International Journal of Molecular Sciences

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18 pages, 3846 KiB

Open AccessArticle

Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy

by Robin Reschke, Philipp Gussek, Andreas Boldt, Ulrich Sack, Ulrike Köhl, Florian Lordick, Thomas Gora, Markus Kreuz, Kristin Reiche, Jan-Christoph Simon, Mirjana Ziemer and Manfred Kunz

Int. J. Mol. Sci. 2021, 22(15), 8017; https://doi.org/10.3390/ijms22158017 - 27 Jul 2021

Cited by 21 | Viewed by 5126

Abstract

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab [...] Read more.

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8⁺ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3⁺ T cells before the second cycle of treatment. The percentage of CD8⁺ effector memory (CD8⁺CD45RA⁻CD45RO⁺CCR7⁻) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4⁺ (CD4⁺CD38⁺HLADR⁺) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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15 pages, 4984 KiB

Open AccessArticle

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

by Albina Fejza, Maurizio Polano, Lucrezia Camicia, Evelina Poletto, Greta Carobolante, Giuseppe Toffoli, Maurizio Mongiat and Eva Andreuzzi

Int. J. Mol. Sci. 2021, 22(14), 7511; https://doi.org/10.3390/ijms22147511 - 13 Jul 2021

Cited by 14 | Viewed by 3043

Abstract

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely [...] Read more.

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2^−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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15 pages, 4233 KiB

Open AccessCommunication

Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma

by Takahiro Tashiro, Kosuke Imamura, Yusuke Tomita, Daisuke Tamanoi, Akira Takaki, Kazuaki Sugahara, Ryo Sato, Koichi Saruwatari, Shinya Sakata, Megumi Inaba, Sunao Ushijima, Naomi Hirata and Takuro Sakagami

Int. J. Mol. Sci. 2020, 21(24), 9705; https://doi.org/10.3390/ijms21249705 - 19 Dec 2020

Cited by 11 | Viewed by 3225

Abstract

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is [...] Read more.

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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13 pages, 2108 KiB

Open AccessArticle

Tn Antigen Expression Defines an Immune Cold Subset of Mismatch-Repair Deficient Colorectal Cancer

by Takuro Matsumoto, Hirokazu Okayama, Shotaro Nakajima, Katsuharu Saito, Hiroshi Nakano, Eisei Endo, Koji Kase, Misato Ito, Naoto Yamauchi, Leo Yamada, Yasuyuki Kanke, Hisashi Onozawa, Shotaro Fujita, Wataru Sakamoto, Motonobu Saito, Zenichiro Saze, Tomoyuki Momma, Kosaku Mimura and Koji Kono

Int. J. Mol. Sci. 2020, 21(23), 9081; https://doi.org/10.3390/ijms21239081 - 29 Nov 2020

Cited by 7 | Viewed by 2574

Abstract

Colorectal cancer (CRC) cells often express Tn antigen, a tumor-associated truncated immature O-glycan (GalNAcα-O-Ser/Thr) that can promote tumor progression. Immunotherapies against Tn antigen have been developed and are being evaluated in clinical trials. Tn antigen can also be considered a novel immune checkpoint [...] Read more.

Colorectal cancer (CRC) cells often express Tn antigen, a tumor-associated truncated immature O-glycan (GalNAcα-O-Ser/Thr) that can promote tumor progression. Immunotherapies against Tn antigen have been developed and are being evaluated in clinical trials. Tn antigen can also be considered a novel immune checkpoint that induces immunosuppressive signaling through glycan-biding lectins to lead effector T cell apoptosis. We evaluated the correlation of Tn antigen expression by immunohistochemistry with mismatch-repair (MMR) status, tumor-infiltrating lymphocytes, tumor cell PD-L1 expression, and clinicopathological characteristics in 507 CRC patients. Although 91.9% of CRCs showed negative or weak Tn antigen staining (Tn-negative/weak), we identified a small subset of CRCs (8.1%) that displayed particularly intense and diffuse distribution of Tn antigen immunoreactivity (Tn-strong) that closely related to deficient MMR (dMMR). Moreover, 40 dMMR CRCs were stratified into 24 Tn-negative/weak dMMR tumors (60.0%) exhibiting dense CD8+ lymphocyte infiltrate concomitant with a high rate of PD-L1 positivity, and 16 Tn-strong dMMR tumors (40.0%) that demonstrated CD8+ T cell exclusion and a lack of PD-L1 expression, which was comparable to those of proficient MMR. Our finding suggests that the immune cold subset of patients with Tn-strong dMMR CRC may be effectively treated with immune checkpoint blockade therapy or cellular immunotherapy targeting Tn antigen. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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18 pages, 4551 KiB

Open AccessArticle

Fragments of gD Protein as Inhibitors of BTLA/HVEM Complex Formation - Design, Synthesis, and Cellular Studies

by Katarzyna Kuncewicz, Claire Battin, Adam Sieradzan, Agnieszka Karczyńska, Marta Orlikowska, Anna Wardowska, Michał Pikuła, Peter Steinberger, Sylwia Rodziewicz-Motowidło and Marta Spodzieja

Int. J. Mol. Sci. 2020, 21(22), 8876; https://doi.org/10.3390/ijms21228876 - 23 Nov 2020

Cited by 11 | Viewed by 3727

Abstract

One of the major current trends in cancer immunotherapy is the blockade of immune checkpoint proteins that negatively regulate the immune response. This has been achieved through antibodies blocking PD-1/PD-L1 and CTLA-4/CD80/CD86 interactions. Such antibodies have revolutionized oncological therapy and shown a new [...] Read more.

One of the major current trends in cancer immunotherapy is the blockade of immune checkpoint proteins that negatively regulate the immune response. This has been achieved through antibodies blocking PD-1/PD-L1 and CTLA-4/CD80/CD86 interactions. Such antibodies have revolutionized oncological therapy and shown a new way to fight cancer. Additional (negative) immune checkpoints are also promising targets in cancer therapy and there is a demand for inhibitors for these molecules. Our studies are focused on BTLA/HVEM complex, which inhibits T-cell proliferation and cytokine production and therefore has great potential as a new target for cancer treatment. The goal of the presented studies was the design and synthesis of compounds able to block BTLA/HVEM interactions. For that purpose, the N-terminal fragment of glycoprotein D (gD), which interacts with HVEM, was used. Based on the crystal structure of the gD/HVEM complex and MM/GBSA analysis performed on it, several peptides were designed and synthesized as potential inhibitors of the BTLA/HVEM interaction. Affinity tests, ELISA tests, and cellular-based reporter assays were performed on these compounds to check their ability to bind to HVEM and to inhibit BTLA/HVEM complex formation. For leading peptides candidates, all-atom and subsequent docking simulations with a coarse-grained force field were performed to determine their binding modes. To further evaluate their potential as drug candidates, their stability in plasma and their cytotoxicity effects on PBMCs were assessed. Our data indicate that the peptide gD(1-36)(K10C-T29C) is the best candidate as a future drug. It interacts with HVEM protein, blocks the BTLA/HVEM interaction, and is nontoxic to cells. The present study provides a new perspective on the development of BTLA/HVEM inhibitors that disrupt protein interactions. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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Review

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16 pages, 877 KiB

Open AccessReview

Immune Aging and Immunotherapy in Cancer

by Melanie Kaiser, Maria Donatella Semeraro, Markus Herrmann, Gudrun Absenger, Armin Gerger and Wilfried Renner

Int. J. Mol. Sci. 2021, 22(13), 7016; https://doi.org/10.3390/ijms22137016 - 29 Jun 2021

Cited by 38 | Viewed by 6219

Abstract

Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. [...] Read more.

Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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15 pages, 1855 KiB

Open AccessReview

Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer

by Florus C. de Jong, Vera C. Rutten, Tahlita C. M. Zuiverloon and Dan Theodorescu

Int. J. Mol. Sci. 2021, 22(6), 2800; https://doi.org/10.3390/ijms22062800 - 10 Mar 2021

Cited by 25 | Viewed by 4346

Abstract

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness [...] Read more.

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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23 pages, 1297 KiB

Open AccessReview

Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

by Fulvio Borella, Mario Preti, Luca Bertero, Giammarco Collemi, Isabella Castellano, Paola Cassoni, Stefano Cosma, Andrea Roberto Carosso, Federica Bevilacqua, Niccolò Gallio, Chiara Benedetto and Leonardo Micheletti

Int. J. Mol. Sci. 2021, 22(1), 190; https://doi.org/10.3390/ijms22010190 - 27 Dec 2020

Cited by 32 | Viewed by 7533

Abstract

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced [...] Read more.

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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17 pages, 2732 KiB

Open AccessReview

The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm

by Quentin Lecocq, Marleen Keyaerts, Nick Devoogdt and Karine Breckpot

Int. J. Mol. Sci. 2021, 22(1), 75; https://doi.org/10.3390/ijms22010075 - 23 Dec 2020

Cited by 99 | Viewed by 7712

Abstract

The blockade of immune checkpoints (ICPs), such as cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed death-1 (PD-1) and its ligand (PD-L1), has propelled the field of immuno-oncology into its current era. Drugs targeting these ICPs have improved clinical outcome in a number [...] Read more.

The blockade of immune checkpoints (ICPs), such as cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed death-1 (PD-1) and its ligand (PD-L1), has propelled the field of immuno-oncology into its current era. Drugs targeting these ICPs have improved clinical outcome in a number of patients with solid and hematological cancers. Nonetheless, some patients have no benefit from these ICP-blocking therapies. This observation has instigated research into alternative pathways that are responsible for the escape of cancer cells from anti-cancer immune responses. From this research, a number of molecules have emerged as promising therapeutic targets, including lymphocyte activating gene-3 (LAG-3), a next-generation ICP. We will review the current knowledge on the biological activity of LAG-3 and linked herewith its expression on activated immune cells. Moreover, we will discuss the prognostic value of LAG-3 and how LAG-3 expression in tumors can be monitored, which is an aspect that is of utmost importance, as the blockade of LAG-3 is actively pursued in clinical trials. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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26 pages, 310 KiB

Open AccessReview

Immune Checkpoint Blockade in Advanced Cutaneous Squamous Cell Carcinoma: What Do We Currently Know in 2020?

by Anja Wessely, Theresa Steeb, Ulrike Leiter, Claus Garbe, Carola Berking and Markus Vincent Heppt

Int. J. Mol. Sci. 2020, 21(23), 9300; https://doi.org/10.3390/ijms21239300 - 6 Dec 2020

Cited by 22 | Viewed by 3332

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal [...] Read more.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal of cSCC is the therapy of choice and mostly curative in early stages. However, a minority of patients develop locally advanced tumors or distant metastases that are still challenging to treat. Immune checkpoint blockade (ICB) targeting CTLA-4, PD-L1 and PD-1 has tremendously changed the field of oncological therapy and especially the treatment of skin cancers as tumors with a high mutational burden. In this review, we focus on the differences between cSCC and cutaneous melanoma (CM) and their implications on therapy, summarize the current evidence on ICB for the treatment of advanced cSCC and discuss the chances and pitfalls of this therapy option for this cancer entity. Furthermore, we focus on special subgroups of interest such as organ transplant recipients, patients with hematologic malignancies, XP and field cancerization. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

16 pages, 557 KiB

Open AccessReview

Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors

by Valentina Tateo, Lisa Manuzzi, Andrea De Giglio, Claudia Parisi, Giuseppe Lamberti, Davide Campana and Maria Abbondanza Pantaleo

Int. J. Mol. Sci. 2020, 21(23), 9056; https://doi.org/10.3390/ijms21239056 - 28 Nov 2020

Cited by 20 | Viewed by 3814

Abstract

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options [...] Read more.

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus’ immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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14 pages, 646 KiB

Open AccessReview

Focus on Biochemical and Clinical Predictors of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma: Where Do We Stand?

by Giandomenico Roviello, Martina Catalano, Stefania Nobili, Raffaella Santi, Enrico Mini and Gabriella Nesi

Int. J. Mol. Sci. 2020, 21(21), 7935; https://doi.org/10.3390/ijms21217935 - 26 Oct 2020

Cited by 17 | Viewed by 3289

Abstract

Urothelial bladder cancer is one of the most lethal cancers worldwide with barely 5% five-year survival in patients with metastatic disease. Intravesical immunotherapy with Bacillus Calmette-Guérin and platinum-based chemotherapy are currently the standard of care for non-muscle invasive and advanced or metastatic urothelial [...] Read more.

Urothelial bladder cancer is one of the most lethal cancers worldwide with barely 5% five-year survival in patients with metastatic disease. Intravesical immunotherapy with Bacillus Calmette-Guérin and platinum-based chemotherapy are currently the standard of care for non-muscle invasive and advanced or metastatic urothelial cancer (mUC), respectively. Recently, a subset of patients with locally advanced or mUC has shown to be responsive to immune checkpoint inhibitors (ICIs), e.g., the anti-cytotoxic T-lymphocyte-associated protein 4 and programmed cell death -1/programmed death-ligand1 (PD-1/PD-L1) antibodies. Due to the relevant clinical benefit of immunotherapy for mUC, in 2016, the United States Food and Drug Administration (FDA) approved five immunotherapeutic agents as second-line or first-line treatments for patients with advanced bladder cancer who did not profit from or were ineligible for standard therapy. In this review, we discuss the role of immunotherapy in bladder cancer and recent clinical applications of PD-1/PD-L1 blockade in mUC. Furthermore, we evaluate a variable response rate to ICIs treatment and outline potential biomarkers predictive of immunotherapy response. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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36 pages, 983 KiB

Open AccessReview

Clinical Application of Oncolytic Viruses: A Systematic Review

by Mary Cook and Aman Chauhan

Int. J. Mol. Sci. 2020, 21(20), 7505; https://doi.org/10.3390/ijms21207505 - 12 Oct 2020

Cited by 67 | Viewed by 7234

Abstract

Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of [...] Read more.

Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic viruses. Trials were reviewed for type of oncolytic virus used, method of administration, study design, disease type, primary outcome, and relevant adverse effects. A total of 120 trials were found; 86 trials were available for our review. Included were 60 phase I trials, five phase I/II combination trials, 19 phase II trials, and two phase III clinical trials. Oncolytic viruses are feverously being evaluated in oncology with over 30 different types of oncolytic viruses being explored either as a single agent or in combination with other antitumor agents. To date, only one oncolytic virus therapy has received an FDA approval but advances in bioengineering techniques and our understanding of immunomodulation to heighten oncolytic virus replication and improve tumor kill raises optimism for its future drug development. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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16 pages, 736 KiB

Open AccessReview

Current Status and Future Perspectives of Checkpoint Inhibitor Immunotherapy for Prostate Cancer: A Comprehensive Review

by Tae Jin Kim and Kyo Chul Koo

Int. J. Mol. Sci. 2020, 21(15), 5484; https://doi.org/10.3390/ijms21155484 - 31 Jul 2020

Cited by 41 | Viewed by 4220

Abstract

The clinical spectrum of prostate cancer (PCa) varies from castration-naive to metastatic castration-resistant disease. Despite the administration of androgen synthesis inhibitors and chemotherapy regimens for castration-resistant prostate cancer, the treatment options for this entity are limited. The utilization of the immune system against [...] Read more.

The clinical spectrum of prostate cancer (PCa) varies from castration-naive to metastatic castration-resistant disease. Despite the administration of androgen synthesis inhibitors and chemotherapy regimens for castration-resistant prostate cancer, the treatment options for this entity are limited. The utilization of the immune system against cancer cells shows potential as a therapeutic modality for various solid tumors and hematologic malignancies. With technological advances over the last decade, immunotherapy has become an integral treatment modality for advanced solid tumors. The feasibility of immunotherapy has shown promise for patients with PCa, and with advances in molecular diagnostic platforms and our understanding of immune mechanisms, immunotherapy is reemerging as a potential treatment modality for PCa. Various combinations of individualized immunotherapy and immune checkpoint blockers with androgen receptor-targeted therapies and conventional cytotoxic agents show promise. This article will review the current status of immunotherapy, including new discoveries and precision approaches to PCa, and discuss future directions in the continuously evolving landscape of immunotherapy. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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26 pages, 748 KiB

Open AccessReview

Manipulation of Metabolic Pathways and Its Consequences for Anti-Tumor Immunity: A Clinical Perspective

by Huang-Yu Yang, Chao-Yi Wu, Jonathan D. Powell and Kun-Lin Lu

Int. J. Mol. Sci. 2020, 21(11), 4030; https://doi.org/10.3390/ijms21114030 - 4 Jun 2020

Cited by 9 | Viewed by 4122

Abstract

In the relatively short history of anti-tumor treatment, numerous medications have been developed against a variety of targets. Intriguingly, although many anti-tumor strategies have failed in their clinical trials, metformin, an anti-diabetic medication, demonstrated anti-tumor effects in observational studies and even showed its [...] Read more.

In the relatively short history of anti-tumor treatment, numerous medications have been developed against a variety of targets. Intriguingly, although many anti-tumor strategies have failed in their clinical trials, metformin, an anti-diabetic medication, demonstrated anti-tumor effects in observational studies and even showed its synergistic potential with immune checkpoint inhibitors (ICIs) in subsequent clinical studies. Looking back from bedside-to-bench, it may not be surprising that the anti-tumor effect of metformin derives largely from its ability to rewire aberrant metabolic pathways within the tumor microenvironment. As one of the most promising breakthroughs in oncology, ICIs were also found to exert their immune-stimulatory effects at least partly via rewiring metabolic pathways. These findings underscore the importance of correcting metabolic pathways to achieve sufficient anti-tumor immunity. Herein, we start by introducing the tumor microenvironment, and then we review the implications of metabolic syndrome and treatments for targeting metabolic pathways in anti-tumor therapies. We further summarize the close associations of certain aberrant metabolic pathways with impaired anti-tumor immunity and introduce the therapeutic effects of targeting these routes. Lastly, we go through the metabolic effects of ICIs and conclude an overall direction to manipulate metabolic pathways in favor of anti-tumor responses. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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35 pages, 1206 KiB

Open AccessReview

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

by Florian Huemer, Michael Leisch, Roland Geisberger, Thomas Melchardt, Gabriel Rinnerthaler, Nadja Zaborsky and Richard Greil

Int. J. Mol. Sci. 2020, 21(8), 2856; https://doi.org/10.3390/ijms21082856 - 19 Apr 2020

Cited by 31 | Viewed by 7008

Abstract

The therapeutic concept of unleashing a pre-existing immune response against the tumor by the application of immune-checkpoint inhibitors (ICI) has resulted in long-term survival in advanced cancer patient subgroups. However, the majority of patients do not benefit from single-agent ICI and therefore new [...] Read more.

The therapeutic concept of unleashing a pre-existing immune response against the tumor by the application of immune-checkpoint inhibitors (ICI) has resulted in long-term survival in advanced cancer patient subgroups. However, the majority of patients do not benefit from single-agent ICI and therefore new combination strategies are eagerly necessitated. In addition to conventional chemotherapy, kinase inhibitors as well as tumor-specific vaccinations are extensively investigated in combination with ICI to augment therapy responses. An unprecedented clinical outcome with chimeric antigen receptor (CAR-)T cell therapy has led to the approval for relapsed/refractory diffuse large B cell lymphoma and B cell acute lymphoblastic leukemia whereas response rates in solid tumors are unsatisfactory. Immune-checkpoints negatively impact CAR-T cell therapy in hematologic and solid malignancies and as a consequence provide a therapeutic target to overcome resistance. Established biomarkers such as programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) help to select patients who will benefit most from ICI, however, biomarker negativity does not exclude responses. Investigating alterations in the antigen presenting pathway as well as radiomics have the potential to determine tumor immunogenicity and response to ICI. Within this review we summarize the literature about specific combination partners for ICI and the applicability of artificial intelligence to predict ICI therapy responses. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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18 pages, 258 KiB

Open AccessReview

Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma

by Stephanie Sanders and Waldemar Debinski

Int. J. Mol. Sci. 2020, 21(8), 2759; https://doi.org/10.3390/ijms21082759 - 16 Apr 2020

Cited by 43 | Viewed by 3897

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant glioma, treatment of which has not improved significantly in many years. This is due to the unique challenges that GBM tumors present when designing and implementing therapies. Recently, immunotherapy in the form of immune [...] Read more.

Glioblastoma (GBM) is the most common and aggressive malignant glioma, treatment of which has not improved significantly in many years. This is due to the unique challenges that GBM tumors present when designing and implementing therapies. Recently, immunotherapy in the form of immune checkpoint inhibition (ICI) has revolutionized the treatment of various malignancies. The application of immune checkpoint inhibition in GBM treatment has shown promising preclinical results. Unfortunately, this has met with little to no success in the clinic thus far. In this review, we will discuss the challenges presented by GBM tumors that likely limit the effect of ICI and discuss the approaches being tested to overcome these challenges. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

22 pages, 962 KiB

Open AccessReview

Immunotherapy in Renal Cell Carcinoma: The Future Is Now

by Antoine Deleuze, Judikaël Saout, Frédéric Dugay, Benoit Peyronnet, Romain Mathieu, Gregory Verhoest, Karim Bensalah, Laurence Crouzet, Brigitte Laguerre, Marc-Antoine Belaud-Rotureau, Nathalie Rioux-Leclercq and Solène-Florence Kammerer-Jacquet

Int. J. Mol. Sci. 2020, 21(7), 2532; https://doi.org/10.3390/ijms21072532 - 5 Apr 2020

Cited by 151 | Viewed by 7572

Abstract

Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare [...] Read more.

Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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13 pages, 540 KiB

Open AccessReview

Systemic Blood Immune Cell Populations as Biomarkers for the Outcome of Immune Checkpoint Inhibitor Therapies

by Carlos Hernandez, Hugo Arasanz, Luisa Chocarro, Ana Bocanegra, Miren Zuazo, Gonzalo Fernandez-Hinojal, Ester Blanco, Ruth Vera, David Escors and Grazyna Kochan

Int. J. Mol. Sci. 2020, 21(7), 2411; https://doi.org/10.3390/ijms21072411 - 31 Mar 2020

Cited by 23 | Viewed by 5114

Abstract

The development of cancer immunotherapy in the last decade has followed a vertiginous rhythm. Nowadays, immune checkpoint inhibitors (ICI) which include anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies are in clinical use for the treatment of numerous cancers. However, approximately only a third of the [...] Read more.

The development of cancer immunotherapy in the last decade has followed a vertiginous rhythm. Nowadays, immune checkpoint inhibitors (ICI) which include anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies are in clinical use for the treatment of numerous cancers. However, approximately only a third of the patients benefit from ICI therapies. Many efforts have been made for the identification of biomarkers allowing patient stratification into potential responders and progressors before the start of ICI therapies or for monitoring responses during treatment. While much attention is centered on biomarkers from the tumor microenvironment, in many cases biopsies are not available. The identification of systemic immune cell subsets that correlate with responses could provide promising biomarkers. Some of them have been reported to influence the response to ICI therapies, such as proliferation and activation status of CD8 and CD4 T cells, the expression of immune checkpoints in peripheral blood cells and the relative numbers of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. In addition, the profile of soluble factors in plasma samples could be associated to response or tumor progression. Here we will review the cellular subsets associated to response or progression in different studies and discuss their accuracy in diagnosis. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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19 pages, 1314 KiB

Open AccessReview

Molecular T-Cell Repertoire Analysis as Source of Prognostic and Predictive Biomarkers for Checkpoint Blockade Immunotherapy

by Ilenia Aversa, Donatella Malanga, Giuseppe Fiume and Camillo Palmieri

Int. J. Mol. Sci. 2020, 21(7), 2378; https://doi.org/10.3390/ijms21072378 - 30 Mar 2020

Cited by 51 | Viewed by 5894

Abstract

The T cells are key players of the response to checkpoint blockade immunotherapy (CBI) and monitoring the strength and specificity of antitumor T-cell reactivity remains a crucial but elusive component of precision immunotherapy. The entire assembly of T-cell receptor (TCR) sequences accounts for [...] Read more.

The T cells are key players of the response to checkpoint blockade immunotherapy (CBI) and monitoring the strength and specificity of antitumor T-cell reactivity remains a crucial but elusive component of precision immunotherapy. The entire assembly of T-cell receptor (TCR) sequences accounts for antigen specificity and strength of the T-cell immune response. The TCR repertoire hence represents a “footprint” of the conditions faced by T cells that dynamically evolves according to the challenges that arise for the immune system, such as tumor neo-antigenic load. Hence, TCR repertoire analysis is becoming increasingly important to comprehensively understand the nature of a successful antitumor T-cell response, and to improve the success and safety of current CBI. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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21 pages, 787 KiB

Open AccessReview

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

by Vera Petrova, Ihor Arkhypov, Rebekka Weber, Christopher Groth, Peter Altevogt, Jochen Utikal and Viktor Umansky

Int. J. Mol. Sci. 2020, 21(7), 2367; https://doi.org/10.3390/ijms21072367 - 30 Mar 2020

Cited by 35 | Viewed by 6032

Abstract

Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein [...] Read more.

Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions 2.0)

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