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Biomedicines
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Immuno-Active Cancer Therapeutics
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Immuno-Active Cancer Therapeutics

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 June 2018) | Viewed by 37086

Special Issue Editors

Dr. Markus Vähä-Koskela

E-Mail Website
Guest Editor
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00100 Helsinki, Finland
Interests: gene therapy; tumor immunology; cancer immunotherapy; oncolytic viruses
Special Issues, Collections and Topics in MDPI journals
Dr. Vincenzo Cerullo

E-Mail Website
Co-Guest Editor
Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
Interests: oncolytic viruses; tumor vaccines; tumor peptides; neoantigens; dendritic cells; checkpoint inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Fabrice Le Boeuf

E-Mail Website1 Website2
Co-Guest Editor
Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, ON, Canada
Interests: oncolytic viruses; central nervous system; in vivo models; virus sensitizers; virus engineering; leukemia screening

Special Issue Information

Dear Colleagues,

Spearheaded by checkpoint inhibitors, immunotherapy has established its role in the treatment of many types of cancer. With promising advances made with dendritic cell-based tumor vaccines, engineered tumor cell vaccines, peptide vaccines, CAR T cell therapy, bi-specific antibodies, and the first oncolytic virus-based immune-active treatment for melanoma, the field is ready for the crucial discoveries that will propel these and other immuno-active modalities to the forefront of cancer treatment. The challenges include gaining a deeper understanding of tumor-stromal interactions and effective tools to remove the obstacles to immune-based recognition of a wider range of tumors than presently possible. In addition, the metabolism, microbial make-up and neurophysiological status of the patients crucially affects various immune functions, constituting a rapidly expanding area of research that is expected to have a major impact for the efficacy of immunotherapies and in treatment design. Moreover, successful eradication of cancer will most likely necessitate rational combinations of immune modulating interventions, be it using chemicals, nanoparticles, microbes, antibodies or physical stimuli, perhaps on a personalized basis.

We welcome studies that highlight how the immune system can be harnessed to combat cancer and what the obstacles to successful cancer immunotherapy are. We hope to be able to showcase a wide berth of immunologically active cancer treatments and clever combinations thereof.

Dr. Markus Vähä-Koskela
Dr. Vincenzo Cerullo
Dr. Fabrice Le Boeuf
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunotherapy
  • oncolytic virus
  • checkpoint inhibitor
  • immunomodulation
  • cancer vaccine
  • cytokine
  • tumor microenvironment
  • tumor immune evasion

Published Papers (5 papers)

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Research

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3056 KiB  
Article
TNF-α and IFN-γ Together Up-Regulates Par-4 Expression and Induce Apoptosis in Human Neuroblastomas
by Ganesh V. Shelke, Jayashree C. Jagtap, Dae-Kyum Kim, Reecha D. Shah, Gowry Das, Mruthyunjaya Shivayogi, Radha Pujari and Padma Shastry
Biomedicines 2018, 6(1), 4; https://doi.org/10.3390/biomedicines6010004 - 26 Dec 2017
Cited by 14 | Viewed by 5109
Abstract
The objective of this study was to examine the combined effect of Interferon-gamma (IFN-γ) and Tumor Necrosis factor-alpha (TNF-α) on cytotoxicity and expression of prostate apoptosis response-4 (Par-4) and Par-4 interacting proteins B-cell lymphoma (Bcl-2), nuclear factor kappa-light-chain-enhancer of activated B cells/p65 subunit [...] Read more.
The objective of this study was to examine the combined effect of Interferon-gamma (IFN-γ) and Tumor Necrosis factor-alpha (TNF-α) on cytotoxicity and expression of prostate apoptosis response-4 (Par-4) and Par-4 interacting proteins B-cell lymphoma (Bcl-2), nuclear factor kappa-light-chain-enhancer of activated B cells/p65 subunit (NF-κB/p65), Ak mouse strain thymoma (Akt) in human neuroblastoma (NB) cells. Materials and methods included human neuroblastoma cell lines-SK-N-MC, SK-N-SH, and SH-SY5Y, which were treated with IFN-γ and TNF-α individually, or in combination, and were assessed for viability by tetrazolium (MTT) assay. Apoptosis was monitored by hypodiploid population (by flow cytometry), DNA fragmentation, Poly (ADP-ribose) polymerase (PARP) cleavage, and caspase-8 activity. Transcript level of Par-4 was measured by RT-PCR. Protein levels of Par-4 and suppressor of cytokine signaling 3 (SOCS-3) were assessed by immunoblotting. Cellular localization of Par-4 and p65 was examined by immunofluorescence. Unbiased transcript analysis for IFN-γ, TNF-α, and Par-4 were analyzed from three independent clinical datasets from neuroblastoma patients. In terms of results, SK-N-MC cells treated with a combination of, but not individually with, IFN-γ and TNF-α induced apoptosis characterized by hypodiploidy, DNA fragmentation, PARP cleavage, and increased caspase-8 activity. Apoptosis was associated with up-regulation of Par-4 mRNA and protein expression. Immunofluorescence studies revealed that Par-4 was localized exclusively in cytoplasm in SK-N-MC cells cultured for 24 h. but showed nuclear localization at 48 h. Treatment with IFN-γ and TNF-α together enhanced the intensity of nuclear Par-4. In gene expression, data from human neuroblastoma patients, levels of IFN-γ, and TNF-α have strong synergy with Par-4 expression and provide good survival advantage. The findings also demonstrated that apoptosis was associated with reduced level of pro-survival proteins–Bcl-2 and Akt and NF-κB/p65. Furthermore, the apoptotic effect induced by IFN-γ-induced Signal Transducer and Activator of Transcription-1(STAT-1), and could be due to down-regulation of suppressor of cytokine signaling-3 (SOCS3). The study concludes that a combinatorial approach using IFN-γ and TNF-α can be explored to maximize the effect in chemotherapy in neuroblastoma, and implies a role for Par-4 in the process. Full article
(This article belongs to the Special Issue Immuno-Active Cancer Therapeutics)
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Review

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11 pages, 445 KiB  
Review
Human Granzyme B Based Targeted Cytolytic Fusion Proteins
by Precious Hlongwane, Neelakshi Mungra, Suresh Madheswaran, Olusiji A. Akinrinmade, Shivan Chetty and Stefan Barth
Biomedicines 2018, 6(2), 72; https://doi.org/10.3390/biomedicines6020072 - 20 Jun 2018
Cited by 23 | Viewed by 5812
Abstract
Cancer immunotherapy aims to selectively target and kill tumor cells whilst limiting the damage to healthy tissues. Controlled delivery of plant, bacterial and human toxins or enzymes has been shown to promote the induction of apoptosis in cancerous cells. The 4th generation of [...] Read more.
Cancer immunotherapy aims to selectively target and kill tumor cells whilst limiting the damage to healthy tissues. Controlled delivery of plant, bacterial and human toxins or enzymes has been shown to promote the induction of apoptosis in cancerous cells. The 4th generation of targeted effectors are being designed to be as humanized as possible—a solution to the problem of immunogenicity encountered with existing generations. Granzymes are serine proteases which naturally function in humans as integral cytolytic effectors during the programmed cell death of cancerous and pathogen-infected cells. Secreted predominantly by cytotoxic T lymphocytes and natural killer cells, granzymes function mechanistically by caspase-dependent or caspase-independent pathways. These natural characteristics make granzymes one of the most promising human enzymes for use in the development of fusion protein-based targeted therapeutic strategies for various cancers. In this review, we explore research involving the use of granzymes as cytolytic effectors fused to antibody fragments as selective binding domains. Full article
(This article belongs to the Special Issue Immuno-Active Cancer Therapeutics)
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13 pages, 519 KiB  
Review
Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells
by Sandra Jordaan, Olusiji A. Akinrinmade, Thomas Nachreiner, Christian Cremer, Krupa Naran, Shivan Chetty and Stefan Barth
Biomedicines 2018, 6(1), 28; https://doi.org/10.3390/biomedicines6010028 - 05 Mar 2018
Cited by 23 | Viewed by 5941
Abstract
Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while [...] Read more.
Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate. Ribonucleases are attractive candidates, due to their ability to induce apoptosis by abrogating protein biosynthesis via tRNA degradation. In fact, several RNases of the pancreatic RNase A superfamily have shown potential as anti-cancer agents. Coupling of a human RNase to a humanized antibody or antibody derivative putatively eliminates the immunogenicity of an IT (now known as a human cytolytic fusion protein, hCFP). However, RNases are tightly regulated in vivo by endogenous inhibitors, controlling the ribonucleolytic balance subject to the cell’s metabolic requirements. Endogenous inhibition limits the efficacy with which RNase-based hCFPs induce apoptosis. However, abrogating the natural interaction with the natural inhibitors by mutation has been shown to significantly enhance RNase activity, paving the way toward achieving cytolytic potency comparable to that of bacterial immunotoxins. Here, we review the immunoRNases that have undergone preclinical studies as anti-cancer therapeutic agents. Full article
(This article belongs to the Special Issue Immuno-Active Cancer Therapeutics)
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1143 KiB  
Review
Restoration of DAP Kinase Tumor Suppressor Function: A Therapeutic Strategy to Selectively Induce Apoptosis in Cancer Cells Using Immunokinase Fusion Proteins
by Mehmet Kemal Tur, Adebukola K. Daramola, Stefan Gattenlöhner, Marco Herling, Shivan Chetty and Stefan Barth
Biomedicines 2017, 5(4), 59; https://doi.org/10.3390/biomedicines5040059 - 04 Oct 2017
Cited by 11 | Viewed by 5282
Abstract
Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of cellular process and have been identified as [...] Read more.
Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of cellular process and have been identified as positive mediators of apoptosis via extrinsic and intrinsic death-regulating signaling pathways. Tumor suppressor activities have been shown for DAPk1 and DAPk2 and they are downregulated in e.g., Hodgkin’s (HL) and B cell lymphoma (CLL), respectively. Here, we review a targeted therapeutic approach which involves reconstitution of DAPks by the generation of immunokinase fusion proteins. These recombinant proteins consist of a disease-specific ligand fused to a modified version of DAPk1 or DAPk2. HL was targeted via CD30 and B-CLL via CD22 cell surface antigens. Full article
(This article belongs to the Special Issue Immuno-Active Cancer Therapeutics)
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1630 KiB  
Review
CD64: An Attractive Immunotherapeutic Target for M1-type Macrophage Mediated Chronic Inflammatory Diseases
by Olusiji A. Akinrinmade, Shivan Chetty, Adebukola K. Daramola, Mukit-ul Islam, Theo Thepen and Stefan Barth
Biomedicines 2017, 5(3), 56; https://doi.org/10.3390/biomedicines5030056 - 12 Sep 2017
Cited by 70 | Viewed by 14255
Abstract
To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical symptoms and are unable to stop the course [...] Read more.
To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical symptoms and are unable to stop the course of disease. In contrast, a new series of immunotherapeutic agents targeting the Fc γ receptor I (CD64) have emerged and demonstrated significant clinical potential to actually resolving chronic inflammation driven by M1-type dysregulated macrophages. This subpopulation plays a key role in the initiation and maintenance of a series of chronic diseases. The novel recombinant M1-specific immunotherapeutics offer the prospect of highly effective treatment strategies as they have been shown to selectively eliminate the disease-causing macrophage subpopulations. In this review, we provide a detailed summary of the data generated, together with the advantages and the clinical potential of CD64-based targeted therapies for the treatment of chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Immuno-Active Cancer Therapeutics)
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