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The Future of the Cancer Treatment: The Immunotherapy Next Generation

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 62122

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Dr. Amedeo Amedei

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Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Interests: microbiota-immunity axis; autoimmunity; cancers; inflammation; T cells; micro and nanoplastic effects on human
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Dr. Elena Niccolai

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Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Interests: microbiome; immunology; gastrointestinal cancers; nutrition; gut-brain axis; neurodegeneration; neuroinflammation
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Dear Colleagues,

Cancer, one of the most widely spread forms of disease, is slowly taking over the world. Over time, a number of conventional cytotoxic approaches has been developed, but their limited effectiveness, in accordance with the heterogeneity of cancer cells, prompts to the constant search for new therapeutic approaches with improved outcomes, such as immunotherapy. Immunotherapy, which utilizes and enhances the normal capacity of the patient's immune system, was first used in the 19th century, but has developed to this day, and continues to do so. The main types of immunotherapeutic approaches include cancer vaccines, monoclonal antibodies, immune checkpoint inhibitors, and other non-specific therapies. After decades of intense effort, the therapeutics that leverage the immune system to contrast the cancer, have now conclusively demonstrated their effectiveness. However, the search for novel methods to improve immunotherapy continues without any reduction in intensity or strength. In this way, the use of small molecule immunotherapeutic approaches for the treatment of cancer are especially interesting. Small molecules can either reduce immune suppression in the tumor milieu or enhance the activation of cytotoxic lymphocyte responses to the tumor, and might be used as monotherapies or combined with other cancer therapies to increase and broaden their efficacy. Insight into the more promising immunotherapeutic approaches in the form of original research articles or reviews in all areas of cancer, experimental designs, and therapeutic approaches are welcome.

Prof. Dr. Amedeo Amedei
Dr. Elena Niccolai
Guest Editors

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Keywords

Immunotherapy
Immune checkpoint inhibitors
CAR-T cells
Small molecules
Cancer

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Published Papers (11 papers)

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Research

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10 pages, 2312 KiB

Open AccessArticle

Association of Systemic Steroid Treatment and Outcome in Patients Treated with Immune Checkpoint Inhibitors: A Real-World Analysis

by Agnese Paderi, Elisabetta Gambale, Cristina Botteri, Roberta Giorgione, Daniele Lavacchi, Marco Brugia, Francesca Mazzoni, Elisa Giommoni, Susanna Bormioli, Amedeo Amedei, Serena Pillozzi, Marco Matucci Cerinic and Lorenzo Antonuzzo

Molecules 2021, 26(19), 5789; https://doi.org/10.3390/molecules26195789 - 24 Sep 2021

Cited by 27 | Viewed by 3612

Abstract

Background: Immune-related adverse events (irAEs) are inflammatory side effects, which can occur during immune-checkpoint(s) inhibitors (ICIs) therapy. Steroids are the first-line agents to manage irAEs because of their immunosuppressive properties. However, it is still debated whether or when steroids can be administered without abrogating the therapeutic efforts of immunotherapy. Methods: We retrospectively evaluated 146 patients with metastatic non-small cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC) treated with ICIs. We assessed the progression-free survival (PFS) of patients treated with steroids due to an irAE compared to a no-steroid group. Results: The early treatment with steroid (within the first 30 days from the beginning of immunotherapy) was not related to a shorter PFS (p = 0.077). Interestingly, patients who were treated with steroids after 30 days from the start of immunotherapy had significantly longer PFS (p = 0.017). In a multivariate analysis, treatment with steroids after 30 days was an independent prognostic factor for PFS (HR: 0.59 [95% CI 0.36–0.97], p = 0.037). Conclusions: This retrospective study points out that early systemic steroids administration to manage irAEs might not have a detrimental effect on patient clinical outcome in NSCLC, melanoma and RCC patients. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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Review

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18 pages, 2175 KiB

Open AccessReview

From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

by Afshin Derakhshani, Zeinab Rostami, Hossein Safarpour, Mahdi Abdoli Shadbad, Niloufar Sadat Nourbakhsh, Antonella Argentiero, Sina Taefehshokr, Neda Jalili Tabrizi, Omid Kooshkaki, Reza Vaezi Astamal, Pankaj Kumar Singh, Nima Taefehshokr, Nazila Alizadeh, Nicola Silvestris and Behzad Baradaran

Molecules 2021, 26(8), 2278; https://doi.org/10.3390/molecules26082278 - 14 Apr 2021

Cited by 34 | Viewed by 5834

Abstract

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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28 pages, 1213 KiB

Open AccessReview

The Future of Cancer Diagnosis, Treatment and Surveillance: A Systemic Review on Immunotherapy and Immuno-PET Radiotracers

by Virginia Liberini, Riccardo Laudicella, Martina Capozza, Martin W. Huellner, Irene A. Burger, Sergio Baldari, Enzo Terreno and Désirée Deandreis

Molecules 2021, 26(8), 2201; https://doi.org/10.3390/molecules26082201 - 11 Apr 2021

Cited by 28 | Viewed by 5756

Abstract

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using an immunohistochemical analysis of the expression of antigens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET in general is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers), able to identify specific immune system targets, are under investigation in pre-clinical and clinical settings to better highlight all the mechanisms involved in immunotherapy. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [¹⁸F]FDG PET in immunotherapy, including the use of artificial intelligence (AI). Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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26 pages, 1940 KiB

Open AccessReview

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

by Claudia Curcio, Silvia Brugiapaglia, Sara Bulfamante, Laura Follia, Paola Cappello and Francesco Novelli

Molecules 2021, 26(6), 1642; https://doi.org/10.3390/molecules26061642 - 15 Mar 2021

Cited by 17 | Viewed by 5594

Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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10 pages, 263 KiB

Open AccessReview

The Current Landscape of Immune Checkpoint Blockade in Metastatic Lung Squamous Cell Carcinoma

by Hong Yuan, Jing Liu and Jun Zhang

Molecules 2021, 26(5), 1392; https://doi.org/10.3390/molecules26051392 - 5 Mar 2021

Cited by 24 | Viewed by 3146

Abstract

In addition to surgery, chemotherapy, radiotherapy, and targeted therapy, immunotherapy has emerged as a standard pillar of cancer treatment. Immune checkpoint inhibitors (ICIs) such as targeting programmed death-1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have been integrated into standard-of-care regimens for patients with advanced lung squamous cell carcinoma (LUSC), who were previously limited by the lack of treatment options. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Recent successes and failures of immune checkpoint blockade-based combination therapies have provided significant insights into implementing combination strategies in LUSC. Therefore, there is an urgent need to correctly select patients who are more likely to respond to immunotherapy and understand the mechanisms of primary or acquired resistance. In this review, we aim at summarizing the emerging clinical data on the promise and challenge of ICIs, discussing the unmet need of potential biomarkers for predicting response or resistance to immunotherapy, and providing an overview of the current immune landscape and future directions in advanced LUSC. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

33 pages, 2297 KiB

Open AccessReview

The Microbiome and Its Implications in Cancer Immunotherapy

by Hani Choudhry

Molecules 2021, 26(1), 206; https://doi.org/10.3390/molecules26010206 - 3 Jan 2021

Cited by 17 | Viewed by 7065

Abstract

Cancer is responsible for ~18 million deaths globally each year, representing a major cause of death. Several types of therapy strategies such as radiotherapy, chemotherapy and more recently immunotherapy, have been implemented in treating various types of cancer. Microbes have recently been found to be both directly and indirectly involved in cancer progression and regulation, and studies have provided novel and clear insights into the microbiome-mediated emergence of cancers. Scientists around the globe are striving hard to identify and characterize these microbes and the underlying mechanisms by which they promote or suppress various kinds of cancer. Microbes may influence immunotherapy by blocking various cell cycle checkpoints and the production of certain metabolites. Hence, there is an urgent need to better understand the role of these microbes in the promotion and suppression of cancer. The identification of microbes may help in the development of future diagnostic tools to cure cancers possibly associated with the microbiome. This review mainly focuses on various microbes and their association with different types of cancer, responses to immunotherapeutic modulation, physiological responses, and prebiotic and postbiotic effects. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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20 pages, 2175 KiB

Open AccessReview

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

by Soehartati A. Gondhowiardjo, Handoko, Vito Filbert Jayalie, Riyan Apriantoni, Andreas Ronald Barata, Fajar Senoaji, IGAA Jayanthi Wulan Utami, Ferdinand Maubere, Endang Nuryadi and Angela Giselvania

Molecules 2020, 25(18), 4096; https://doi.org/10.3390/molecules25184096 - 8 Sep 2020

Cited by 11 | Viewed by 3865

Abstract

Cancer treatment has evolved tremendously in the last few decades. Immunotherapy has been considered to be the forth pillar in cancer treatment in addition to conventional surgery, radiotherapy, and chemotherapy. Though immunotherapy has resulted in impressive response, it is generally limited to a small subset of patients. Understanding the mechanisms of resistance toward cancer immunotherapy may shed new light to counter that resistance. In this review, we highlighted and summarized two major hurdles (recognition and attack) of cancer elimination by the immune system. The mechanisms of failure of some available immunotherapy strategies were also described. Moreover, the significance role of immune compartment for various established cancer treatments were also elucidated in this review. Then, the mechanisms of combinatorial treatment of various conventional cancer treatment with immunotherapy were discussed. Finally, a strategy to improve immune cancer killing by characterizing cancer immune landscape, then devising treatment based on that cancer immune landscape was put forward. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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13 pages, 1235 KiB

Open AccessReview

Interaction between Immunotherapy and Antiangiogenic Therapy for Cancer

by Koichi Furukawa, Tatsuya Nagano, Motoko Tachihara, Masatsugu Yamamoto and Yoshihiro Nishimura

Molecules 2020, 25(17), 3900; https://doi.org/10.3390/molecules25173900 - 26 Aug 2020

Cited by 27 | Viewed by 3945

Abstract

Although immunotherapy has led to durable responses in diverse cancers, unfortunately, there has been limited efficacy and clinical response rates due to primary or acquired resistance to immunotherapy. To maximize the potential of immunotherapy, combination therapy with antiangiogenic drugs seems to be promising. Some phase III trials showed superiority for survival with the combination of immunotherapy and antiangiogenic therapy. In this study, we describe a synergistic mechanism of immunotherapy and antiangiogenic therapy and summarize current clinical trials of these combinations. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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22 pages, 1223 KiB

Open AccessReview

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

by Bernardo L. Rapoport, Helen C. Steel, Annette J. Theron, Teresa Smit and Ronald Anderson

Molecules 2020, 25(7), 1618; https://doi.org/10.3390/molecules25071618 - 1 Apr 2020

Cited by 33 | Viewed by 5948

Abstract

Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated these cells in the pathogenesis of the later phases of cancer development, specifically progression and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype. In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME. Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the development of a range of adjunctive strategies targeting the recruitment of these cells and/or the harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic, allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted therapy in patients with various types of advanced malignancy. The current review updates the origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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19 pages, 1806 KiB

Open AccessFeature PaperReview

Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets?

by Eugenio Cavalli, Rosella Ciurleo, Maria Cristina Petralia, Paolo Fagone, Rita Bella, Katia Mangano, Ferdinando Nicoletti, Placido Bramanti and Maria Sofia Basile

Molecules 2020, 25(5), 1194; https://doi.org/10.3390/molecules25051194 - 6 Mar 2020

Cited by 32 | Viewed by 5847

Abstract

Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Despite the current available multiple therapeutic options, the prognosis for high-risk NB patients remains unsatisfactory and makes the disease a clear unmet medical need. Thus, more tailored therapeutic approaches are warranted to improve both the quality of life and the survival of the patients. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in several diseases, including cancer. Preclinical and clinical studies in NB patients convergently indicate that MIF exerts pro-tumorigenic properties in NB. MIF is upregulated in NB tumor tissues and cell lines and it contributes to NB aggressiveness and immune-escape. To date, there are only a few data about the role of the second member of the MIF family, the MIF homolog d-dopachrome tautomerase (DDT), in NB. Here, we review the preclinical and clinical studies on the role of the MIF family of cytokines in NB and suggest that MIF and possibly DDT inhibitors may be promising novel prognostic and therapeutic targets in NB management. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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12 pages, 762 KiB

Open AccessReview

Sex Differences in Cancer Immunotherapy Efficacy, Biomarkers, and Therapeutic Strategy

by Shixiang Wang, Li An Cowley and Xue-Song Liu

Molecules 2019, 24(18), 3214; https://doi.org/10.3390/molecules24183214 - 4 Sep 2019

Cited by 115 | Viewed by 9938

Abstract

Sex differences in innate and adaptive immune responses are known, and women generally mount a stronger immune response than men. Cancer immunotherapy, represented by immune checkpoint inhibitors (ICIs), has revolutionized the treatment of cancer, and sex differences in cancer immunotherapy are just starting to be revealed. Here, we summarize recent research progress concerning sex differences in cancer immunotherapy efficacy. On their own, ICIs tend to be more effective in male cancer patients compared with female patients, while ICIs combined with chemotherapy tend to be more effective in female patients than male patients. Male tumors are usually more antigenic than female tumors, and this is reflected by their increased number of tumor mutations and cancer germline antigens. The biomarker tumor mutational burden (TMB), which reflects tumor antigenicity, is more effective at predicting immunotherapy response for female lung cancer patients than for male patients. In this review, we propose different therapeutic strategies for the different sexes: For male cancer patients, the immune environment should be enhanced, whereas for female cancer patients, tumor antigenicity should be enhanced. Full article

(This article belongs to the Special Issue The Future of the Cancer Treatment: The Immunotherapy Next Generation)

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