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Biomedicines
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State-of-the-Art Immunology and Immunotherapy in USA
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State-of-the-Art Immunology and Immunotherapy in USA

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

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 26956

Special Issue Editor

Prof. Dr. David T. Harris

E-Mail Website
Guest Editor
Department of Immunobiology & Medicine, College of Medicine-Tucson, University of Arizona Health Sciences, University of Arizona, Tucson, AZ 85724, USA
Interests: stem cells; regenerative medicine; tissue engineering; cancer; umbilical cord blood and tissue; adipose-derived stem cells; aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunotherapy has become a hot topic in recent years due to its success in treating b-cell hematopoietic cancers (e.g., keytruda and car-t). However, not all blood cancers have been successfully amenable and solid tumors are still problematic. This Special Issue is concerned with applications of immunotherapy to not only novel b-cell cancers (e.g., hodgkins and NHL in addition to typical leukemias), but to other hematologic malignancies (e.g., t-cell leukemias, myeloid cancers and multiple myelomas) as well. In addition, applications of immunotherapy to the treatment of solid tumors would be welcome. Finally, the use of immunotherapy to address unmet needs in the area of autoimmune diseases is encouraged.

Prof. Dr. David Harris
Guest Editor

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
  • car-t
  • stem cells
  • autoimmune disease
  • cancer

Published Papers (7 papers)

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Research

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12 pages, 2095 KiB  
Article
Lung Inflammation Predictors in Combined Immune Checkpoint-Inhibitor and Radiation Therapy—Proof-of-Concept Animal Study
by Benjamin Spieler, Teresa M. Giret, Scott Welford, Tulasigeri M. Totiger and Ivaylo B. Mihaylov
Biomedicines 2022, 10(5), 1173; https://doi.org/10.3390/biomedicines10051173 - 19 May 2022
Cited by 4 | Viewed by 2096
Abstract
Purpose: Combined radiotherapy (RT) and immune checkpoint-inhibitor (ICI) therapy can act synergistically to enhance tumor response beyond what either treatment can achieve alone. Alongside the revolutionary impact of ICIs on cancer therapy, life-threatening potential side effects, such as checkpoint-inhibitor-induced (CIP) pneumonitis, remain underreported [...] Read more.
Purpose: Combined radiotherapy (RT) and immune checkpoint-inhibitor (ICI) therapy can act synergistically to enhance tumor response beyond what either treatment can achieve alone. Alongside the revolutionary impact of ICIs on cancer therapy, life-threatening potential side effects, such as checkpoint-inhibitor-induced (CIP) pneumonitis, remain underreported and unpredictable. In this preclinical study, we hypothesized that routinely collected data such as imaging, blood counts, and blood cytokine levels can be utilized to build a model that predicts lung inflammation associated with combined RT/ICI therapy. Materials and Methods: This proof-of-concept investigational work was performed on Lewis lung carcinoma in a syngeneic murine model. Nineteen mice were used, four as untreated controls and the rest subjected to RT/ICI therapy. Tumors were implanted subcutaneously in both flanks and upon reaching volumes of ~200 mm3 the animals were imaged with both CT and MRI and blood was collected. Quantitative radiomics features were extracted from imaging of both lungs. The animals then received RT to the right flank tumor only with a regimen of three 8 Gy fractions (one fraction per day over 3 days) with PD-1 inhibitor administration delivered intraperitoneally after each daily RT fraction. Tumor volume evolution was followed until tumors reached the maximum size allowed by the Institutional Animal Care and Use Committee (IACUC). The animals were sacrificed, and lung tissues harvested for immunohistochemistry evaluation. Tissue biomarkers of lung inflammation (CD45) were tallied, and binary logistic regression analyses were performed to create models predictive of lung inflammation, incorporating pretreatment CT/MRI radiomics, blood counts, and blood cytokines. Results: The treated animal cohort was dichotomized by the median value of CD45 infiltration in the lungs. Four pretreatment radiomics features (3 CT features and 1 MRI feature) together with pre-treatment neutrophil-to-lymphocyte (NLR) ratio and pre-treatment granulocyte-macrophage colony-stimulating factor (GM-CSF) level correlated with dichotomized CD45 infiltration. Predictive models were created by combining radiomics with NLR and GM-CSF. Receiver operating characteristic (ROC) analyses of two-fold internal cross-validation indicated that the predictive model incorporating MR radiomics had an average area under the curve (AUC) of 0.834, while the model incorporating CT radiomics had an AUC of 0.787. Conclusions: Model building using quantitative imaging data, blood counts, and blood cytokines resulted in lung inflammation prediction models justifying the study hypothesis. The models yielded very-good-to-excellent AUCs of more than 0.78 on internal cross-validation analyses. Full article
(This article belongs to the Special Issue State-of-the-Art Immunology and Immunotherapy in USA)
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11 pages, 2466 KiB  
Article
Novel CS1 CAR-T Cells and Bispecific CS1-BCMA CAR-T Cells Effectively Target Multiple Myeloma
by Vita Golubovskaya, Hua Zhou, Feng Li, Robert Berahovich, Jinying Sun, Michael Valentine, Shirley Xu, Hizkia Harto, John Sienkiewicz, Yanwei Huang and Lijun Wu
Biomedicines 2021, 9(10), 1422; https://doi.org/10.3390/biomedicines9101422 - 9 Oct 2021
Cited by 9 | Viewed by 3078
Abstract
Multiple myeloma (MM) is a hematological cancer caused by abnormal proliferation of plasma cells in the bone marrow, and novel types of treatment are needed for this deadly disease. In this study, we aimed to develop novel CS1 CAR-T cells and bispecific CS1-BCMA [...] Read more.
Multiple myeloma (MM) is a hematological cancer caused by abnormal proliferation of plasma cells in the bone marrow, and novel types of treatment are needed for this deadly disease. In this study, we aimed to develop novel CS1 CAR-T cells and bispecific CS1-BCMA CAR-T cells to specifically target multiple myeloma. We generated a new CS1 (CD319, SLAM-7) antibody, clone (7A8D5), which specifically recognized the CS1 antigen, and we applied it for the generation of CS1-CAR. CS1-CAR-T cells caused specific killing of CHO-CS1 target cells with secretion of IFN-gamma and targeted multiple myeloma cells. In addition, bispecific CS1-BCMA-41BB-CD3 CAR-T cells effectively killed CHO-CS1 and CHO-BCMA target cells, killed CS1/BCMA-positive multiple myeloma cells, and secreted IFN-gamma. Moreover, CS1-CAR-T cells and bispecific CS1-BCMA CAR-T cells effectively blocked MM1S multiple myeloma tumor growth in vivo. These data for the first time demonstrate that novel CS1 and bispecific CS1-BCMA-CAR-T cells are effective in targeting MM cells and provide a basis for future clinical trials. Full article
(This article belongs to the Special Issue State-of-the-Art Immunology and Immunotherapy in USA)
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Review

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17 pages, 767 KiB  
Review
PD-1/PD-L1 Pathway: A Therapeutic Target in CD30+ Large Cell Lymphomas
by Wei Xie, L. Jeffrey Medeiros, Shaoying Li, Guilin Tang, Guang Fan and Jie Xu
Biomedicines 2022, 10(7), 1587; https://doi.org/10.3390/biomedicines10071587 - 4 Jul 2022
Cited by 8 | Viewed by 5184
Abstract
The programmed death-ligands, PD-L1 and PD-L2, reside on tumor cells and can bind with programmed death-1 protein (PD-1) on T-cells, resulting in tumor immune escape. PD-1 ligands are highly expressed in some CD30+ large cell lymphomas, including classic Hodgkin lymphoma (CHL), primary mediastinal [...] Read more.
The programmed death-ligands, PD-L1 and PD-L2, reside on tumor cells and can bind with programmed death-1 protein (PD-1) on T-cells, resulting in tumor immune escape. PD-1 ligands are highly expressed in some CD30+ large cell lymphomas, including classic Hodgkin lymphoma (CHL), primary mediastinal large B-cell lymphoma (PMBL), Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL), and anaplastic large cell lymphoma (ALCL). The genetic alteration of the chromosome 9p24.1 locus, the location of PD-L1, PD-L2, and JAK2 are the main mechanisms leading to PD-L1 and PD-L2 overexpression and are frequently observed in these CD30+ large cell lymphomas. The JAK/STAT pathway is also commonly constitutively activated in these lymphomas, further contributing to the upregulated expression of PD-L1 and PD-L2. Other mechanisms underlying the overexpression of PD-L1 and PD-L2 in some cases include EBV infection and the activation of the mitogen-activated protein kinase (MAPK) pathway. These cellular and molecular mechanisms provide a scientific rationale for PD-1/PD-L1 blockade in treating patients with relapsed/refractory (R/R) disease and, possibly, in newly diagnosed patients. Given the high efficacy of PD-1 inhibitors in patients with R/R CHL and PMBL, these agents have become a standard treatment in these patient subgroups. Preliminary studies of PD-1 inhibitors in patients with R/R EBV+ DLBCL and R/R ALCL have also shown promising results. Future directions for these patients will likely include PD-1/PD-L1 blockade in combination with other therapeutic agents, such as brentuximab or traditional chemotherapy regimens. Full article
(This article belongs to the Special Issue State-of-the-Art Immunology and Immunotherapy in USA)
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11 pages, 274 KiB  
Review
First-Line Targeted Therapy for Hepatocellular Carcinoma: Role of Atezolizumab/Bevacizumab Combination
by Sri Harsha Tella, Anuhya Kommalapati, Amit Mahipal and Zhaohui Jin
Biomedicines 2022, 10(6), 1304; https://doi.org/10.3390/biomedicines10061304 - 2 Jun 2022
Cited by 9 | Viewed by 3496
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy accounting for 90% of primary liver malignancies. Therapeutic options for HCC are primarily based on the baseline functional status, the extent of disease at presentation and the underlying liver function that is clinically evaluated by the [...] Read more.
Hepatocellular carcinoma (HCC) is an aggressive malignancy accounting for 90% of primary liver malignancies. Therapeutic options for HCC are primarily based on the baseline functional status, the extent of disease at presentation and the underlying liver function that is clinically evaluated by the Barcelona-Clinic Liver Cancer system and Child–Pugh score. In patients with advanced HCC, the United States Food and Drug Administration (US-FDA) approved systemic therapies include the combination of atezolizumab–bevacizumab, sorafenib, and lenvatinib in the first line setting while cabozantinib, regorafenib, ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL), pembrolizumab, nivolumab, and nivolumab-ipilimumab combination are reserved for patients who progressed on sorafenib. European Medical Agency (EMA) approved the use of atezolizumab–bevacizumab, sorafenib, and lenvatinib in the first line setting, while cabozantinib, regorafenib, and ramucirumab (in patients with alfa-fetoprotein [AFP] > 400 ng/mL) are approved for use in patients that progressed on first-line therapy. In the first line setting, sorafenib demonstrated a median overall survival (OS) benefit of 3 months as compared to that of best supportive care in randomized phase III trials, while lenvatinib was shown to be non-inferior to sorafenib. Recently, phase 3 studies with immunotherapeutic agents including atezolizumab plus a bevacizumab combination and tremelimumab plus durvalumab combination demonstrated a better OS and progression free survival (PFS) compared to sorafenib in the first-line setting, making them attractive first-line options in advanced HCC. In this review, we outlined the tumorigenesis and immune landscape of HCC in brief and discussed the role and rationale of combining immunotherapy and anti-VEGF therapy. We further expanded on potential limitations and the future directions of immunotherapy in combination with targeted agents in the management of advanced HCC. Full article
(This article belongs to the Special Issue State-of-the-Art Immunology and Immunotherapy in USA)
30 pages, 485 KiB  
Review
The Current State of Treatment and Future Directions in Cutaneous Malignant Melanoma
by Madison Ernst and Alessio Giubellino
Biomedicines 2022, 10(4), 822; https://doi.org/10.3390/biomedicines10040822 - 31 Mar 2022
Cited by 17 | Viewed by 3774
Abstract
Malignant melanoma is the leading cause of death among cutaneous malignancies. While its incidence is increasing, the most recent cancer statistics show a small but clear decrease in mortality rate. This trend reflects the introduction of novel and more effective therapeutic regimens, including [...] Read more.
Malignant melanoma is the leading cause of death among cutaneous malignancies. While its incidence is increasing, the most recent cancer statistics show a small but clear decrease in mortality rate. This trend reflects the introduction of novel and more effective therapeutic regimens, including the two cornerstones of melanoma therapy: immunotherapies and targeted therapies. Immunotherapies exploit the highly immunogenic nature of melanoma by modulating and priming the patient’s own immune system to attack the tumor. Treatments combining immunotherapies with targeted therapies, which disable the carcinogenic products of mutated cancer cells, have further increased treatment efficacy and durability. Toxicity and resistance, however, remain critical challenges to the field. The present review summarizes past treatments and novel therapeutic interventions and discusses current clinical trials and future directions. Full article
(This article belongs to the Special Issue State-of-the-Art Immunology and Immunotherapy in USA)
17 pages, 1982 KiB  
Review
Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models
by Adrienn Markovics, Ken S. Rosenthal, Katalin Mikecz, Roy E. Carambula, Jason C. Ciemielewski and Daniel H. Zimmerman
Biomedicines 2022, 10(1), 44; https://doi.org/10.3390/biomedicines10010044 - 26 Dec 2021
Cited by 18 | Viewed by 4678
Abstract
Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies—(1) [...] Read more.
Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies—(1) disease-modifying anti-rheumatic drugs (DMARDs) and (2) Janus kinase (JAK) inhibitors (jakinibs)—to a newer approach—(3) therapeutic vaccines (using the LEAPS vaccine approach). The Ligand Epitope Antigen Presentation System (LEAPS) therapies are capable of inhibiting ongoing disease progression in animal models. Whereas DMARDs ablate or inhibit specific proinflammatory cytokines or cells and jakinibs inhibit the receptor activation cascade for expression of proinflammatory cytokines, the LEAPS therapeutic vaccines specifically modulate the ongoing antigen-specific, disease-driving, proinflammatory T memory cell responses. This decreases disease presentation and changes the cytokine conversation to decrease the expression of inflammatory cytokines (IL-17, IL-1(α or β), IL-6, IFN-γ, TNF-α) while increasing the expression of regulatory cytokines (IL-4, IL-10, TGF-β). This review refocuses the purpose of therapy for RA towards rebalancing the immune system rather than compromising specific components to stop disease. This review is intended to be thought provoking and look forward towards new therapeutic modalities rather than present a final definitive report. Full article
(This article belongs to the Special Issue State-of-the-Art Immunology and Immunotherapy in USA)
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12 pages, 891 KiB  
Review
Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave
by Xinfang Yu, Wei Li, Ken H. Young and Yong Li
Biomedicines 2021, 9(11), 1702; https://doi.org/10.3390/biomedicines9111702 - 16 Nov 2021
Cited by 11 | Viewed by 3717
Abstract
Programmed death-ligand 1 (PD-L1) is one of the most classic immune checkpoint molecules. Cancer cells express PD-L1 to inhibit the activity of effector T cells’ cytotoxicity through programmed death 1 (PD-1) engagement in exposure to inflammatory cytokines. PD-L1 expression levels on cancer cells [...] Read more.
Programmed death-ligand 1 (PD-L1) is one of the most classic immune checkpoint molecules. Cancer cells express PD-L1 to inhibit the activity of effector T cells’ cytotoxicity through programmed death 1 (PD-1) engagement in exposure to inflammatory cytokines. PD-L1 expression levels on cancer cells might affect the clinical response to anti-PD-1/PD-L1 therapies. Hence, understanding molecular mechanisms for regulating PD-L1 expression is essential for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade. Posttranslational modifications (PTMs), including phosphorylation, glycosylation, ubiquitination, and acetylation, regulate PD-L1 stability, cellular translocation, and interaction with its receptor. A coordinated positive and negative regulation via PTMs is required to ensure the balance and function of the PD-L1 protein. In this review, we primarily focus on the roles of PTMs in PD-L1 expression, trafficking, and antitumor immune response. We also discuss the implication of PTMs in anti-PD-1/PD-L1 therapies. Full article
(This article belongs to the Special Issue State-of-the-Art Immunology and Immunotherapy in USA)
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