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Cancer Immunotherapy: Recent Progress

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 14861

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Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warszawa, Poland
Interests: carotid plaques; atherosclerotic plaque; checkpoint inhibitors; exosomes; cancer immunotherapy
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Special Issue Information

Dear Colleagues,

The emergence of targeted therapies has led to significant breakthroughs in cancer therapy and in the development of novel agents for the treatment of patients with advanced cancer. Personalized immunotherapy is one of the most promising approaches to the management of cancer. This therapy includes pharmaceuticals such as immune checkpoint inhibitors and monoclonal antibodies, as well as cell therapy. The combination of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4) and other drugs with chemotherapy and radiation therapy may improve the clinical outcomes in a large proportion of patients with cancer. Advances in immuno-oncology are also attributed to the use of nanoparticles for precision targeting and selective delivery of drugs. Moreover, a breakthrough in cell therapy cancer included T cells engineered with expressed chimeric antigen receptors (CARs) that are programmed to kill cancer. Despite the success of many of these therapies, the key factor for treatment failure may be severe life-threatening toxicities, antigen escape, modest anti-tumor activity, and limited tumor infiltration. To avoid these adverse effects, further developments need to be considered to enhance the effectiveness of immunotherapy.

Dr. Wioletta Olejarz
Guest Editor

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Keywords

  • gene therapy
  • gene delivery
  • nanoparticicles
  • peptides
  • checkpoint inhibitors
  • exosomes

Published Papers (5 papers)

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Research

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19 pages, 3491 KiB  
Article
A2AR as a Prognostic Marker and a Potential Immunotherapy Target in Human Glioma
by Soumaya Rafii, Amina Ghouzlani, Oumayma Naji, Saadia Ait Ssi, Sarah Kandoussi, Abdelhakim Lakhdar and Abdallah Badou
Int. J. Mol. Sci. 2023, 24(7), 6688; https://doi.org/10.3390/ijms24076688 - 3 Apr 2023
Cited by 5 | Viewed by 1968
Abstract
Gliomas are considered one of the most malignant tumors in the body. The immune system has the ability to control the initiation and development of tumors, including gliomas. Thus, immune cells find themselves controlled by various molecular pathways, inhibiting their activation, such as [...] Read more.
Gliomas are considered one of the most malignant tumors in the body. The immune system has the ability to control the initiation and development of tumors, including gliomas. Thus, immune cells find themselves controlled by various molecular pathways, inhibiting their activation, such as the immunosuppressive adenosine 2A receptor (A2AR). Our objective was to establish the expression profile and role of A2AR at the transcriptomic level, using real-time RT-PCR in Moroccan glioma patients, in addition to TCGA and CGGA cohorts. The real-time RT-PCR results in Moroccan patients showed that high expression of this gene was associated with poor survival in males. Our study on the CGGA cohort corroborated these results. In addition, there was a positive association of A2AR with T-cell exhaustion genes. A2AR also correlated strongly with genes that are primarily enriched in focal adhesion and extracellular matrix interactions, inducing epithelial mesenchymal transition, angiogenesis, and glioma growth. However, in the TCGA cohort, the A2AR showed results that were different from the two previously examined cohorts. In fact, this gene was instead linked to a good prognosis in patients with the astrocytoma histological type. The correlation and enrichment results reinforced the prognostic role of A2AR in this TCGA cohort, in which its high expression was shown to be related to lymphocyte differentiation and a successful cytolytic response, suggesting a more efficient anti-tumor immune response. Correlations and differential analyses based on A2AR gene expression, to understand the cause of the association of this gene with two different prognoses (CGGA males and TCGA Astrocytoma), showed that the overexpression of A2AR in Chinese male patients could be associated with the overexpression of extracellular adenosine, which binds to A2AR to induce immunosuppression and consequently a poor prognosis. However, in the second group (TCGA astrocytomas), the overexpression of the gene could be associated with an adenosine deficiency, and therefore this receptor does not undergo activation. The absence of A2AR activation in these patients may have protected them from immunosuppression, which could reflect the good prognosis. A2AR can be considered a promising therapeutic target in male CGGA and Moroccan patients with gliomas. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Recent Progress)
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20 pages, 4421 KiB  
Article
Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
by Wei Liu, Mohamad-Gabriel Alameh, June F. Yang, Jonathan R. Xu, Paulo J. C. Lin, Ying K. Tam, Drew Weissman and Jianxin You
Int. J. Mol. Sci. 2022, 23(23), 14504; https://doi.org/10.3390/ijms232314504 - 22 Nov 2022
Cited by 10 | Viewed by 3216
Abstract
Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically “cold” tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) [...] Read more.
Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically “cold” tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC). In this study, we demonstrated that mRNA-lipid nanoparticle (LNP) technology could be used to efficiently deliver naturally occurring constitutively active STING mutant STINGR284S into these cancer cells to reactivate STING antitumor immunity and trigger robust killing of tumor cells. STING agonists are being actively pursued as cancer immunotherapies. However, traditional STING agonists can induce T cell cytotoxicity, counteracting the desired antitumor immune response. In addition, the antitumor efficacy of traditional STING agonists obligatorily depends on STING expression and does not work in STING-silenced cancers. Importantly, we found that STINGR284S mRNA-LNP does not introduce T cell cytotoxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S can reactivate the antitumor response without introducing antiproliferative effects in lymphocytic immune cells, overcoming the toxicity and limitations of conventional STING agonists. Our work therefore identifies a novel therapeutic tool for reactivating antitumor immunity in an array of STING-silenced immunologically “cold” tumors that are refractory to current therapies. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Recent Progress)
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Review

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14 pages, 283 KiB  
Review
An Update on Clinical Trials and Potential Therapeutic Strategies in T-Cell Acute Lymphoblastic Leukemia
by Janisha Patel, Xueliang Gao and Haizhen Wang
Int. J. Mol. Sci. 2023, 24(8), 7201; https://doi.org/10.3390/ijms24087201 - 13 Apr 2023
Cited by 2 | Viewed by 2911
Abstract
Current therapies for T-cell acute leukemia are based on risk stratification and have greatly improved the survival rate for patients, but mortality rates remain high owing to relapsed disease, therapy resistance, or treatment-related toxicities/infection. Patients with relapsed disease continue to have poor outcomes. [...] Read more.
Current therapies for T-cell acute leukemia are based on risk stratification and have greatly improved the survival rate for patients, but mortality rates remain high owing to relapsed disease, therapy resistance, or treatment-related toxicities/infection. Patients with relapsed disease continue to have poor outcomes. In the past few years, newer agents have been investigated to optimize upfront therapies for higher-risk patients in the hopes of decreasing relapse rates. This review summarizes the progress of chemo/targeted therapies using Nelarabine/Bortezomib/CDK4/6 inhibitors for T-ALL in clinical trials and novel strategies to target NOTCH-induced T-ALL. We also outline immunotherapy clinical trials using monoclonal/bispecific T-cell engaging antibodies, anti-PD1/anti-PDL1 checkpoint inhibitors, and CAR-T for T-ALL therapy. Overall, pre-clinical studies and clinical trials showed that applying monoclonal antibodies or CAR-T for relapsed/refractory T-ALL therapy is promising. The combination of target therapy and immunotherapy may be a novel strategy for T-ALL treatment. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Recent Progress)
25 pages, 3596 KiB  
Review
Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review
by Alvin Man Lung Chan, Jin Min Cheah, Yogeswaran Lokanathan, Min Hwei Ng and Jia Xian Law
Int. J. Mol. Sci. 2023, 24(4), 4026; https://doi.org/10.3390/ijms24044026 - 16 Feb 2023
Cited by 6 | Viewed by 3407
Abstract
Cancer is the second leading contributor to global deaths caused by non-communicable diseases. The cancer cells are known to interact with the surrounding non-cancerous cells, including the immune cells and stromal cells, within the tumor microenvironment (TME) to modulate the tumor progression, metastasis [...] Read more.
Cancer is the second leading contributor to global deaths caused by non-communicable diseases. The cancer cells are known to interact with the surrounding non-cancerous cells, including the immune cells and stromal cells, within the tumor microenvironment (TME) to modulate the tumor progression, metastasis and resistance. Currently, chemotherapy and radiotherapy are the standard treatments for cancers. However, these treatments cause a significant number of side effects, as they damage both the cancer cells and the actively dividing normal cells indiscriminately. Hence, a new generation of immunotherapy using natural killer (NK) cells, cytotoxic CD8+ T-lymphocytes or macrophages was developed to achieve tumor-specific targeting and circumvent the adverse effects. However, the progression of cell-based immunotherapy is hindered by the combined action of TME and TD-EVs, which render the cancer cells less immunogenic. Recently, there has been an increase in interest in using immune cell derivatives to treat cancers. One of the highly potential immune cell derivatives is the NK cell-derived EVs (NK-EVs). As an acellular product, NK-EVs are resistant to the influence of TME and TD-EVs, and can be designed for “off-the-shelf” use. In this systematic review, we examine the safety and efficacy of NK-EVs to treat various cancers in vitro and in vivo. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Recent Progress)
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20 pages, 3789 KiB  
Review
Modern Advances in CARs Therapy and Creating a New Approach to Future Treatment
by Karol Sadowski, Wioletta Olejarz and Grzegorz Basak
Int. J. Mol. Sci. 2022, 23(23), 15006; https://doi.org/10.3390/ijms232315006 - 30 Nov 2022
Cited by 4 | Viewed by 2725
Abstract
Genetically engineered T and NK cells expressing a chimeric antigen receptor (CAR) are promising cytotoxic cells for the treatment of hematological malignancies and solid tumors. Despite the successful therapies using CAR-T cells, they have some disadvantages, such as cytokine release syndrome (CRS), neurotoxicity, [...] Read more.
Genetically engineered T and NK cells expressing a chimeric antigen receptor (CAR) are promising cytotoxic cells for the treatment of hematological malignancies and solid tumors. Despite the successful therapies using CAR-T cells, they have some disadvantages, such as cytokine release syndrome (CRS), neurotoxicity, or graft-versus-host-disease (GVHD). CAR-NK cells have lack or minimal cytokine release syndrome and neurotoxicity, but also multiple mechanisms of cytotoxic activity. NK cells are suitable for developing an “off the shelf” therapeutic product that causes little or no graft versus host disease (GvHD), but they are more sensitive to apoptosis and have low levels of gene expression compared to CAR-T cells. To avoid these adverse effects, further developments need to be considered to enhance the effectiveness of adoptive cellular immunotherapy. A promising approach to enhance the effectiveness of adoptive cellular immunotherapy is overcoming terminal differentiation or senescence and exhaustion of T cells. In this case, EVs derived from immune cells in combination therapy with drugs may be considered in the treatment of cancer patients, especially effector T and NK cells-derived exosomes with the cytotoxic activity of their original cells. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Recent Progress)
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