316788 -
Molecular Therapy : the Journal of the... Dec 2022The full potential of tumor-infiltrating lymphocyte (TIL) therapy has been hampered by the inadequate activation and low persistence of TILs, as well as inefficient...
The full potential of tumor-infiltrating lymphocyte (TIL) therapy has been hampered by the inadequate activation and low persistence of TILs, as well as inefficient neoantigen presentation by tumors. We transformed tumor cells into artificial antigen-presenting cells (aAPCs) by infecting them with a herpes simplex virus 1 (HSV-1)-based oncolytic virus encoding OX40L and IL12 (OV-OX40L/IL12) to provide local signals for optimum T cell activation. The infected tumor cells displayed increased expression of antigen-presenting cell-related markers and induced enhanced T cell activation and killing in coculture with TILs. Combining OV-OX40L/IL12 and TIL therapy induced complete tumor regression in patient-derived xenograft and syngeneic mouse tumor models and elicited an antitumor immunological memory. In addition, the combination therapy produced aAPC properties in tumor cells, activated T cells, and reprogrammed macrophages to a more M1-like phenotype in the tumor microenvironment. This combination strategy unleashes the full potential of TIL therapy and warrants further evaluation in clinical studies.
Topics: Humans; Animals; Mice; Oncolytic Viruses; Lymphocytes, Tumor-Infiltrating; Antigen-Presenting Cells
PubMed: 35715953
DOI: 10.1016/j.ymthe.2022.06.010 -
The Oncologist Mar 2020Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis,... (Review)
Review
Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T-VEC), a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T-VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM-CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T-VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T-VEC in the treatment of advanced melanoma as a model for future solid tumor indications. IMPLICATIONS FOR PRACTICE: This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T-VEC is the only U.S. Food and Drug Administration (FDA)-approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T-VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.
Topics: Humans; Immunologic Factors; Immunotherapy; Melanoma; Oncolytic Virotherapy; Oncolytic Viruses
PubMed: 32162802
DOI: 10.1634/theoncologist.2019-0438 -
Frontiers in Bioscience (Landmark... Feb 2022Malignant melanoma recurrence remains heterogeneous in presentation, ranging from locoregional disease (i.e., local recurrence, satellites, in transit disease) to... (Review)
Review
Malignant melanoma recurrence remains heterogeneous in presentation, ranging from locoregional disease (i.e., local recurrence, satellites, in transit disease) to distant dermal and visceral metastases. This diverse spectrum of disease requires a personalized approach to management and has resulted in the development of both local (e.g., surgery, radiation, intralesional injection) and systemic (intravenous or oral) treatment strategies. Intralesional agents such as oncolytic viruses may also evoke local immune stimulation to induce and enhance the antitumor immune response. Further, it is hypothesized that these oncolytic viruses may convert immunologically "cold" tumors to more reactive "hot" tumor microenvironments and thereby overcome anti-PD-1 therapy resistance. Currently, talimogene laherparepvec (T-VEC), a modified herpes virus, is FDA-approved in this population, with many other oncolytic viruses under investigation in both preclinical and trial settings. Herein, we detail the scientific rationale, current landscape, and future directions of oncolytic viruses in melanoma.
Topics: Humans; Immunotherapy; Melanoma; Oncolytic Virotherapy; Oncolytic Viruses; Skin Neoplasms; Tumor Microenvironment
PubMed: 35227006
DOI: 10.31083/j.fbl2702063