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Clinical Development of Immune Checkpoint Inhibitors for Cancers

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (20 September 2020) | Viewed by 35827

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Special Issue Editor

Dr. David J. Pinato

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Guest Editor

Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK
Interests: anticancer immunotherapy; immune checkpoint inhibitors; biomarkers; early-phase clinical trials; hepatocellular carcinoma

Special Issue Information

Dear Colleagues,

Immune checkpoint inhibitors have truly revolutionised the treatment landscape of a growing number of malignancies, including some that were previously untreatable with conventional chemotherapy or targeted agents. After decades of frustration and scepticism, the clinical development of immunotherapy has grown exponentially. The immunobiological factors that underpin responsiveness and resistance to immunotherapy are, however, poorly understood. Similarly, the development of biomarkers that can effectively predict who is going to respond to these therapies is at its infancy, leaving the clinical development of immune checkpoint inhibitors unsupported by solid predictive correlates of response in many oncological indications. The multifaceted relationship between the host immunity and progressive malignancy needs to take into account complex relationships with novel important domains, including the phenotypic characteristics of the intratumoural infiltrate, the status of the gut microbiota, the somatic mutational landscape of tumours, the emergence of immunotoxicity, and the concomitant prescription of medications, including corticosteroids and antibiotics, that might modulate immune responsiveness through various not always fully clarified mechanisms.

In the present Special Issue, we aim to collect a number of review and original articles that highlight significant advances in the clinical development of immunotherapy for cancer. Alongside the illustration of challenges that have accompanied the delivery of this new treatment modality, we will highlight the main trajectories in the expansion of cancer immunotherapy in the clinic and describe new challenges imposed by the development of immunotherapeutic combinations, extension of immunotherapy in early-stage disease, and optimal discovery and selection of biomarkers to guide clinical decision making across various lines of therapy and oncological indications. In summary, this Special Issue will help readers to get an up-to-date and authoritative view of how immunotherapy will continue to improve the systemic management of patients with cancer in the forthcoming future.

Dr. David J. Pinato
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer immunotherapy
immune checkpoint inhibitors
toxicity
predictive biomarkers
drug development
cellular therapies
adoptive immunotherapy
vaccines
tumour microenvironment
adaptive immunity
innate immunity

Published Papers (7 papers)

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Research

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10 pages, 534 KiB

Open AccessArticle

Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up

by Manon Levy, Juliette Abeillon, Stéphane Dalle, Souad Assaad, Françoise Borson-Chazot, Emmanuel Disse, Gérald Raverot and Christine Cugnet-Anceau

J. Clin. Med. 2020, 9(10), 3280; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9103280 - 13 Oct 2020

Cited by 22 | Viewed by 2718

Abstract

Hypophysitis, secondary to programmed cell death 1 protein (PD1) and programmed cell death 1 ligand 1 (PDL1) inhibitors, were thought to be rare, with only a few studies describing more than one case with long-term follow-up. The aim of the present study was to describe the clinical, laboratory, and morphological characteristics of PD1/PDL1 inhibitor-induced hypophysitis, and its long-term course. This cohort study was conducted at the University Hospital of Lyon, France, with longitudinal follow-up of patients. Seventeen cases of PD1/PDL1 inhibitor-induced hypophysitis were included. The median time to onset of hypophysitis was 28 weeks (range: 10–46). At diagnosis, 16 patients complained of fatigue, 12 of nausea or loss of appetite, while headache was rare. We found no imaging pituitary abnormality. All patients presented adrenocorticotropic hormone (ACTH) deficiency; other pituitary deficiencies were less common (n = 7). At last follow-up (median: 13 months), ACTH deficiency persisted in all but one patient and one patient recovered from gonadotropic deficiency. PD1/PDL1 inhibitor-induced hypophysitis is a clinical entity different from those associated to cytotoxic T-lymphocyte antigen-4 (CTLA4) inhibitors, with less obvious clinical and radiological signs, and probably a different mechanism. The paucity of symptoms demonstrates the need for systematic hormonal follow-up for patients receiving PD1/PDL1 inhibitors. Full article

(This article belongs to the Special Issue Clinical Development of Immune Checkpoint Inhibitors for Cancers)

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10 pages, 881 KiB

Open AccessArticle

Immune Checkpoint Inhibitors versus VEGF Targeted Therapy as Second Line Regimen in Advanced Hepatocellular Carcinoma (HCC): A Retrospective Study

by Anwaar Saeed, Hannah Hildebrand, Robin Park, Mohammed Al-Jumayli, Saqib Abbasi, Tina Melancon, Azhar Saeed, Raed Al-Rajabi, Anup Kasi, Joaquina Baranda, Stephen Williamson and Weijing Sun

J. Clin. Med. 2020, 9(9), 2682; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9092682 - 19 Aug 2020

Cited by 5 | Viewed by 2584

Abstract

Several targeted agents including multi-tyrosine kinase inhibitors (mTKIs) and immunotherapy (IO) agents have been approved for use beyond the frontline setting in patients with advanced hepatocellular carcinoma (HCC). Due to lack of prospective head-to-head comparative trials, there is no standardized way for alternating those agents beyond frontline. Therefore, we performed a retrospective review of the Kansas University (KU) cancer registry to determine whether IO may be superior to non-IO therapy. Patients with advanced HCC were divided into two groups based on the second-line systemic regimen received (IO vs. non-IO). Progression-free survival (PFS) and overall survival (OS) were calculated under the Kaplan–Meier and Cox proportional hazards models. No statistically significant differences in PFS and OS were found, although a non-significant delayed separation in the survival curve favoring IO was identified (median PFS 3.9 months vs. 3 months; median OS 10 months vs. 10 months respectively for IO vs. non-IO). This retrospective analysis is one of the earliest and largest studies comparing second-line IO and non-IO therapies thus far reported. Future studies should aim to define specific biomarkers for response prediction and treatment optimization based on individual patient and tumor characteristics. Furthermore, combinatorial therapeutic strategies is an evolving approach showing early promising signal. Full article

(This article belongs to the Special Issue Clinical Development of Immune Checkpoint Inhibitors for Cancers)

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10 pages, 593 KiB

Open AccessArticle

Efficacy and Safety of Pembrolizumab for Gemcitabine/Cisplatin-Refractory Biliary Tract Cancer: A Multicenter Retrospective Study

by Sang Hoon Lee, Hee Seung Lee, Sang Hyub Lee, Sang Myung Woo, Dong Uk Kim and Seungmin Bang

J. Clin. Med. 2020, 9(6), 1769; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9061769 - 7 Jun 2020

Cited by 26 | Viewed by 3345

Abstract

Pembrolizumab, an anti-programmed cell death (PD)-1 monoclonal antibody, is an anticancer agent showing substantial benefit in lung cancer and melanoma treatment. Biliary tract cancer (BTC) has been shown to respond to pembrolizumab; however, no credible data of such treatment outcomes exist. Therefore, we assessed the clinical outcomes and safety of pembrolizumab in patients with gemcitabine/cisplatin-refractory BTC. In this multicenter study, we retrospectively analyzed 51 patients with programmed cell death 1-ligand 1 (PD-L1)-positive gemcitabine/cisplatin-refractory BTC treated with pembrolizumab in four tertiary hospitals in Korea. PD-L1 positivity was defined as the expression of PD-L1 in ≥1% of tumor cells based on immunohistochemical staining (22C3, SP263, and E1L3N assays). The median age of the patients was 66 (range, 43–83) years and 29 (56.9%) were male. Extrahepatic cholangiocarcinoma was the most common cancer type (n = 30, 58.8%). Partial response and stable disease were achieved in 5 (9.8%) and 13 (25.5%) patients, respectively. Median progression-free survival and overall survival were 2.1 (95% CI, 1.7–2.4) and 6.9 (95% CI, 5.4–8.3) months, respectively. Overall, 30 (58.8%) patients experienced treatment-related adverse events (AEs). Only four (7.8%) patients experienced grades 3 and 4 AEs. In PD-L1-positive gemcitabine/cisplatin-refractory BTC, pembrolizumab presented durable efficacy, with a 9.8% response rate and manageable toxicity. Full article

(This article belongs to the Special Issue Clinical Development of Immune Checkpoint Inhibitors for Cancers)

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11 pages, 1315 KiB

Open AccessCommunication

Survival of Patients Treated with Antibiotics and Immunotherapy for Cancer: A Systematic Review and Meta-Analysis

by Fausto Petrelli, Alessandro Iaculli, Diego Signorelli, Antonio Ghidini, Lorenzo Dottorini, Gianluca Perego, Michele Ghidini, Alberto Zaniboni, Stefania Gori and Alessandro Inno

J. Clin. Med. 2020, 9(5), 1458; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9051458 - 13 May 2020

Cited by 27 | Viewed by 3070

Abstract

Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumours treated with ICIs. PubMed, the Cochrane Library and Embase were searched from inception until September 2019 for observational or prospective studies reporting the prognoses of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI) and an HR > 1 associated with a worse outcome in ABs users compared to AB non-users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51–2.84; p < 0.01). Similarly, PFS was inferior in AB users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22–1.93; p < 0.01). In cancer patients treated with ICIs, AB use significantly reduced OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed. Full article

(This article belongs to the Special Issue Clinical Development of Immune Checkpoint Inhibitors for Cancers)

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Review

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29 pages, 1737 KiB

Open AccessReview

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

by Leila Motedayen Aval, James E. Pease, Rohini Sharma and David J. Pinato

J. Clin. Med. 2020, 9(10), 3323; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9103323 - 16 Oct 2020

Cited by 126 | Viewed by 12834

Abstract

Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy. Full article

(This article belongs to the Special Issue Clinical Development of Immune Checkpoint Inhibitors for Cancers)

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23 pages, 285 KiB

Open AccessReview

Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies

by Anita Mazloom, Nima Ghalehsari, Victor Gazivoda, Neil Nimkar, Sonal Paul, Peter Gregos, Janice Rateshwar and Uqba Khan

J. Clin. Med. 2020, 9(8), 2533; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9082533 - 6 Aug 2020

Cited by 15 | Viewed by 3904

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer. Full article

(This article belongs to the Special Issue Clinical Development of Immune Checkpoint Inhibitors for Cancers)

26 pages, 607 KiB

Open AccessReview

Combining Immune Checkpoint Inhibitors with Anti-Angiogenic Agents

by Paola Ciciola, Priscilla Cascetta, Cataldo Bianco, Luigi Formisano and Roberto Bianco

J. Clin. Med. 2020, 9(3), 675; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9030675 - 3 Mar 2020

Cited by 58 | Viewed by 6736

Abstract

Immunotherapy has recently emerged as a novel strategy for treating different types of solid tumors, with promising results. However, still a large fraction of patients do not primarily respond to such approaches, and even responders sooner or later develop resistance. Moreover, immunotherapy is a promising strategy for certain malignancies but not for others, with this discrepancy having been attributed to a more immunogenic microenvironment of some tumors. As abnormal and augmented tumor vessels often occur in cancerogenesis, anti-angiogenic drugs have already demonstrated their effectiveness both in preclinical and in clinical settings. By targeting abnormal formation of tumor vessels, anti-angiogenetic agents potentially result in an enhanced infiltration of immune effector cells. Moreover, crosstalks downstream of the immune checkpoint axis and vascular endothelial growth factor receptor (VEGFR) signaling may result in synergistic effects of combined treatment in tumor cells. In this review, we will describe and discuss the biological rationale of a combined therapy, underlying the modification in tumor microenvironment as well as in tumor cells after exposure to checkpoint inhibitors and anti-angiogenic drugs. Moreover, we will highlight this strategy as a possible way for overcoming drug resistance. By first discussing potential prognostic and predictive factors for combined treatment, we will then turn to clinical settings, focusing on clinical trials where this strategy is currently being investigated. Full article

(This article belongs to the Special Issue Clinical Development of Immune Checkpoint Inhibitors for Cancers)

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