Targeting Solid Tumors and the Microenvironment with Novel Immunotherapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 January 2024) | Viewed by 7845

Special Issue Editors

1. Research and Business Development, Promab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA
2. Department of Medicine, University of Oklahoma, Oklahoma, OK 73126, USA
Interests: immunotherapy; CAR-T cells; tumor microenvironment; checkpoint protein; hypoxia; tumor survival signaling
Special Issues, Collections and Topics in MDPI journals
Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, UK
Interests: colorectal carcinogenesis; immunology; genetics

Special Issue Information

Dear Colleagues,

It is very important to understand the mechanisms of tumorigenesis and surrounding tumor microenvironment in order to more efficiently target tumors. Recently, novel cell therapies such as CAR-T cells have been developed against hematological cancers, but these are not very effective against solid tumors. In addition, tumors adapt to different targeted therapies and develop resistance to treatment. Thus, novel therapeutic combination approaches and immunotherapies are needed to best target not only tumors but the surrounding microenvironment, as well.

The goal of this Special Issue is to highlight novel immunotherapies against solid tumors such as oncolytic viruses, vaccines, dendritic vaccines, TCR mimics, neoantigens, personalized medicine approaches, epigenetic and genetic signaling, nanoparticle-based immunotherapies, NK cells, CAR-T cells, checkpoint inhibitors, and modulators of the microenvironment.

In this Special Issue, original research articles and reviews are welcome. Research areas may include but are not limited to the following: personalized therapy, vaccines, oncolytic viruses, dendritic vaccines, monoclonal antibodies, bispecific antibodies, cell therapies, mechanisms of tumor resistance, and tumor microenvironment pathways.

Dr. Vita Golubovskaya
Prof. Dr. Walter F. Bodmer
Guest Editors

Manuscript Submission Information

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Keywords

  • vaccine
  • checkpoint inhibitor
  • TCR mimics
  • T cells
  • B cells
  • NK cells
  • macrophages
  • antibodies
  • oncolytic viruses

Published Papers (5 papers)

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Research

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10 pages, 1054 KiB  
Article
Cardiotoxicity Secondary to Immune Checkpoint Inhibitors in the Elderly: Safety in Real-World Data
Cancers 2023, 15(17), 4293; https://doi.org/10.3390/cancers15174293 - 28 Aug 2023
Cited by 1 | Viewed by 731
Abstract
Introduction: Immunotherapy represents a key pillar of cancer treatments, with high response rates and long survival. Its use is increasing, mainly at the expense of the geriatric population due to the ageing of this population. However, despite its benefit, its safety in certain [...] Read more.
Introduction: Immunotherapy represents a key pillar of cancer treatments, with high response rates and long survival. Its use is increasing, mainly at the expense of the geriatric population due to the ageing of this population. However, despite its benefit, its safety in certain areas such as cardiotoxicity is largely unknown. The aim of this study is to assess the safety of immunotherapy in elderly patients using real-world data. Methods: This is an ambispective study of patients ≥ 70 years old with solid tumours who were treated with immunotherapy at the University Hospital of Salamanca. Cardiotoxicity was assessed using the CTCAEv5.0 criteria. Results: In total, 195 patients were included (76.9% male and 23.1% female), with a mean age of 75 years [70–93]. The percentage of patients with cardiotoxicity was 1.54%; 1.35% of patients with previous heart disease were diagnosed with cardiotoxicity, and 1.65% of those without previous heart disease were diagnosed with cardiotoxicity. The median time from the initiation of treatment until the cardiac event was 45 days [14–96]. The most frequent toxicity was myocarditis in 66.7% of patients, followed by arrhythmias in 33.3% of patients. Conclusions: Immunotherapy is shown to be a safe treatment in elderly cancer patients in terms of cardiotoxicity. The event rate shows no difference between patients with or without cardiac comorbidity. Full article
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15 pages, 2508 KiB  
Article
A Novel Bispecific Antibody for EpCAM-Directed Inhibition of the CD73/Adenosine Immune Checkpoint in Ovarian Cancer
Cancers 2023, 15(14), 3651; https://doi.org/10.3390/cancers15143651 - 17 Jul 2023
Cited by 1 | Viewed by 1117
Abstract
PD-1/PD-L1-inhibiting antibodies have shown disappointing efficacy in patients with refractory ovarian cancer (OC). Apparently, OC cells exploit nonoverlapping immunosuppressive mechanisms to evade the immune system. In this respect, the CD73-adenosine inhibitory immune checkpoint is of particular interest, as it rapidly converts pro-inflammatory ATP [...] Read more.
PD-1/PD-L1-inhibiting antibodies have shown disappointing efficacy in patients with refractory ovarian cancer (OC). Apparently, OC cells exploit nonoverlapping immunosuppressive mechanisms to evade the immune system. In this respect, the CD73-adenosine inhibitory immune checkpoint is of particular interest, as it rapidly converts pro-inflammatory ATP released from cancer cells to immunosuppressive adenosine (ADO). Moreover, cancer-cell-produced ADO is known to form a highly immunosuppressive extra-tumoral ‘halo’ that chronically inhibits the anticancer activity of various immune effector cells. Thus far, conventional CD73-blocking antibodies such as oleclumab show limited clinical efficacy, probably due to the fact that it indiscriminately binds to and blocks CD73 on a massive surplus of normal cells. To address this issue, we constructed a novel bispecific antibody (bsAb) CD73xEpCAM that inhibits CD73 expressed on the OC cell surface in an EpCAM-directed manner. Importantly, bsAb CD73xEpCAM showed potent capacity to inhibit the CD73 enzyme activity in an EpCAM-directed manner and restore the cytotoxic activity of ADO-suppressed anticancer T cells. Additionally, treatment with bsAb CD73xEpCAM potently inhibited the proliferative capacity of OC cells and enhanced their sensitivity to cisplatin, doxorubicin, 5FU, and ionizing radiation. BsAb CD73xEpCAM may be useful in the development of tumor-directed immunotherapeutic approaches to overcome the CD73-mediated immunosuppression in patients with refractory OC. Full article
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21 pages, 4549 KiB  
Article
CAR-NK Cells Targeting HER1 (EGFR) Show Efficient Anti-Tumor Activity against Head and Neck Squamous Cell Carcinoma (HNSCC)
Cancers 2023, 15(12), 3169; https://doi.org/10.3390/cancers15123169 - 13 Jun 2023
Cited by 1 | Viewed by 1945
Abstract
(1) Background: HNSCC is a highly heterogeneous and relapse-prone form of cancer. We aimed to expand the immunological tool kit against HNSCC by conducting a functional screen to generate chimeric antigen receptor (CAR)-NK-92 cells that target HER1/epidermal growth factor receptor (EGFR). (2) Methods: [...] Read more.
(1) Background: HNSCC is a highly heterogeneous and relapse-prone form of cancer. We aimed to expand the immunological tool kit against HNSCC by conducting a functional screen to generate chimeric antigen receptor (CAR)-NK-92 cells that target HER1/epidermal growth factor receptor (EGFR). (2) Methods: Selected CAR-NK-92 cell candidates were tested for enhanced reduction of target cells, CD107a expression and IFNγ secretion in different co-culture models. For representative HNSCC models, patient-derived primary HNSCC (pHNSCC) cell lines were generated by employing an EpCAM-sorting approach to eliminate the high percentage of non-malignant cells found. (3) Results: 2D and 3D spheroid co-culture experiments showed that anti-HER1 CAR-NK-92 cells effectively eliminated SCC cell lines and primary HNSCC (pHNSCC) cells. Co-culture of tumor models with anti-HER1 CAR-NK-92 cells led to enhanced degranulation and IFNγ secretion of NK-92 cells and apoptosis of target cells. Furthermore, remaining pHNSCC cells showed upregulated expression of putative cancer stem cell marker CD44v6. (4) Conclusions: These results highlight the promising potential of CAR-NK cell therapy in HNSCC and the likely necessity to target multiple tumor-associated antigens to reduce currently high relapse rates. Full article
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Review

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22 pages, 3121 KiB  
Review
Applications of Anti-Cytomegalovirus T Cells for Cancer (Immuno)Therapy
Cancers 2023, 15(15), 3767; https://doi.org/10.3390/cancers15153767 - 25 Jul 2023
Viewed by 1214
Abstract
Infection with cytomegalovirus (CMV) is highly prevalent in the general population and largely controlled by CD8pos T cells. Intriguingly, anti-CMV T cells accumulate over time to extraordinarily high numbers, are frequently present as tumor-resident ‘bystander’ T cells, and remain functional in cancer [...] Read more.
Infection with cytomegalovirus (CMV) is highly prevalent in the general population and largely controlled by CD8pos T cells. Intriguingly, anti-CMV T cells accumulate over time to extraordinarily high numbers, are frequently present as tumor-resident ‘bystander’ T cells, and remain functional in cancer patients. Consequently, various strategies for redirecting anti-CMV CD8pos T cells to eliminate cancer cells are currently being developed. Here, we provide an overview of these strategies including immunogenic CMV peptide-loading onto endogenous HLA complexes on cancer cells and the use of tumor-directed fusion proteins containing a preassembled CMV peptide/HLA-I complex. Additionally, we discuss conveying the advantageous characteristics of anti-CMV T cells in adoptive cell therapy. Utilization of anti-CMV CD8pos T cells to generate CAR T cells promotes their in vivo persistence and expansion due to appropriate co-stimulation through the endogenous (CMV-)TCR signaling complex. Designing TCR-engineered T cells is more challenging, as the artificial and endogenous TCR compete for expression. Moreover, the use of expanded/reactivated anti-CMV T cells to target CMV peptide-expressing glioblastomas is discussed. This review highlights the most important findings and compares the benefits, disadvantages, and challenges of each strategy. Finally, we discuss how anti-CMV T cell therapies can be further improved to enhance treatment efficacy. Full article
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24 pages, 3755 KiB  
Review
Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment
Cancers 2023, 15(12), 3147; https://doi.org/10.3390/cancers15123147 - 11 Jun 2023
Cited by 2 | Viewed by 2394
Abstract
The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. [...] Read more.
The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma. Full article
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