scholarly journals Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 588
Author(s):  
Ke-Tao Jin ◽  
Wen-Lin Du ◽  
Yu-Yao Liu ◽  
Huan-Rong Lan ◽  
Jing-Xing Si ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Tumor Antigens ◽  
Adoptive Cell Therapy ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Immunosuppressive Tumor Microenvironment ◽  
Delivery Strategies ◽  
Therapeutic Tools ◽  
Immune Checkpoint Blockers

Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.

scholarly journals Implantable and Injectable Biomaterial Scaffolds for Cancer Immunotherapy

2020 ◽  
Vol 8 ◽  
Author(s):  
Jie Li ◽  
Yiqian Luo ◽  
Baoqin Li ◽  
Yuanliang Xia ◽  
Hengyi Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Efficacy And Safety ◽  
Broad Application ◽  
Immunosuppressive Tumor Microenvironment ◽  
Biomaterial Scaffolds ◽  
Delivery Strategies ◽  
Cancer Immunotherapies

Cancer immunotherapy has become an emerging strategy recently producing durable immune responses in patients with varieties of malignant tumors. However, the main limitation for the broad application of immunotherapies still to reduce side effects by controlling and regulating the immune system. In order to improve both efficacy and safety, biomaterials have been applied to immunotherapies for the specific modulation of immune cells and the immunosuppressive tumor microenvironment. Recently, researchers have constantly developed biomaterials with new structures, properties and functions. This review provides the most recent advances in the delivery strategies of immunotherapies based on localized biomaterials, focusing on the implantable and injectable biomaterial scaffolds. Finally, the challenges and prospects of applying implantable and injectable biomaterial scaffolds in the development of future cancer immunotherapies are discussed.

scholarly journals Designer nanocarriers for navigating the systemic delivery of oncolytic viruses

Nanomedicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 93-110 ◽  
Author(s):  
Faith Howard ◽  
Munitta Muthana
Keyword(s):  
Optimal Design ◽  
Immune Responses ◽  
Systemic Administration ◽  
Oncolytic Viruses ◽  
Cellular Interaction ◽  
Oncolytic Virotherapy ◽  
Specific Cell ◽  
Systemic Delivery ◽  
Cell Binding ◽  
Carrier Systems

Nanotechnology is paving the way for new carrier systems designed to overcome the greatest challenges of oncolytic virotherapy; systemic administration and subsequent implications of immune responses and specific cell binding and entry. Systemic administration of oncolytic agents is vital for disseminated neoplasms, however transition of nanoparticles (NP) to virotherapy has yielded modest results. Their success relies on how they navigate the merry-go-round of often-contradictory phases of NP delivery: circulatory longevity, tissue permeation and cellular interaction, with many studies postulating design features optimal for each phase. This review discusses the optimal design of NPs for the transport of oncolytic viruses within these phases, to determine whether improved virotherapeutic efficacy lies in the pharmacokinetic/pharmacodynamics characteristics of the NP–oncolytic viruses complexes rather than manipulation of the virus and targeting ligands.

scholarly journals Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5452
Author(s):  
Masmudur M. Rahman ◽  
Grant McFadden
Keyword(s):  
Clinical Trials ◽  
Immune Responses ◽  
Cancer Patient ◽  
Cancer Cells ◽  
Treatment Modality ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Therapeutic Approaches ◽  
Cancer Treatments ◽  
The Past

Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert “immune-cold” tumors to “immune-hot” will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy.

Oncolytic virotherapy as promising immunotherapy against cancer: mechanisms of resistance to oncolytic viruses

2021 ◽  
Author(s):  
Nasser Hashemi Goradel ◽  
Arezoo Alizadeh ◽  
Shahnaz Hosseinzadeh ◽  
Mitra Taghipour ◽  
Zeinab Ghesmati ◽  
...  
Keyword(s):  
Immune Responses ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Early 20Th Century ◽  
Mechanisms Of Resistance ◽  
Talimogene Laherparepvec ◽  
Aberrant Expression ◽  
Expression Of Genes ◽  
History Of ◽  
Interferon Responses

Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.

Messenger RNA vaccination and B-cell responses in NSCLC patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2573-2573 ◽  
Author(s):  
Martin Sebastian ◽  
Lotta von Boehmer ◽  
Alfred Zippelius ◽  
Frank Mayer ◽  
Martin Reck ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase I ◽  
Injection Site ◽  
B Cell ◽  
Cancer Immunotherapy ◽  
Messenger Rna ◽  
Tumor Antigens ◽  
Fold Increase ◽  
Cell Responses ◽  
B Cell Responses

2573^ Background: Vaccination with mRNA is a novel technology in cancer immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules (RNActive) coding for five non small cell lung cancer (NSCLC)-associated tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC. Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3 pts. were treated at three dose levels (400µg, 800µg and 1600µg CV9201) and observed for DLTs to select the highest tolerated dose for phase IIa. Primary endpoint was safety and tolerability; secondary endpoints were immune response, clinical efficacy and survival. Pts. received up to five vaccinations of CV9201 within 15 weeks. Antigen-specific immune responses against each of the 5 antigens were measured at baseline, and two weeks after the 3rd and 5th vaccination. Frequency of lymphocyte subsets and expression of activation and maturation markers were measured and retrospectively correlated with immunological and clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase IIa); No DLTs occurred, and the 1600 µg dose was investigated in phase IIa. The most frequent related adverse events were mild to moderate injection site reactions and flu-like symptoms. 3 patients (7%) had potentially related grade 3 AEs (fatigue, injection site granuloma, asthma attack) and no related SAEs were reported. There were no objective responses. Data on PFS and survival will be presented. Antigen specific immune responses against at least one antigen were induced in 65% of pts. (39% cellular and 49% humoral). Consistently, a significant ≥2 fold increase of pre germinal center B cells (pGCB) was observed in 61% of pts. This increase of pGCB correlated significantly (p=0.0028) with increase of total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase during treatment. Conclusions: Vaccination with CV9201 has a favorable safety profile and induces T and B cell responses against all included antigens. Vaccine-induced increase of pGCB is a new finding and might be used as a biomarker in cancer immunotherapy.

scholarly journals Engineering Therapeutic Strategies in Cancer Immunotherapy via Exogenous Delivery of Toll-like Receptor Agonists

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1374
Author(s):  
Sehwan Jeong ◽  
Yunyoung Choi ◽  
Kyobum Kim
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Cell Activation ◽  
The Body ◽  
Toll Like Receptor ◽  
Tlr Agonists ◽  
Cytokines And Chemokines ◽  
Adaptive Immune Cells ◽  
Delivery Strategies

As a currently spotlighted method for cancer treatment, cancer immunotherapy has made a lot of progress in recent years. Among tremendous cancer immunotherapy boosters available nowadays, Toll-like receptor (TLR) agonists were specifically selected, because of their effective activation of innate and adaptive immune cells, such as dendritic cells (DCs), T cells, and macrophages. TLR agonists can activate signaling pathways of DCs to express CD80 and CD86 molecules, and secrete various cytokines and chemokines. The maturation of DCs stimulates naïve T cells to differentiate into functional cells, and induces B cell activation. Although TLR agonists have anti-tumor ability by activating the immune system of the host, their drawbacks, which include poor efficiency and remarkably short retention time in the body, must be overcome. In this review, we classify and summarize the recently reported delivery strategies using (1) exogenous TLR agonists to maintain the biological and physiological signaling activities of cargo agonists, (2) usage of multiple TLR agonists for synergistic immune responses, and (3) co-delivery using the combination with other immunomodulators or stimulants. In contrast to naked TLR agonists, these exogenous TLR delivery strategies successfully facilitated immune responses and subsequently mediated anti-tumor efficacy.

scholarly journals Strategies for developing and optimizing cancer vaccines

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 654 ◽  
Author(s):  
Hoyoung M. Maeng ◽  
Jay A. Berzofsky
Keyword(s):  
Immune Responses ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Adoptive Cell Therapy ◽  
Immune Recognition ◽  
Cancer Therapies ◽  
Immunologic Assays ◽  
Humoral Responses

With the spotlight on cancer immunotherapy and the expanding use of immune checkpoint inhibitors, strategies to improve the response rate and duration of current cancer immunotherapeutics are highly sought. In that sense, investigators around the globe have been putting spurs on the development of effective cancer vaccines in humans after decades of efforts that led to limited clinical success. In more than three decades of research in pursuit of targeted and personalized immunotherapy, several platforms have been incorporated into the list of cancer vaccines from live viral or bacterial agents harboring antigens to synthetic peptides with the hope of stronger and durable immune responses that will tackle cancers better. Unlike adoptive cell therapy, cancer vaccines can take advantage of using a patient’s entire immune system that can include more than engineered receptors or ligands in developing antigen-specific responses. Advances in molecular technology also secured the use of genetically modified genes or proteins of interest to enhance the chance of stronger immune responses. The formulation of vaccines to increase chances of immune recognition such as nanoparticles for peptide delivery is another area of great interest. Studies indicate that cancer vaccines alone may elicit tumor-specific cellular or humoral responses in immunologic assays and even regression or shrinkage of the cancer in select trials, but novel strategies, especially in combination with other cancer therapies, are under study and are likely to be critical to achieve and optimize reliable objective responses and survival benefit. In this review, cancer vaccine platforms with different approaches to deliver tumor antigens and boost immunity are discussed with the intention of summarizing what we know and what we need to improve in the clinical trial setting.

scholarly journals Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000200 ◽  
Author(s):  
Shibin Qu ◽  
Tejaswi Worlikar ◽  
Amy E Felsted ◽  
Anutosh Ganguly ◽  
Megan V Beems ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Thermal Ablation ◽  
Tumor Antigens ◽  
Immune Cell ◽  
Checkpoint Inhibition ◽  
Non Invasive ◽  
Adaptive Immune ◽  
The Impact

BackgroundDeveloping the ability to use tumor-directed therapies to trigger potentially therapeutic immune responses against cancer antigens remains a high priority for cancer immunotherapy. We hypothesized that histotripsy, a novel non-invasive, non-thermal ablation modality that uses ultrasound-generated acoustic cavitation to disrupt tissues, could engender adaptive immune responses to tumor antigens.MethodsImmunocompetent C57BL/6 mice inoculated with flank melanoma or hepatocellular carcinoma tumors were treated with histotripsy, thermal ablation, radiation therapy, or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) blockade checkpoint inhibition. Lymphocyte responses were measured using flow cytometric and immunohistochemical analyses. The impact of histotripsy on abscopal immune responses was assessed in mice bearing bilateral tumors, or unilateral tumors with pulmonary tumors established via tail vein injection.ResultsHistotripsy ablation of subcutaneous murine melanoma tumors stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations. The magnitude of this immunostimulation was stronger than that seen with tumor irradiation or thermal ablation. Histotripsy also promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity, and this immunostimulatory effect was associated with calreticulin translocation to the cellular membrane and local and systemic release of high mobility group box protein 1. Histotripsy ablation potentiated the efficacy of checkpoint inhibition immunotherapy in murine models of melanoma and hepatocellular carcinoma.ConclusionsThese preclinical observations suggest that non-invasive histotripsy ablation can be used to stimulate tumor-specific immune responses capable of magnifying the impact of checkpoint inhibition immunotherapy.

scholarly journals Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 204 ◽  
Author(s):  
Zong Sheng Guo ◽  
Michael T. Lotze ◽  
Zhi Zhu ◽  
Walter J. Storkus ◽  
Xiao-Tong Song
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
T Cell Receptor ◽  
Tumor Antigens ◽  
Cell Receptor ◽  
Oncolytic Viruses ◽  
Current Status ◽  
Great Promise ◽  
Specific Antibodies ◽  
Anti Cancer

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies.

scholarly journals Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

Cancers ◽  
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.

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