Oncolytic viruses in immunotherapy

Background: HER2-based retargeted viruses are in advanced phases of preclinical development of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors renders it an attractive target, presently investigated in clinical trials employing antibody drug conjugates and CAR-T cells. The availability of MSLN-retargeted oncolytic viruses may complement the current immunotherapeutic panel of biological drugs against HER2-negative breast and non-breast tumors. Methods: A fully virulent, tumor-targeted oncolytic Herpes simplex virus-1 (MSLN-THV) with a selectivity for mesothelin-expressing cancer cells was generated. Recombineering technology was used to replace an essential moiety of the viral glycoprotein D with antibody fragments derived from clinically validated MSLN monoclonal antibodies, and to allow IL12 cargo expression in infected cells. Panels of breast and female reproductive system cell lines were used to verify the oncolytic potential of the viral constructs. A platform for production of the retargeted viruses was developed in HEK 293 cells, providing stable expression of a suitable chimeric receptor. Results: We demonstrated the selectivity of viral infection and cytotoxicity by MSLN-retargeted viruses in a panel of mesothelin-positive cancer cells, originating from breast and female reproductive system tumors. We also developed a second-generation oncolytic MSLN-THV, encoding IL12, to enhance the immunotherapeutic potential of the viral backbone. A non-tumor cell line expressing a chimeric MSLN/Nectin-1 receptor, de-sensitized from antiviral responses by genetic inactivation of the Stimulator of Interferon Genes (STING)-dependent pathway was engineered, to optimize viral yields. Conclusions: Our proof-of-concept study proposes MSLN-retargeted herpesviruses as potential cancer immunotherapeutics for assessments in preclinical models of MSLN-positive tumors, complementing the available panel of oncolytic viruses to HER2-negative breast tumors.

Download Full-text

Using oncolytic viruses to ignite the tumour immune microenvironment in bladder cancer

Nature Reviews Urology ◽

10.1038/s41585-021-00483-z ◽

2021 ◽

Author(s):

Roger Li ◽

Jingsong Zhang ◽

Scott M. Gilbert ◽

José Conejo-Garcia ◽

James J. Mulé

Keyword(s):

Bladder Cancer ◽

Oncolytic Viruses ◽

Immune Microenvironment

Download Full-text

Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

Cancers ◽

10.3390/cancers13143386 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3386

Author(s):

Bart Spiesschaert ◽

Katharina Angerer ◽

John Park ◽

Guido Wollmann

Keyword(s):

Immune Response ◽

Immune Responses ◽

Tumor Cells ◽

Small Molecule ◽

Antiviral Immunity ◽

Oncolytic Viruses ◽

Antitumor Immune Response ◽

Antiviral Responses ◽

Small Molecule Therapeutics ◽

Immunosuppressive Factors

The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.

Download Full-text

Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity

Cancers ◽

10.3390/cancers13010086 ◽

2020 ◽

Vol 13 (1) ◽

pp. 86

Author(s):

Mohit Kumar ◽

Chellappagounder Thangavel ◽

Richard C. Becker ◽

Sakthivel Sadayappan

Keyword(s):

Cancer Patients ◽

Immune Modulation ◽

Checkpoint Inhibitors ◽

Survival Rates ◽

Induced Pluripotent Stem Cell ◽

High Volume ◽

Oncolytic Viruses ◽

Model Systems ◽

Volume Data ◽

Late Cardiotoxicity

Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.

Download Full-text

Oncolytic viruses as a promising therapeutic strategy for hematological malignancies

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111573 ◽

2021 ◽

Vol 139 ◽

pp. 111573

Author(s):

Chen Yang ◽

Nanni Hua ◽

Shufang Xie ◽

Yi Wu ◽

Lifeng Zhu ◽

...

Keyword(s):

Therapeutic Strategy ◽

Hematological Malignancies ◽

Oncolytic Viruses

Download Full-text

Inflammation and tumor progression: signaling pathways and targeted intervention

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00658-5 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Huakan Zhao ◽

Lei Wu ◽

Guifang Yan ◽

Yu Chen ◽

Mingyue Zhou ◽

...

Keyword(s):

Growth Factor ◽

Tumor Progression ◽

Signaling Pathways ◽

Transforming Growth Factor ◽

Response To Therapy ◽

Janus Kinase ◽

Oncolytic Viruses ◽

Mitogen Activated Protein Kinase ◽

Resolution Of Inflammation ◽

Chemokine Ligands

AbstractCancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

Download Full-text

Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

Biomarker Research ◽

10.1186/s40364-021-00264-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Laura Castelletti ◽

Dannel Yeo ◽

Nico van Zandwijk ◽

John E. J. Rasko

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Malignant Mesothelioma ◽

Oncolytic Viruses ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

Download Full-text

Prospects of immune checkpoint blockade and vaccine-based immunotherapy for glioblastoma

Innovative Surgical Sciences ◽

10.1515/iss-2020-0034 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Stefanie Tietze ◽

Susanne Michen ◽

Gabriele Schackert ◽

Achim Temme

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Primary Brain Tumor ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Oncolytic Viruses ◽

Therapeutic Vaccines ◽

Dismal Prognosis ◽

Tumor Parenchyma ◽

Immunosuppressive Microenvironment

Abstract Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor endowed with a dismal prognosis. Nowadays, immunotherapy in a particular immune checkpoint blockade and therapeutic vaccines are being extensively pursued. Yet, several characteristics of GBM may impact such immunotherapeutic approaches. This includes tumor heterogeneity, the relatively low mutational load of primary GBM, insufficient delivery of antibodies to tumor parenchyma and the unique immunosuppressive microenvironment of GBM. Moreover, standard treatment of GBM, comprising temozolomide chemotherapy, radiotherapy and in most instances the application of glucocorticoids for management of brain edema, results in a further increased immunosuppression. This review will provide a brief introduction to the principles of vaccine-based immunotherapy and give an overview of the current clinical studies, which employed immune checkpoint inhibitors, oncolytic viruses-based vaccination, cell-based and peptide-based vaccines. Recent experiences as well as the latest developments are reviewed. Overcoming obstacles, which limit the induction and long-term immune response against GBM when using vaccination approaches, are necessary for the implementation of effective immunotherapy of GBM.

Download Full-text