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Lee SW, Yun JS, Kim YJ, Jeong S, Noh JE, Kim HO, Cho HJ, Park CK, Oh IJ, Cho JH. Progressive accumulation of circulating CD27 -CD28 - effector/memory CD8 + T cells in patients with lung cancer blunts responses to immune checkpoint inhibitor therapy. Exp Mol Med 2025:10.1038/s12276-025-01448-7. [PMID: 40307573 DOI: 10.1038/s12276-025-01448-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 12/30/2024] [Accepted: 03/03/2025] [Indexed: 05/02/2025] Open
Abstract
Suppression of tumor-reactive CD8+ T cells is common within the tumor microenvironment. However, little is known about how tumors systemically affect the overall CD8+ T cell compartment. Here we demonstrate that peripheral blood CD8+ T cells from patients with lung cancer showed altered compositions particularly within CD45RA-CCR7- effector memory subpopulation. Specifically, patients with lung cancer exhibited increased frequency of more differentiated effector memory cells, which are less susceptible to T cell-receptor-induced proliferation. Further analysis using single-cell RNA sequencing revealed that these alterations were correlated with reduced quiescence and increased spontaneous activation at a systemic level, indicative of homeostatic dysregulation of the entire CD8+ T cell population. This phenomenon was found to be correlated with a poor clinical response to immune checkpoint inhibitor therapy across four independent cohorts, consisting of a total of 224 patients with lung cancer. These findings suggest that lung cancers continue to counteract potentially tumor-reactive CD8+ T cells by inducing homeostatic dysregulation of the entire CD8+ T cell compartment systematically.
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Affiliation(s)
- Sung-Woo Lee
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Ju Sik Yun
- Department of Thoracic and Cardiovascular Surgery, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea
| | - Young Ju Kim
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Saei Jeong
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jeong Eun Noh
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Hee-Ok Kim
- Selecxine Inc., Seoul, Republic of Korea
| | - Hyun-Ju Cho
- Department of Internal Medicine, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea
| | - Cheol-Kyu Park
- Department of Internal Medicine, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea
| | - In-Jae Oh
- Department of Internal Medicine, Chonnam National University Medical School, Hwasun Hospital, Gwangju, Republic of Korea.
| | - Jae-Ho Cho
- Department of Microbiology and Immunology, Chonnam National University Medical School, Gwangju, Republic of Korea.
- Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Gwangju, Republic of Korea.
- National Immunotherapy Innovation Center, Chonnam National University Medical School, Gwangju, Republic of Korea.
- BioMedical Sciences Graduate Program, Chonnam National University Medical School, Gwangju, Republic of Korea.
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Hong E, Sun Y, Qin Y, Zhao W, Qin Y, Li X, Zhang L. Building a Risk Scoring Model for ARDS in Lung Adenocarcinoma Patients Using Machine Learning Algorithms. J Cell Mol Med 2024; 28:e70280. [PMID: 39656479 PMCID: PMC11629804 DOI: 10.1111/jcmm.70280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/17/2024] [Accepted: 10/22/2024] [Indexed: 12/12/2024] Open
Abstract
Lung adenocarcinoma (LUAD), the predominant form of non-small-cell lung cancer, is frequently complicated by acute respiratory distress syndrome (ARDS), which increases mortality risks. Investigating the prognostic implications of ARDS-related genes in LUAD is crucial for improving clinical outcomes. Data from TCGA, GEO and GTEx were used to identify 276 ARDS-related genes in LUAD via differential expression analysis. Univariate Cox regression, consensus clustering and machine learning algorithms were used to develop a prognostic risk scoring model. Functional enrichment, immune infiltration analyses, copy number variations and mutational burdens were examined, and the results were validated at the single-cell level. ARDS-related genes significantly impact the prognosis of LUAD patients. A machine learning-based risk scoring model accurately predicted survival rates. Functional enrichment and immune infiltration analyses revealed that these genes are primarily involved in cell cycle regulation and immune cell infiltration. Single-cell expression data supported these findings, and the assessments of copy number variations and mutational burdens highlighted distinct genetic characteristics. This study establishes the prognostic relevance of ARDS-associated genes in LUAD and provides potential biomarkers for personalized therapy and prognosis. Future studies will validate these findings and explore their clinical applications.
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Affiliation(s)
- Erchun Hong
- Department of Emergency Medicine, Bengbu Third People's HospitalBengbu Medical UniversityBengbuAnhui ProvinceChina
| | - Yunyun Sun
- Department of Neurology, Bengbu Third People's HospitalBengbu Medical UniversityBengbuAnhui ProvinceChina
| | - Yongming Qin
- Department of Emergency Medicine, Bengbu Third People's HospitalBengbu Medical UniversityBengbuAnhui ProvinceChina
| | - Wenjun Zhao
- Department of Emergency Medicine, Bengbu Third People's HospitalBengbu Medical UniversityBengbuAnhui ProvinceChina
| | - Yanzi Qin
- Department of PathologyBengbu Medical UniversityBengbuAnhui ProvinceChina
| | - Xincan Li
- Department of Emergency Medicine, Bengbu Third People's HospitalBengbu Medical UniversityBengbuAnhui ProvinceChina
| | - Liang Zhang
- Department of Emergency Medicine, Bengbu Third People's HospitalBengbu Medical UniversityBengbuAnhui ProvinceChina
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La-Beck NM, Owoso J. Updates and emerging trends in the management of immune-related adverse events associated with immune checkpoint inhibitor therapy. Asia Pac J Oncol Nurs 2024; 11:100549. [PMID: 39234578 PMCID: PMC11372807 DOI: 10.1016/j.apjon.2024.100549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 06/26/2024] [Indexed: 09/06/2024] Open
Abstract
The rapidly expanding class of therapies targeting immune checkpoints for the treatment of various cancers now includes 8 clinically approved agents: a lymphocyte-activation gene 3 (LAG-3) inhibitor (relatlimab), a cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitor (ipilimumab), three programmed cell death protein 1 (PD-1) inhibitors (nivolumab, pembrolizumab and cemiplimab), and three programmed cell death ligand-1 (PD-L1) inhibitors (atezolizumab, durvalumab, and avelumab). Previously, we reviewed the mechanisms of immune-related adverse events (irAEs), strategies for management of irAEs, and highlighted similarities as well as differences amongst clinical guidelines from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC), and European Society for Medical Oncology (ESMO). Herein, we provide an update that includes discussion of changes to these clinical guidelines since our last review, the new LAG-3 targeted agents, emerging patterns of irAEs, and new directions for improved monitoring and treatment of irAEs that could incorporate interdisciplinary pharmacist-led teams, artificial intelligence, and pharmacogenomics.
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Affiliation(s)
- Ninh M La-Beck
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA
| | - Jesuwapelumi Owoso
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA
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Orillard E, Adhikari A, Malouf RS, Calais F, Marchal C, Westeel V. Immune checkpoint inhibitors plus platinum-based chemotherapy compared to platinum-based chemotherapy with or without bevacizumab for first-line treatment of older people with advanced non-small cell lung cancer. Cochrane Database Syst Rev 2024; 8:CD015495. [PMID: 39136258 PMCID: PMC11320659 DOI: 10.1002/14651858.cd015495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Abstract
BACKGROUND Lung cancer is a cancer of the elderly, with a median age at diagnosis of 71. More than one-third of people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) are special antibodies that target a pathway in the immune system called the programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway. These antibodies help the immune system fight cancer cells by blocking signals that cancer cells use to avoid being attacked by the immune system. ICIs have changed the treatment of people with lung cancer. In particular, for people with previously-untreated advanced non-small cell lung cancer (NSCLC), current first-line treatment now comprises ICIs plus platinum-based chemotherapy, rather than platinum-based chemotherapy alone, regardless of their PD-L1 expression status. However, as people age, their immune system changes, becoming less effective in its T cell responses. This raises questions about how well ICIs work in older adults. OBJECTIVES To assess the effects of immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy compared to platinum-based chemotherapy (with or without bevacizumab) in treatment-naïve adults aged 65 years and older with advanced NSCLC. SEARCH METHODS We searched the Cochrane Lung Cancer Group Trial Register, CENTRAL, MEDLINE, Embase, two other trial registers, and the websites of drug regulators. The latest search date was 23 August 2023. We also checked references and searched abstracts from the meetings of seven cancer organisations from 2019 to August 2023. SELECTION CRITERIA We included randomised controlled trials (RCTs) that reported on the efficacy and safety of adding ICIs to platinum-based chemotherapy compared to platinum-based chemotherapy alone for people 65 years and older who had not previously been treated. All data emanated from international multicentre studies involving adults with histologically-confirmed advanced NSCLC who had not received any previous systemic anticancer therapy for their advanced disease. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival and treatment-related adverse events (grade 3 or higher). Our secondary outcomes were progression-free survival, objective response rate, time to response, duration of response, and health-related quality of life (HRQoL). MAIN RESULTS We included 17 primary studies, with a total of 4276 participants, in the review synthesis. We identified nine ongoing studies, and listed one study as 'awaiting classification'. Twelve of the 17 studies included people older than 75 years, accounting for 9% to 13% of their participants. We rated some studies as having 'some concerns' for risk of bias arising from the randomisation process, deviations from the intended interventions, or measurement of the outcome. The overall GRADE rating for the certainty of the evidence ranged from moderate to low because of the risk of bias, imprecision, or inconsistency. People aged 65 years and older The addition of ICIs to platinum-based chemotherapy probably increased overall survival compared to platinum-based chemotherapy alone (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.70 to 0.88; 8 studies, 2093 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events may not differ between the two treatment groups (risk ratio (RR) 1.09, 95% CI 0.89 to 1.32; 1 study, 127 participants; low-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improves progression-free survival (HR 0.61, 95% CI 0.54 to 0.68; 7 studies, 1885 participants; moderate-certainty evidence). People aged 65 to 75 years, inclusive The addition of ICIs to platinum-based chemotherapy probably improved overall survival compared to platinum-based chemotherapy alone (HR 0.75, 95% CI 0.65 to 0.87; 6 studies, 1406 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events probably increased in people treated with ICIs plus platinum-based chemotherapy compared to those treated with platinum-based chemotherapy alone (RR 1.47, 95% CI 1.02 to 2.13; 1 study, 97 participants; moderate-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improved progression-free survival (HR 0.64, 95% CI 0.57 to 0.73; 8 studies, 1466 participants; moderate-certainty evidence). People aged 75 years and older There may be no difference in overall survival in people treated with ICIs combined with platinum-based chemotherapy compared to platinum-based chemotherapy alone (HR 0.90, 95% CI 0.70 to 1.16; 4 studies, 297 participants; low-certainty evidence). No data on treatment-related adverse events were available in this age group. The effect of combination ICI and platinum-based chemotherapy on progression-free survival is uncertain (HR 0.83, 95% CI 0.51 to 1.36; 3 studies, 226 participants; very low-certainty evidence). Only three studies assessed the objective response rate. For time to response, duration of response, and health-related quality of life, we do not have any evidence yet. AUTHORS' CONCLUSIONS Compared to platinum-based chemotherapy alone, adding ICIs to platinum-based chemotherapy probably leads to higher overall survival and progression-free survival, without an increase in treatment-related adverse events (grade 3 or higher), in people 65 years and older with advanced NSCLC. These data are based on results from studies dominated by participants between 65 and 75 years old. However, the analysis also suggests that the improvements reported in overall survival and progression-free survival may not be seen in people older than 75 years.
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Affiliation(s)
- Emeline Orillard
- Department of Medical Oncology, University Hospital of Besançon, Besançon, France
- EFS, INSERM, UMR RIGHT, Université de Franche-Comté, CHU Besançon, Besançon, France
| | - Arjab Adhikari
- Internal Medicine, Ascension Saint Francis Hospital, Evanston, Illinois, USA
| | - Reem S Malouf
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - François Calais
- Bibliothèque Universitaire de Santé, Université de Franche-Comté, Besançon, France
| | | | - Virginie Westeel
- EFS, INSERM, UMR RIGHT, Université de Franche-Comté, CHU Besançon, Besançon, France
- Department of Chest Diseases and Thoracic Oncology, University Hospital of Besançon, Besançon, France
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Tyagi S, Kumar A. Safety of immune checkpoint inhibitors: An updated comprehensive disproportionality analysis and meta-analysis. Crit Rev Oncol Hematol 2024; 200:104398. [PMID: 38810844 DOI: 10.1016/j.critrevonc.2024.104398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 03/12/2024] [Accepted: 05/21/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND The exact safety profile of Immune checkpoint inhibitors (ICIs) is unclear so far. AIM The aim of the current study is to analyse the safety profile of ICIs in cancer patients. METHODOLOGY The updated comprehensive disproportionality analysis of post-marketing data using the FAERS database and meta-analysis of randomized clinical trials (RCTs) was conducted. Disproportionality measures were calculated in terms of PRR associated with chi-square value and ROR with 95% confidence intervals whereas overall estimate measures with 95% CIs, publication bias and heterogeneity were calculated using RevMan 5.4. The GRADE analysis was also done to check the quality of evidence for each outcome. RESULTS Various novel signals such as cholangitis, encephalitis, anuria, myelosuppression, and cachexia related to different system organ class were identified with ICIs. The sensitivity analysis results have indicated the influence of concomitant drugs on the identified signals. The meta-analysis results have shown a good safety profile of atezolizumab in non-small cell lung cancer (NSCLC) and melanoma, pembrolizumab in gastro-oesophageal cancer, urothelial cancer and head and neck squamous cell carcinoma (HNSCC), nivolumab in HNSCC as compared to the non-ICI group. CONCLUSION The safety of ICIs is dependent on their types as well as on the types of cancer.
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Affiliation(s)
- Simran Tyagi
- Department of Pharmaceutical Biotechnology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Anoop Kumar
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India.
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Pini F, Grigoriu B, Lieveke A, Meert AP. Management and outcome of oncological patients under immune checkpoint inhibitors presenting at the emergency department. Emerg Med J 2024; 41:417-421. [PMID: 38688713 DOI: 10.1136/emermed-2023-213605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 04/16/2024] [Indexed: 05/02/2024]
Abstract
INTRODUCTION With the rising use of immune checkpoint inhibitors (ICIs) in oncology, emergency physicians are increasingly confronted with their immune-related adverse events (irAEs). We described the types of irAEs presenting to the ED of a Belgian cancer centre and determined associations with the development of an irAE and other patient's characteristics. Secondary objectives describe the therapeutic management and determine 7 and 30-day mortality. METHODS A retrospective chart review of ED visits of patients on ICI from 15 December 2016 to 6 December 2020 was performed. Clinical presentation, cancer characteristics and type of ICI were extracted by a single abstractor. We recorded any suspicion of irAE in the ED and confirmation of an irAE was based on the patient's oncologist report. Outcome was based on mortality at date of last follow-up. RESULTS 227 patients on ICI presented to the ED, with a total of 451 visits. 54 (12%) of the visits resulted in a diagnosis of irAE. Four clinical features were associated with an irAE: gastrointestinal complaints (p=0.01), skin rashes (p=0.02), acute renal failure (p=0.002) and abnormal liver function (p=0.04). An irAE was also associated with three different factors: a cancer status in remission (OR=5.33, 95% CI 2.57 to 11.04), a combination of two ICIs (OR=4.43, 95% CI 2.09 to 9.42) and a medical history of irAE (OR=2.44, 95% CI 1.27 to 4.68). 30-day mortality was lower in the irAE group (0%) than in the non-irAE group (13%, 95% CI 9% to 19%). CONCLUSIONS Oncological patients under ICI presenting in the ED are more likely to have an irAE if they present with gastrointestinal and dermatological complaints, acute renal failure and abnormal liver function. This is also true for patients with any history of irAE, a concomitant use of two ICIs and with a cancer status in remission.
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Guven DC, Martinez-Cannon BA, Testa GD, Martins JC, Velasco RN, Kalsi T, Gomes F. Immunotherapy use in older adults with cancer with frailty: A young SIOG review paper. J Geriatr Oncol 2024; 15:101742. [PMID: 38472009 DOI: 10.1016/j.jgo.2024.101742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 02/04/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024]
Abstract
Immune checkpoint inhibitors (ICIs) became a treatment option in most tumor types and improved survival in patients with cancer in the last decade. Older patients with cancer are underrepresented in the pivotal clinical trials with ICIs. Older patients with cancer often have significant comorbidities and geriatric syndromes like frailty, which can complicate cancer care and treatment decisions. Frailty is among the most prevalent geriatric syndromes in patients with cancer and could lead to inferior survival and a higher risk of complications in patients treated with chemotherapy. However, the effect of frailty on the efficacy and safety of ICIs is understudied. This review focuses on the available evidence regarding the association between frailty and ICI efficacy and safety. Although the survival benefits of ICIs have generally been shown to be independent of age, the available real-world data has generally suggested higher rates of immune-related adverse events (irAEs) and treatment discontinuation in older patients. While international organizations recommend conducting a comprehensive geriatric assessment CGA to assess and address frailty before the start of anti-cancer therapies, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher is frequently used in clinical practice as synonymous with frailty, albeit with significant limitations. The available data has generally demonstrated diminished ICI efficacy in patients with an ECOG 2 or higher compared to patients with better performance status, while the incidence of high-grade irAEs were similar. Whilst evidence regarding outcomes with ICI in older patients and in those with sub-optimal performance status is growing, there is very limited data specifically evaluating the role of frailty with ICIs. These studies found a shortened overall survival, yet no evidence of a lower response rate to ICIs. These patients experienced more AEs, but they did not necessarily have a higher incidence of irAEs.
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Affiliation(s)
- Deniz Can Guven
- Medical Oncology Clinic, Health Sciences University, Elazig City Hospital, Elazig, Turkey.
| | | | - Giuseppe Dario Testa
- Division of Geriatric and Intensive Care Medicine, University of Florence and Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50139 Florence, Italy
| | | | - Rogelio N Velasco
- Clinical Trial and Research Division, Philippine Heart Center, Quezon City, Philippines
| | - Tania Kalsi
- Department of Ageing and Health, Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Fabio Gomes
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK
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Silva LGDO, Lemos FFB, Luz MS, Rocha Pinheiro SL, Calmon MDS, Correa Santos GL, Rocha GR, de Melo FF. New avenues for the treatment of immunotherapy-resistant pancreatic cancer. World J Gastrointest Oncol 2024; 16:1134-1153. [PMID: 38660642 PMCID: PMC11037047 DOI: 10.4251/wjgo.v16.i4.1134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Affiliation(s)
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana dos Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Imai H, Kijima T, Azuma K, Kishi K, Saito H, Yamaguchi T, Tanizaki J, Yoneshima Y, Fujita K, Watanabe S, Kitazono S, Fukuhara T, Hataji O, Toi Y, Mizutani H, Hamakawa Y, Maemondo M, Ohsugi T, Suzuki K, Horinouchi H, Ohe Y. First-line nivolumab plus ipilimumab with or without chemotherapy for Japanese patients with non-small cell lung cancer: LIGHT-NING study. Jpn J Clin Oncol 2024; 54:452-462. [PMID: 38271158 PMCID: PMC10999773 DOI: 10.1093/jjco/hyad195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/29/2023] [Indexed: 01/27/2024] Open
Abstract
OBJECTIVE As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.
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Affiliation(s)
- Hisao Imai
- Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan
| | - Takashi Kijima
- Department of Respiratory Medicine and Hematology, Hyogo Medical University, School of Medicine, Nishinomiya, Hyogo, Japan
| | - Koichi Azuma
- Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine, Kurume University, School of Medicine, Fukuoka, Japan
| | - Kazuma Kishi
- Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
| | - Haruhiro Saito
- Department of Thoracic Oncology, Kanagawa Cancer Center, Kanagawa, Japan
| | - Teppei Yamaguchi
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Junko Tanizaki
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasuto Yoneshima
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Fujita
- Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
| | - Satoshi Watanabe
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Satoru Kitazono
- Department of Thoracic Medical Oncology, the Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tatsuro Fukuhara
- Department of Respiratory Medicine, Miyagi Cancer Center, Miyagi, Japan
| | - Osamu Hataji
- Respiratory Center, Matsusaka Municipal Hospital, Mie, Japan
| | - Yukihiro Toi
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Miyagi, Japan
| | - Hideaki Mizutani
- Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan
| | - Yusuke Hamakawa
- Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan
| | - Makoto Maemondo
- Division of Pulmonary Medicine, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan
| | | | - Keisuke Suzuki
- Oncology Medical Affairs, Ono Pharmaceutical Co, Ltd, Osaka, Japan
| | - Hidehito Horinouchi
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yuichiro Ohe
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
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10
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Smith A, Boby JM, Benny SJ, Ghazali N, Vermeulen E, George M. Immunotherapy in Older Patients with Cancer: A Narrative Review. Int J Gen Med 2024; 17:305-313. [PMID: 38298248 PMCID: PMC10830099 DOI: 10.2147/ijgm.s435001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 01/09/2024] [Indexed: 02/02/2024] Open
Abstract
Purpose Immunotherapies have revolutionized cancer treatment; however, relatively little is known about their efficacy and toxicity in the elderly, a cohort accounting for more than half of total cancer cases. In this review, we aim to provide insight into the current knowledge base regarding the clinical utility and side effects of immunotherapies in the geriatric population as well as identify key gaps in the literature where further research is essential. Methods We conducted a rapid critical review of available literature, focusing on studies reporting on use of immunotherapy in cancer patients aged ≥65 years. The review assessed studies that included different types of cancer, were of multiple study types (although predominantly retrospective), had different study duration, and reported different outcomes of interest. Owing to this heterogeneity, meta-analysis and a direct comparison between studies were not feasible. Results Overall, the review findings indicate that certain malignancies have shown comparable survival rates in younger and older age groups when managed with immunotherapeutic drugs, the incidence of immunotherapy-related side effects varies only slightly by age groups, and in general there is a lack of studies on the determinants of the clinical outcomes of immunotherapy in or including geriatric patients. Conclusion Enhanced clinical benefits along with better tolerability associated with immunotherapies make it an attractive alternative to conventional chemotherapeutic drugs, especially in elderly patients. There is currently a limited number of studies assessing the clinical outcomes of immunotherapies, particularly in the elderly. Overall, our findings reflect a need for further prospective studies focussing on geriatric patients representative of the real-life population, in order to derive a more precise understanding of the clinical utility, toxicity profile, and cost-effectiveness of immune checkpoint inhibitors in older patients with cancer.
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Affiliation(s)
- Alexandra Smith
- Tamworth Hospital, Hunter New England Local Health District (NSW Health), Tamworth, NSW, Australia
| | | | | | | | - Elke Vermeulen
- Tamworth Hospital, Hunter New England Local Health District (NSW Health), Tamworth, NSW, Australia
| | - Mathew George
- Tamworth Hospital, Hunter New England Local Health District (NSW Health), Tamworth, NSW, Australia
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11
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Hou C, Wang Z, Lu X. Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors. CANCER PATHOGENESIS AND THERAPY 2024; 2:24-30. [PMID: 38328711 PMCID: PMC10846300 DOI: 10.1016/j.cpt.2023.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/01/2023] [Accepted: 08/05/2023] [Indexed: 02/09/2024]
Abstract
Immune checkpoint inhibitors (ICIs) are employed in immunotherapeutic applications for patients with weakened immune systems and can improve the ability of T cells to kill cancer cells. Although ICIs can potentially treat different types of cancers in various groups of patients, their effectiveness may differ among older individuals. The reason ICIs are less effective in older adults is not yet clearly understood, but age-related changes in the immune system, such as immunosenescence and inflammation, may play a role. Therefore, this review focuses on recent advances in understanding the effects of immunosenescence and inflammation on the efficacy of ICIs.
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Affiliation(s)
- Chuandong Hou
- Medical School of Chinese PLA, Beijing 100853, China
- Department of Hematology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
| | - Zining Wang
- Medical School of Chinese PLA, Beijing 100853, China
- Department of Hematology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
| | - Xuechun Lu
- Department of Hematology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
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12
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Ebrahimi S, Habibzadeh A, Khojasteh-Kaffash S, Valizadeh P, Samieefar N, Rezaei N. Immune checkpoint inhibitors therapy as the game-changing approach for pediatric lymphoma: A brief landscape. Crit Rev Oncol Hematol 2024; 193:104225. [PMID: 38049077 DOI: 10.1016/j.critrevonc.2023.104225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/06/2023] Open
Abstract
Lymphoma is known as the third most common malignancy in children, and its prevalence and mortality are increasing. Common treatments, including chemotherapy, radiotherapy, and also surgery, despite their efficacy, have many side effects and, have a high chance of disease relapse. Immune Checkpoint Inhibitors (ICIs) offer a promising alternative with potentially fewer risks of relapse and toxicity. This review article aims to investigate the efficacy and safety of ICIs, either as monotherapy or in combination, for pediatric lymphoma patients. ICIs have revolutionized cancer treatment in recent years and have shown remarkable results in several adult cancers. However, their efficacy in treating pediatrics requires further investigation. Nevertheless, some ICIs, including nivolumab, pembrolizumab, and ipilimumab, have demonstrated encouraging outcomes. ICIs therapy is not without risks and can cause side effects, including rash, itching, vitiligo, abdominal pain, diarrhea, dysphagia, epigastric pain, nausea, vomiting, thyroid, and pituitary dysfunction. Overall, this review article highlights the potential benefits and risks of ICIs in treating pediatric lymphoma.
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Affiliation(s)
- Sara Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Adrina Habibzadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran
| | - Soroush Khojasteh-Kaffash
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Student Research Committee, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Parya Valizadeh
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Noosha Samieefar
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
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13
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Sahin E, Cabuk D, Tuncer Kuru F, Yazici A. Atezolizumab-induced myositis in a patient with small-cell lung cancer. J Oncol Pharm Pract 2024; 30:220-224. [PMID: 37750202 DOI: 10.1177/10781552231203190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
OBJECTIVE Myositis, an inflammatory disease affecting muscles, is a rare and potentially fatal immune-related adverse event associated with immune checkpoint inhibitors. There are limited data on its clinical features and management. CASE PRESENTATION Atezolizumab, in combination with etoposide and carboplatin, was initiated in the patient diagnosed with metastatic small-cell lung cancer. After four cycles, maintenance atezolizumab was initiated. At the third visit of the maintenance therapy, the patient reported weakness, edema, and tightness in the muscles that had progressed over the course of a week. Mild solid-food dysphagia was also observed. Neutrophilic leukocytosis with elevated creatine phosphokinase (9234 U/L), erythrocyte sedimentation rate (111 mm/h), and transaminase levels were observed. A diagnosis of myositis was considered based on clinical findings. Atezolizumab was omitted and an oral 0.5 mg/kg/day dose of methylprednisolone was administered. The myositis resolved within 10 days. During the treatment of myositis, the patient underwent prophylactic cranial irradiation. The steroid dose was tapered off within 35 days and then atezolizumab was restarted. CONCLUSION The literature contains only a few case reports about atezolizumab-induced myositis, highlighting the challenges in defining its clinical features and management. Prompt diagnosis and treatment are crucial to prevent severe complications, such as myocarditis or respiratory muscle paralysis.
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Affiliation(s)
- Elif Sahin
- Department of Medical Oncology, Kocaeli University Faculty of Medicine, Izmit, Turkey
| | - Devrim Cabuk
- Department of Medical Oncology, Kocaeli University Faculty of Medicine, Izmit, Turkey
| | - Fatma Tuncer Kuru
- Department of Rheumatology, Kocaeli University Faculty of Medicine, Izmit, Turkey
| | - Ayten Yazici
- Department of Rheumatology, Kocaeli University Faculty of Medicine, Izmit, Turkey
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14
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Bulaon CJI, Khorattanakulchai N, Rattanapisit K, Sun H, Pisuttinusart N, Strasser R, Tanaka S, Soon-Shiong P, Phoolcharoen W. Antitumor effect of plant-produced anti-CTLA-4 monoclonal antibody in a murine model of colon cancer. FRONTIERS IN PLANT SCIENCE 2023; 14:1149455. [PMID: 37711295 PMCID: PMC10497774 DOI: 10.3389/fpls.2023.1149455] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 08/16/2023] [Indexed: 09/16/2023]
Abstract
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an immune checkpoint regulator exclusively expressed on T cells that obstructs the cell's effector functions. Ipilimumab (Yervoy®), a CTLA-4 blocking antibody, emerged as a notable breakthrough in modern cancer treatment, showing upfront clinical benefits in multiple carcinomas. However, the exhilarating cost of checkpoint blockade therapy is discouraging and even utmost prominent in developing countries. Thereby, affordability of cancer care has become a point of emphasis in drug development pipelines. Plant expression system blossomed as a cutting-edge platform for rapid, facile to scale-up, and economical production of recombinant therapeutics. Here, we describe the production of an anti-CTLA-4 2C8 antibody in Nicotiana benthamiana. ELISA and bio-layer interferometry were used to analyze antigen binding and binding kinetics. Anticancer responses in vivo were evaluated using knocked-in mice implanted with syngeneic colon tumor. At 4 days post-infiltration, the antibody was transiently expressed in plants with yields of up to 39.65 ± 8.42 μg/g fresh weight. Plant-produced 2C8 binds to both human and murine CTLA-4, and the plant-produced IgG1 also binds to human FcγRIIIa (V158). In addition, the plant-produced 2C8 monoclonal antibody is as effective as Yervoy® in inhibiting tumor growth in vivo. In conclusion, our study underlines the applicability of plant platform to produce functional therapeutic antibodies with promising potential in cancer immunotherapy.
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Affiliation(s)
- Christine Joy I. Bulaon
- Center of Excellence in Plant-Produced Pharmaceuticals, Chulalongkorn University, Bangkok, Thailand
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Graduate Program of Pharmaceutical Sciences and Technology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | | | | | | | - Nuttapat Pisuttinusart
- Center of Excellence in Plant-Produced Pharmaceuticals, Chulalongkorn University, Bangkok, Thailand
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Graduate Program of Pharmaceutical Sciences and Technology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Richard Strasser
- Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Shiho Tanaka
- ImmunityBio, Inc., Culver City, CA, United States
| | | | - Waranyoo Phoolcharoen
- Center of Excellence in Plant-Produced Pharmaceuticals, Chulalongkorn University, Bangkok, Thailand
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
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15
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Bronte G, Cosi DM, Magri C, Frassoldati A, Crinò L, Calabrò L. Immune Checkpoint Inhibitors in "Special" NSCLC Populations: A Viable Approach? Int J Mol Sci 2023; 24:12622. [PMID: 37628803 PMCID: PMC10454231 DOI: 10.3390/ijms241612622] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/23/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most pivotal phase III studies; this precludes the generalization of ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common "special" NSCLC subpopulations.
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Affiliation(s)
- Giuseppe Bronte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica Delle Marche, Via Tronto 10/A, 60121 Ancona, Italy
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), 60124 Ancona, Italy
| | | | - Chiara Magri
- Department of Oncology, University Hospital of Ferrara, 44124 Cona, Italy
| | | | - Lucio Crinò
- Department of Medical Oncology, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Luana Calabrò
- Department of Oncology, University Hospital of Ferrara, 44124 Cona, Italy
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
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16
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Lee YH, Chou XY, Lai YH, Liang YH, Hung CT, Hsaio CC, Gao ZX. Decisional conflict and its determinants among patients with cancer undergoing immunotherapy combined with chemotherapy or targeted therapy: a cross-sectional study. Sci Rep 2023; 13:12715. [PMID: 37543690 PMCID: PMC10404258 DOI: 10.1038/s41598-023-39280-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 07/22/2023] [Indexed: 08/07/2023] Open
Abstract
Decisional conflict might occur during shared decision-making (SDM) because immunotherapy is a rather novel treatment option for patients with cancer. To explore the prevalence and severity of physical and psychological symptoms and the effort invested in SDM in relation to decisional conflict among patients with cancer undergoing immunotherapy combined with chemotherapy or targeted therapy. This was a cross-sectional survey study. The SURE version of the Decisional Conflict Scale was used to screen cancer patients' decisional conflict status. Demographic or clinical characteristics, physical symptoms and psychological distress; efforts invested in the SDM process were also assessed as potential factors related to decisional conflict. One hundred seventeen patients surveyed, the prevalence of fatigue (79.5%), sleep disturbance (78.6%), poor appetite (67.5%), and pain (58.1%) symptoms were high and the severity was at moderate levels. The prevalence of pruritus (40.2%), rash (34.2%), dry skin (41.9%), and diarrhea (17.1%) symptoms were low and the severity was at mild levels. 65.8% of patients reported uncertainty, with mild to moderate levels. Furthermore, 97.4% of the patients made some effort in SDM, and the effort level was moderate (mean: 5.56 ± 2.02). 64.1% of patients were certain that immunotherapy was the best option. Age, uncertainty, and effort in the SDM process were major factors related to decisional conflict. We observed that older patients (age: ≥ 65) and those with higher uncertainty levels and less effort in SDM reported higher levels of decisional conflict. Future studies should explore older patients' decisional related needs of immunotherapy. Interventions should be designed to reduce the uncertainty experienced by patients with cancer and enhance their understanding of immunotherapy to enable them to take more effort in the SDM process.
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Affiliation(s)
- Yun-Hsiang Lee
- School of Nursing, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan.
| | - Xiao-Yin Chou
- Department of Nursing, Deh Yu College of Nursing and Health, Keelung City, Taiwan
| | - Yeur-Hur Lai
- School of Nursing, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan
- Department of Nursing, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yi-Hsin Liang
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Tai Hung
- Department of Nursing, Mackay Medical College, New Taipei City, Taiwan
| | - Chu-Chi Hsaio
- Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan
| | - Zi-Xuan Gao
- Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan
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17
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Dabiri H, Safarzadeh Kozani P, Habibi Anbouhi M, Mirzaee Godarzee M, Haddadi MH, Basiri M, Ziaei V, Sadeghizadeh M, Hajizadeh Saffar E. Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies. Biomark Res 2023; 11:67. [PMID: 37403182 DOI: 10.1186/s40364-023-00509-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/09/2023] [Indexed: 07/06/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cells and natural killer (NK) cells are genetically engineered immune cells that can detect target antigens on the surface of target cells and eliminate them following adoptive transfer. Recent progress in CAR-based therapies has led to outstanding clinical success in certain patients with leukemias and lymphomas and offered therapeutic benefits to those resistant to conventional therapies. The universal approach to stable CAR transgene delivery into the T/NK cells is the use of viral particles. Such approaches mediate semi-random transgene insertions spanning the entire genome with a high preference for integration into sites surrounding highly-expressed genes and active loci. Regardless of the variable CAR expression level based on the integration site of the CAR transgene, foreign integrated DNA fragments may affect the neighboring endogenous genes and chromatin structure and potentially change a transduced T/NK cell behavior and function or even favor cellular transformation. In contrast, site-specific integration of CAR constructs using recent genome-editing technologies could overcome the limitations and disadvantages of universal random gene integration. Herein, we explain random and site-specific integration of CAR transgenes in CAR-T/NK cell therapies. Also, we tend to summarize the methods for site-specific integration as well as the clinical outcomes of certain gene disruptions or enhancements due to CAR transgene integration. Also, the advantages and limitations of using site-specific integration methods are discussed in this review. Ultimately, we will introduce the genomic safe harbor (GSH) standards and suggest some appropriate safety prospects for CAR integration in CAR-T/NK cell therapies.
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Affiliation(s)
- Hamed Dabiri
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Pooria Safarzadeh Kozani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Mohadeseh Mirzaee Godarzee
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | | | - Mohsen Basiri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Vahab Ziaei
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ensiyeh Hajizadeh Saffar
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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18
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Dabiri H, Safarzadeh Kozani P, Habibi Anbouhi M, Mirzaee Godarzee M, Haddadi MH, Basiri M, Ziaei V, Sadeghizadeh M, Hajizadeh Saffar E. Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies. Biomark Res 2023; 11:67. [DOI: https:/doi.org/10.1186/s40364-023-00509-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/09/2023] [Indexed: 09/15/2023] Open
Abstract
AbstractChimeric antigen receptor (CAR) T cells and natural killer (NK) cells are genetically engineered immune cells that can detect target antigens on the surface of target cells and eliminate them following adoptive transfer. Recent progress in CAR-based therapies has led to outstanding clinical success in certain patients with leukemias and lymphomas and offered therapeutic benefits to those resistant to conventional therapies. The universal approach to stable CAR transgene delivery into the T/NK cells is the use of viral particles. Such approaches mediate semi-random transgene insertions spanning the entire genome with a high preference for integration into sites surrounding highly-expressed genes and active loci. Regardless of the variable CAR expression level based on the integration site of the CAR transgene, foreign integrated DNA fragments may affect the neighboring endogenous genes and chromatin structure and potentially change a transduced T/NK cell behavior and function or even favor cellular transformation. In contrast, site-specific integration of CAR constructs using recent genome-editing technologies could overcome the limitations and disadvantages of universal random gene integration. Herein, we explain random and site-specific integration of CAR transgenes in CAR-T/NK cell therapies. Also, we tend to summarize the methods for site-specific integration as well as the clinical outcomes of certain gene disruptions or enhancements due to CAR transgene integration. Also, the advantages and limitations of using site-specific integration methods are discussed in this review. Ultimately, we will introduce the genomic safe harbor (GSH) standards and suggest some appropriate safety prospects for CAR integration in CAR-T/NK cell therapies.
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19
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Deng H, Deng J, Lin X, Guan W, Lin Z, Qiu Y, Yang Y, Wu J, Qiu G, Sun N, Zhou M, Deng J, Xie X, Xie Z, Liu M, Qin Y, Zhou Y, Zhou C. A Risk-Scoring Model for Severe Checkpoint Inhibitor-Related Pneumonitis: A Case-Control Study. Clin Drug Investig 2023; 43:347-357. [PMID: 37097608 DOI: 10.1007/s40261-023-01267-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND AND OBJECTIVE Checkpoint inhibitor-related pneumonitis (CIP) is one of the most common serious and fatal adverse events associated with immune checkpoint inhibitors (ICIs). The study sought to identify risk factors of all-grade and severe CIP and to construct a risk-scoring model specifically for severe CIP. METHODS This observational, retrospective case-control study involved 666 lung cancer patients who received ICIs between April 2018 and March 2021. The study analyzed patient demographic, preexisting lung diseases, and the characteristics and treatment of lung cancer to determine the risk factors for all-grade and severe CIP. A risk score for severe CIP was developed and validated in a separate patient cohort of 187 patients. RESULTS Among 666 patients, 95 patients were afflicted with CIP, of which 37 were severe cases. Multivariate analysis revealed age ≥ 65 years, current smoking, chronic obstructive pulmonary disease, squamous cell carcinoma, prior thoracic radiotherapy, and extra-thoracic radiotherapy during ICI were independently associated with CIP events. Five factors, emphysema (odds ratio [OR] 2.87), interstitial lung disease (OR 4.76), pleural effusion (OR 3.00), history of radiotherapy during ICI (OR 4.30), and single-agent immunotherapy (OR 2.44) were independently associated with severe CIP and were incorporated into a risk-score model (score ranging 0-17). The area under the model receiver operating characteristic curve for the model was 0.769 in the development cohort and 0.749 in the validation cohort. CONCLUSIONS The simple risk-scoring model may predict severe CIP in lung cancer patients receiving ICIs. For patients with high scores, clinicians should use ICIs with caution or strengthen the monitoring of these patients.
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Affiliation(s)
- Haiyi Deng
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Jiating Deng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xinqing Lin
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Wenhui Guan
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Ziying Lin
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanli Qiu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yilin Yang
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Jianhui Wu
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Guihuan Qiu
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Ni Sun
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Maolin Zhou
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Jiaxi Deng
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Xiaohong Xie
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Zhanhong Xie
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Ming Liu
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Yinyin Qin
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China
| | - Yanbin Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Chengzhi Zhou
- Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China.
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20
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Spagnuolo A, Gridelli C. The Role of Immunotherapy in the First-Line Treatment of Elderly Advanced Non-Small Cell Lung Cancer. Cancers (Basel) 2023; 15:cancers15082319. [PMID: 37190247 DOI: 10.3390/cancers15082319] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/20/2023] [Accepted: 04/01/2023] [Indexed: 05/17/2023] Open
Abstract
Immune checkpoint inhibitors have changed the history of NSCLC treatment by becoming, alone or in combination with platinum-based chemotherapy, a mainstay of first-line therapy for advanced NSCLC. This increasingly dictates the identification of predictive biomarkers of response that can guide patient selection, in order to rationalize and personalize therapies, particularly in elderly patients. Immunotherapy in these patients raises questions of efficacy and tolerability related to aging, which is accompanied by a progressive decline in various body functions. Physical, biological and psychological changes contribute to individual validity status and, preferably, 'fit' patients are generally enrolled in clinical trials. In elderly patients, especially frail and complex patients with more than one chronic disease, data are poor and specific prospective studies are needed. This review reports the main available results on the use of immune checkpoint inhibitors in older patients with advanced NSCLC, in terms of efficacy and toxicity, and aims to highlight the need to better predict which patients might benefit from immunotherapy agents by probing knowledge and integrating information on immune system changes and age-related physiopathological modifications.
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Affiliation(s)
- Alessia Spagnuolo
- Division of Medical Oncology, 'S. G. Moscati' Hospital, 83100 Avellino, Italy
| | - Cesare Gridelli
- Division of Medical Oncology, 'S. G. Moscati' Hospital, 83100 Avellino, Italy
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21
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Khan M, Du K, Ai M, Wang B, Lin J, Ren A, Chen C, Huang Z, Qiu W, Yuan Y, Tian Y. PD-L1 expression as biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in metastatic triple negative breast cancer: A systematic review and meta-analysis. Front Immunol 2023; 14:1060308. [PMID: 36949944 PMCID: PMC10027008 DOI: 10.3389/fimmu.2023.1060308] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Background Inhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in patients positive for PD-L1 expression. Negative results from the recent phase III trials (IMPassion131 and IMPassion132) have raises questions on the efficacy of PD-1/PD-L1 checkpoint inhibitors and the predictive value of PD-L1 expression. Here we attempt to systematically analyze the biomarker value of PD-L1 expression for predicting the response of PD-1/PD-L1 checkpoint inhibitors in mTNBC. Materials and methods PubMed database was searched until Dec 2021 for studies evaluating PD-1/PD-L1 checkpoint inhibitors plus/minus chemotherapy in mTNBC. Outcome of interest included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Review Manager (RevMan) version 5.4. was used for data-analysis. Results In total, 20 clinical trials comprising 3962 mTNBC patients (ICT: 2665 (67%); CT: 1297 (33%) were included in this study. Overall ORR was 22% (95%CI, 14-30%) and significant improvement was observed for PD-L1+ patients (ORR 1.78 [95%CI, 1.45-2.19], p<0.00001) as compared to PD-L1- cohort. Pooled outcome also indicated a significant 1-year PFS and 2-year OS advantage for patients with PD-L1 expression (1-year PFS: ORR 1.39 [95%CI, 1.04-1.85], p=0.02; I2 = 0%; 2-year OS: (ORR 2.47 [95%CI, 1.30-4.69], p=0.006; I2 = 63%). Subgroup analysis indicated that PD-L1 expression can successfully predict tumor response and 2-year OS benefit in mTNBC patients regardless of the type of investigating agent, line of treatment administration, and to some extent the type of treatment. Biomarker ability of PD-L1 expression to predict 1-year PFS was slightly better with pembrolizumab (p=0.09) than atezolizumab (p=0.18), and significantly better when treatment was administered in the first-line setting (OR 1.38 [95%CI, 1.02-1.87], p=0.04) and chemotherapy was added (OR 1.38 [95%CI, 1.02-1.86], p=0.03). Immune-related toxicity of any grade and grade≥3 was 39% (95%CI, 26%-52%) and 10% (95%CI, 8%-13%), respectively. Conclusions PD-L1 expression can predict objective response rate and 2-year OS in mTNBC patients receiving PD-1/PD-L1 checkpoint inhibitors. One-year PFS is also predicted in selected patients. PD-L1 expression can be a useful biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in mTNBC.
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Affiliation(s)
- Muhammad Khan
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Kunpeng Du
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Meiling Ai
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Baiyao Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Jie Lin
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Anbang Ren
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Chengcong Chen
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Zhong Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Wenze Qiu
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Yunhong Tian
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
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22
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Rusch VW, Nicholas A, Patterson GA, Waqar SN, Toloza EM, Haura EB, Raz DJ, Reckamp KL, Merritt RE, Owen DH, Finley DJ, McNamee CJ, Blasberg JD, Garon EB, Mitchell JD, Doebele RC, Baciewicz F, Nagasaka M, Pass HI, Schulze K, Johnson A, Bunn PA, Johnson BE, Kris MG, Kwiatkowski DJ, Wistuba II, Chaft JE, Carbone DP, Lee JM. Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer. J Thorac Cardiovasc Surg 2023; 165:828-839.e5. [PMID: 36369159 PMCID: PMC10288861 DOI: 10.1016/j.jtcvs.2022.10.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/07/2022] [Accepted: 10/01/2022] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.
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Affiliation(s)
- Valerie W Rusch
- Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.
| | | | | | | | | | | | - Dan J Raz
- Cedars Sinai (previously City of Hope Comprehensive Cancer Center), Los Angeles, Calif
| | - Karen L Reckamp
- Cedars Sinai (previously City of Hope Comprehensive Cancer Center), Los Angeles, Calif
| | - Robert E Merritt
- The Ohio State Medical Center and the Pelotonia Institute for Immune Oncology, Columbus, Ohio
| | - Dwight H Owen
- The Ohio State Medical Center and the Pelotonia Institute for Immune Oncology, Columbus, Ohio
| | | | | | | | - Edward B Garon
- David Geffen School of Medicine at UCLA, Los Angeles, Calif
| | | | | | | | | | | | | | | | - Paul A Bunn
- University of Colorado Cancer Center, Aurora, Colo
| | | | - Mark G Kris
- Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
| | | | | | - Jamie E Chaft
- Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
| | - David P Carbone
- The Ohio State Medical Center and the Pelotonia Institute for Immune Oncology, Columbus, Ohio
| | - Jay M Lee
- David Geffen School of Medicine at UCLA, Los Angeles, Calif
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23
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Pollini T, Adsay V, Capurso G, Dal Molin M, Esposito I, Hruban R, Luchini C, Maggino L, Matthaei H, Marchegiani G, Scarpa A, Wood LD, Bassi C, Salvia R, Mino-Kenudson M, Maker AV. The tumour immune microenvironment and microbiome of pancreatic intraductal papillary mucinous neoplasms. Lancet Gastroenterol Hepatol 2022; 7:1141-1150. [PMID: 36057265 PMCID: PMC9844533 DOI: 10.1016/s2468-1253(22)00235-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 01/19/2023]
Abstract
Pancreatic intraductal papillary mucinous neoplasms (IPMNs) have gained substantial attention because they represent one of the only radiographically identifiable precursors of invasive pancreatic ductal adenocarcinoma. Although most of these neoplasms have low-grade dysplasia and will remain indolent, a subset of IPMNs will progress to invasive cancer. The role of the immune system in the progression of IPMNs is unclear, but understanding its role could reveal the mechanism of neoplastic progression and targets for immunotherapy to inhibit progression or treat invasive disease. The available evidence supports a shift in the immune composition of IPMNs during neoplastic progression. Although low-grade lesions contain a high proportion of effector T cells, high-grade IPMNs, and IPMNs with an associated invasive carcinoma lose the T-cell infiltrate and are characterised by a predominance of immunosuppressive elements. Several possible therapeutic strategies emerge from this analysis that are unique to IPMNs and its microbiome.
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Affiliation(s)
- Tommaso Pollini
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, USA; Department of General and Pancreatic Surgery, The Pancreas Institute, Section of Pathology University of Verona, Verona, Italy
| | - Volcan Adsay
- Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine, Istanbul, Turkey
| | - Gabriele Capurso
- Department of Pancreatobiliary Endoscopy and Endosonography, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele, Milan, Italy
| | - Marco Dal Molin
- Department of Surgery, University of Maryland Medical Center, Baltimore, MD, USA
| | - Irene Esposito
- Department of Pathology, Heinrich Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Ralph Hruban
- Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MA, USA
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology University of Verona, Verona, Italy
| | - Laura Maggino
- Department of General and Pancreatic Surgery, The Pancreas Institute, Section of Pathology University of Verona, Verona, Italy
| | - Hanno Matthaei
- Department of Surgery, University Hospital of Bonn, Bonn, Germany
| | - Giovanni Marchegiani
- Department of General and Pancreatic Surgery, The Pancreas Institute, Section of Pathology University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology University of Verona, Verona, Italy
| | - Laura D Wood
- Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MA, USA
| | - Claudio Bassi
- Department of General and Pancreatic Surgery, The Pancreas Institute, Section of Pathology University of Verona, Verona, Italy
| | - Roberto Salvia
- Department of General and Pancreatic Surgery, The Pancreas Institute, Section of Pathology University of Verona, Verona, Italy
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ajay V Maker
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
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24
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Xiang Z, Deng X, He W, Yang Q, Ni L, Dehghan Shasaltaneh M, Maghsoudloo M, Yang G, Wu J, Imani S, Wen Q. Treatment of malignant pleural effusion in non-small cell lung cancer with VEGF-directed therapy. Ann Med 2022; 54:1357-1371. [PMID: 35543207 PMCID: PMC9103356 DOI: 10.1080/07853890.2022.2071977] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) is a critical regulator of malignant pleural effusion (MPE) in non-small-cell lung cancer (NSCLC). Bevacizumab (BEV) and apatinib (APA) are novel VEGF blockers that inhibit lung cancer cell proliferation and the development of pleural effusion. METHODS In this study, we established Lewis lung cancer (LLC) xenograft mouse models to compare the therapeutic effect of APA and BEV in combination with cisplatin (CDDP) against MPE. The anti-tumour and anti-angiogenic effects of this combination therapy were evaluated by 18F-FDG PET/CT imaging, TUNEL assay and Immunohistochemistry. RESULTS The triple drug combination significantly prolonged the overall survival of the tumour-bearing mice by reducing MPE and glucose metabolism and was more effective in lowering VEGF/soluble VEGFR-2 levels in the serum and pleural exudates compared to either of the monotherapies. Furthermore, CDDP + APA + BEV promoted in vivo apoptosis and decreased microvessel density. CONCLUSIONS Mechanistically, LLC-induced MPE was inhibited by targeting the VEGF-MEK/ERK pathways. Further studies are needed to establish the synergistic therapeutic effect of these drugs in NSCLC patients with MPE.KEY MESSAGESCombined treatment of MPE with apatinib, bevacizumab and cisplatin can prolong the survival time of mice, reduce the content of MPE, decrease the SUVmax of thoracic tumour tissue, down-regulate the content of VEGF and sVEGFR-2 in serum and pleural fluid, and promote the apoptosis of tumour cells. Angiogenesis and MPE formation can be inhibited by down-regulation of HIF-1α, VEGF, VEGFR-2, MEK1 and MMP-2 molecular signalling pathway proteins.
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Affiliation(s)
- Zhangqiang Xiang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Phase 1 Clinical Trial Center, Deyang People's Hospital, Deyang, China
| | - Xiangyu Deng
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenfeng He
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qian Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Laichao Ni
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | | | - Mazaher Maghsoudloo
- Laboratory of Systems Biology and Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.,Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Gang Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, Anyue Hospital of Traditional Chinese Medicine, Second Ziyang Hospital of Traditional Chinese Medicine, Ziyang, China
| | - Jingbo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China. The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Saber Imani
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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25
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Ruiz JI, Singh G, Erck M, Geng Y, Suarez-Almazor ME, Lopez-Olivo MA. Quality and content evaluation of websites with information about immune checkpoint inhibitors: An environmental scan. PLoS One 2022; 17:e0275676. [PMID: 36215234 PMCID: PMC9550065 DOI: 10.1371/journal.pone.0275676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/21/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Trustworthy educational information for patients is critical for increasing their knowledge base and preparing them for shared decision making with clinicians. As the internet has become an important source of health information for many patients, the purpose of this study was to assess the quality and content of websites with educational content about immune checkpoint inhibitors. METHODS We performed an environmental scan of the currently available websites providing educational information for patients about immune checkpoint inhibitors. We used three search engines: Google, Bing, and Yahoo! (9/20/2021). Two independent investigators selected relevant uniform resource locators (URLs), appraised the quality of the websites, and collected their characteristics. We evaluated the accuracy, completeness, technical elements, design and aesthetics, readability, usability, and accessibility of the websites. The user experience was also evaluated. RESULTS We identified 37 websites for analysis. In 10 websites (27%), it was not possible to know the source of the information provided. Thirty-three (89%) provided a definition with a simple explanation of cancer and treatment and 30 (81%) on complications of immune checkpoint inhibitors; only seven (19%) provided information about the balance between risks and benefits. Thirty-five (95%) provided a statement of purpose. Regarding the design, all 37 (100%) had appropriate visual aspects, typography, and grammar. Thirty-six (97%) were well organized. For most of the websites (n = 35, 95%) the content was easy to find. Only two websites had a readability score of 6, while the others had higher scores. Regarding the user experience, the overall quality of websites was rated as excellent in 16 (43%), good in 14 (38%), and fair in 7 (19%). CONCLUSIONS Our findings reveal that websites with information about immune checkpoint inhibitors mostly have general information about cancer, the treatments, and adverse events. Few websites provide information about the balance between harms and benefits of treatment, costs, the source of the information, or the hierarchy of evidence. These findings identify the gap in the quality and content of websites for patients treated with immune checkpoint inhibitors and can help website creators and developers.
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Affiliation(s)
- Juan Ignacio Ruiz
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Gagandeep Singh
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, United States of America
| | - McKenna Erck
- Texas A&M University, College Station, TX, United States of America
| | - Yimin Geng
- Research Medical Library, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Maria E. Suarez-Almazor
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Maria A. Lopez-Olivo
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
- * E-mail:
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26
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Choucair K, Naqash AR, Nebhan CA, Nipp R, Johnson DB, Saeed A. Immune Checkpoint Inhibitors: The Unexplored Landscape of Geriatric Oncology. Oncologist 2022; 27:778-789. [PMID: 35781739 PMCID: PMC9438919 DOI: 10.1093/oncolo/oyac119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer is classically considered a disease of aging, with over half of all new cancer diagnoses occurring in patients over the age of 65 years. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet the participation of older adults with cancer in ICI trials has been suboptimal, particularly at the extremes of age. Despite significant improvement in treatment response and an improved toxicity profile when compared with conventional cytotoxic chemotherapies, many cancers develop resistance to ICIs, and these drugs are not free of toxicities. This becomes particularly important in the setting of older adults with cancer, who are generally frailer and harbor more comorbidities than do their younger counterparts. Immunosenescence, a concept involving age-related changes in immune function, may also play a role in differential responses to ICI treatment in older patients. Data on ICI treatment response in older adult with cancers remains inconclusive, with multiple studies revealing conflicting results. The molecular mechanisms underlying response to ICIs in older cancer patients are poorly understood, and predictors of response that can delineate responders from non-responders remain to be elucidated. In this review, we explore the unique geriatric oncology population by analyzing existing retrospective datasets, and we also sought to highlight potential cellular, inflammatory, and molecular changes associated with aging as potential biomarkers for response to ICIs.
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Affiliation(s)
- Khalil Choucair
- University of Kansas School of Medicine-Wichita, Department of Internal Medicine, Wichita, KS, USA
| | - Abdul Rafeh Naqash
- The University of Oklahoma College of Medicine, Department of Internal Medicine, Division of Hematology/Oncology; Stephenson Cancer Center, Oklahoma City, OK, USA
| | - Caroline A Nebhan
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology/Oncology, Nashville, TN, USA
| | - Ryan Nipp
- The University of Oklahoma College of Medicine, Department of Internal Medicine, Division of Hematology/Oncology; Stephenson Cancer Center, Oklahoma City, Oklahoma, USA
| | - Douglas B Johnson
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology/Oncology, Nashville, Tennessee, USA
| | - Anwaar Saeed
- Kansas University Cancer Center, Department of Medicine, Division of Medical Oncology, Kansas City, KS, USA
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27
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Levy DA, Patel JJ, Nguyen SA, Nicholas Jungbauer W, Neskey DM, Cohen EEW, Paulos CM, Kaczmar JA, Knochelmann HM, Day TA. Programmed death 1 (PD-1) and ligand (PD-L1) inhibitors in head and neck squamous cell carcinoma: A meta-analysis. World J Otorhinolaryngol Head Neck Surg 2022; 8:177-186. [PMID: 36159902 PMCID: PMC9479482 DOI: 10.1002/wjo2.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/23/2021] [Indexed: 11/23/2022] Open
Abstract
Background PD-1 and PD-L1 inhibitors have emerged as promising treatments for patients with head and neck squamous cell carcinoma (HNSCC). Methods Systematic review and meta-analysis of PD-1 and PD-L1 inhibitors in HNSCC. Outcomes: median overall survival (mOS), median progression-free survival (mPFS), Response Evaluation Criteria in Solid Tumors (RECIST) and treatment-related adverse events (TRAEs). Results Eleven trials reported data on 1088 patients (mean age: 59.9 years, range: 18-90). The total mOS was 7.97 months (range: 6.0-16.5). Mean mPFS for all studies was 2.84 months (range: 1.9-6.5). PD-1 inhibitors had a lower rate of RECIST Progressive Disease than PD-L1 inhibitors (42.61%, 95% confidence interval [CI]: 36.29-49.06 vs. 56.79%, 95% CI: 49.18-64.19, P < 0.001). The rate of TRAEs of any grade (62.7%, 95% CI: 59.8-65.6) did not differ. Conclusions Meta-analysis shows the efficacy of PD-1 and PD-L1 inhibitors in HNSCC and suggests a possible difference in certain RECIST criterion between PD-1 and PD-L1 inhibitors. Future work to investigate the clinical significance of these findings is warranted.
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Affiliation(s)
- Dylan A. Levy
- Department of Otolaryngology‐Head and Neck SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Jaimin J. Patel
- Department of Otolaryngology‐Head and Neck SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Shaun A. Nguyen
- Department of Otolaryngology‐Head and Neck SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - W. Nicholas Jungbauer
- Department of Otolaryngology‐Head and Neck SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - David M. Neskey
- Department of Otolaryngology‐Head and Neck SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Department of Cell and Molecular Pharmacology and Developmental TherapeuticsMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Ezra E. W. Cohen
- Department of Medicine, Division of Hematology‐OncologyUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Chrystal M. Paulos
- Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Department of Dermatology and Dermatologic SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - John A. Kaczmar
- Division of Hematology & OncologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Hannah M. Knochelmann
- Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Department of Dermatology and Dermatologic SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Terry A. Day
- Department of Otolaryngology‐Head and Neck SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
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Ren X, Li Y, Nishimura C, Zang X. Crosstalk between the B7/CD28 and EGFR pathways: Mechanisms and therapeutic opportunities. Genes Dis 2022; 9:1181-1193. [PMID: 35873032 PMCID: PMC9293717 DOI: 10.1016/j.gendis.2021.08.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 12/31/2022] Open
Abstract
Somatic activating mutations in the epidermal growth factor receptor (EGFR) are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer (NSCLC), metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy, but patients inevitably experience acquired resistance. Although immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types, their efficacy is limited in cancers harboring activating gene alterations of EGFR. Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3, B7x and HHLA2, is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment (TME). In this review, we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways. Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies. We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers, as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.
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Affiliation(s)
- Xiaoxin Ren
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Yixian Li
- Division of Pediatric Hematology/Oncology/Transplant and Cellular Therapy, Children's Hospital at Montefiore, Bronx, NY 10467, USA
| | - Christopher Nishimura
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA.,Department of Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA.,Department of Urology, Albert Einstein College of Medicine, New York, NY 10461, USA
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Yang W, Xuan B, Chen M, Li X, He J, Si H, Zhang Y. Comparison of Efficacy and Safety Between Immunotherapy and Docetaxel Monotherapy in NSCLC Patients. Front Oncol 2022; 12:883514. [PMID: 36033487 PMCID: PMC9399650 DOI: 10.3389/fonc.2022.883514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveMeta analysis was used to compare the efficacy and safety of immune checkpoint inhibitor and docetaxel in the treatment of non-small cell lung cancer.MethodsCNKI, CBM, PubMed, EMBASE, Cochrane Library, web of science and other databases were searched by computer, and the randomized controlled trials of immune checkpoint inhibitors and docetaxel in the treatment of NSCLC published as of February 2022 were collected. Two researchers searched independently, screened the literature and extracted the data according to the nanodischarge criteria, and used Revman5.4. The included studies were statistically analyzed, and publication bias was analyzed with Egger test in Stata12.ResultsA total of 8 RCTs were included, including 2444 cases treated with immune checkpoint inhibitors and 2097 cases treated with docetaxel. Compared with docetaxel, the overall survival (HR = 1.40, 95%CI: 1.30-1.50, P < 0.00001) and progression free survival (HR = 1.22, 95%CI: 1.13-1.32, P < 0.00001) of NSCLC treated with ICIs were longer. The risk ratio of any grade of adverse reactions (HR = 0.41, 95%CI: 0.32-0.52, P < 0.00001) and above grade III adverse reactions (HR = 0.27, 95%CI: 0.18-0.41, P < 0.00001) in the treatment of NSCLC with ICIs was lower. There was no publication bias in Egger test.ConclusionCompared with docetaxel, immune checkpoint inhibitor treatment can improve the clinical efficacy of NSCLC patients and has a lower incidence of adverse reactions. This treatment may be a promising treatment for NSCLC patients.
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Affiliation(s)
- Wenchao Yang
- Department of Pharmacy, Traditional Chinese Medical Hospital of Zhuji, Zhuji, China
| | - Bixia Xuan
- Department of Pharmacy, Traditional Chinese Medical Hospital of Zhuji, Zhuji, China
| | - Mengqi Chen
- Department of Pharmacy, Traditional Chinese Medical Hospital of Zhuji, Zhuji, China
| | - Xiaofang Li
- Department of Pharmacy, Traditional Chinese Medical Hospital of Zhuji, Zhuji, China
| | - Jiana He
- Department of Pharmacy, Traditional Chinese Medical Hospital of Zhuji, Zhuji, China
| | - Haiyan Si
- Department of Gastroenterology, Traditional Chinese Medical Hospital of Zhuji, Zhuji, China
| | - Yefei Zhang
- Department of Pharmacy, Zhuji People’s Hospital of Zhejiang Province, Zhuji, China
- *Correspondence: Yefei Zhang,
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Rahman MM, Behl T, Islam MR, Alam MN, Islam MM, Albarrati A, Albratty M, Meraya AM, Bungau SG. Emerging Management Approach for the Adverse Events of Immunotherapy of Cancer. Molecules 2022; 27:molecules27123798. [PMID: 35744922 PMCID: PMC9227460 DOI: 10.3390/molecules27123798] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 06/09/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy, which stimulates the body’s immune system, has received a considerable amount of press in recent years because of its powerful benefits. Cancer immunotherapy has shown long-term results in patients with advanced disease that are not seen with traditional chemotherapy. Immune checkpoint inhibitors, cytokines like interleukin 2 (IL-2) and interferon-alpha (IFN), and the cancer vaccine sipuleucel-T have all been licensed and approved by the FDA for the treatment of various cancers. These immunotherapy treatments boost anticancer responses by stimulating the immune system. As a result, they have the potential to cause serious, even fatal, inflammatory and immune-related side effects in one or more organs. Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell therapy are two immunotherapy treatments that are increasingly being used to treat cancer. Following their widespread usage in the clinic, a wave of immune-related adverse events (irAEs) impacting virtually every system has raised concerns about their unpredictability and randomness. Despite the fact that the majority of adverse effects are minimal and should be addressed with prudence, the risk of life-threatening complications exists. Although most adverse events are small and should be treated with caution, the risk of life-threatening toxicities should not be underestimated, especially given the subtle and unusual indications that make early detection even more difficult. Treatment for these issues is difficult and necessitates a multidisciplinary approach involving not only oncologists but also other internal medicine doctors to guarantee quick diagnosis and treatment. This study’s purpose is to give a fundamental overview of immunotherapy and cancer-related side effect management strategies.
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Affiliation(s)
- Md. Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.N.A.); (M.M.I.)
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India
- Correspondence: (T.B.); (S.G.B.)
| | - Md. Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.N.A.); (M.M.I.)
| | - Md. Noor Alam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.N.A.); (M.M.I.)
| | - Md. Mohaimenul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh; (M.M.R.); (M.R.I.); (M.N.A.); (M.M.I.)
| | - Ali Albarrati
- Rehabilitation Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia;
| | - Mohammed Albratty
- Department of Pharmaceutical Chemsitry, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Abdulkarim M. Meraya
- Practice Research Unit, Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan 45124, Saudi Arabia;
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410073 Oradea, Romania
- Correspondence: (T.B.); (S.G.B.)
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Chen Y, Kang S, Yan M. Atezolizumab plus carboplatin and nab-paclitaxel versus carboplatin and nab-paclitaxel as treatments for Chinese, treatment-naïve, stage IV, non-squamous, non-small-cell lung cancer patients: A retrospective analysis. Pharmacol Res Perspect 2022; 10:e00941. [PMID: 35568997 PMCID: PMC9107600 DOI: 10.1002/prp2.941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 02/06/2022] [Indexed: 11/09/2022] Open
Abstract
The IMpower trials reported significant effects of atezolizumab-containing chemotherapies on Caucasian patients. Chinese patients differ from their Western counterparts in terms of driver mutations, etiologies, and regimen tolerance. In China, atezolizumab-containing chemotherapies are not cost-effective. Atezolizumab addition triggers grade >3 adverse events. Here, we evaluated the effectiveness and the safety profile of atezolizumab plus carboplatin and nab-paclitaxel compared to carboplatin and nab-paclitaxel in treatment-naïve Chinese patients with confirmed stage IV, non-squamous, non-small-cell lung cancer. All patients completed six cycles of 1200 mg of atezolizumab/3 weeks plus 6 mg/ml/min area-under-the-curve carboplatin/3 weeks plus 100 mg/m2 nab-paclitaxel/week (n = 115; ACN cohort) or 6 mg/ml/min area-under-the-curve carboplatin/3 weeks plus 100 mg/m2 nab-paclitaxel/week (n = 130; CNP cohort). The progression-free survival (12.98 ± 2.57 months vs. 10.89 ± 2.18 months, p < .0001) and overall survival (38.04 ± 19.8 months vs. 33.59 ± 87 months, p = .012) of patients in the ACN cohort were higher than those of patients in the CNP cohort after 48 weeks of follow-up. A total of 97 (84%) patients in the ACN cohort and 94 (72%) in the CNP cohort developed grade ≥3 adverse events (p = .030). A total of 84 (73%) patients from the ACN cohort and 107 (82%) from the CNP cohort died during 48 weeks of follow-up (p = .091). The addition of atezolizumab to carboplatin and nab-paclitaxel enhanced progression-free and overall survival but increased the risk of grade ≥3 adverse events in Chinese, treatment-naïve, stage IV, non-squamous, non-small-cell lung cancer patients who completed treatment (Level of Evidence: III; Technical Efficacy Stage: 4).
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Affiliation(s)
- Yingkai Chen
- Department of thoracic surgeryThe People's Hospital of Rongchang DistrictChongqingChina
| | - Shizhou Kang
- Department of thoracic surgeryThe People's Hospital of Rongchang DistrictChongqingChina
| | - Ming Yan
- Department of Respiratory and Critical Care MedicineThe People's Hospital of Rongchang DistrictChongqingChina
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Daniel Humberto Pozza, Ramon Bezerra Andrade de Mello. Treatment Sequencing Strategies in Lung Cancer. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:323-336. [PMID: 35599008 PMCID: PMC9127753 DOI: 10.3779/j.issn.1009-3419.2022.104.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 04/22/2022] [Accepted: 04/23/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND The advances in the lung cancer screening methods and therapeutics, together with awareness towards deleterious habits, such as smoking, is increasing the overall survival with better quality of life for the patients. However, lung cancer is still one of the most common and fatal neoplasm with a high incidence and consequently burden to public health worldwide. Thus, based on guidelines and recent phases II and III clinical trials studies, this manuscript summarizes the current treatment sequencing strategies in lung cancer. METHODS A comprehensive search of related articles was performed focused on phases II and III clinical trials studies. RESULTS The lung cancer management should take into consideration the tumor characteristics, histology, molecular pathology and be discussed in a multidisciplinary team. Lung cancer treatment options comprises surgery whenever possible, radiotherapy associate with/or chemotherapy and immunotherapy as monotherapy, or combined with chemotherapy and best palliative care. CONCLUSIONS The screening predictability in more patients, smoking reduction, early diagnosis, better disease understanding and individualized, more effective and tolerable therapeutics are related to an increasing in overall survival and quality of life. In the near future improvement of personalized therapy in precision medicine is expected, enhancing new predictive biomarkers, optimal doses and optimal treatment sequencing as well as anti-cancer vaccines development.
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Affiliation(s)
- Daniel Humberto Pozza
- Department of Biomedicine, Faculty of Medicine and i3s, University of Porto, 4200-319 Porto, Portugal
| | - Ramon Bezerra Andrade de Mello
- Discipline of Medical Oncology, Post-graduation Program in Medicine, Nine of July University (UNINOVE), São Paulo, Brazil./Nine of July Hospital, São Paulo, Brazil
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Hurwitz JT, Vaffis S, Grizzle AJ, Nielsen S, Dodson A, Parry S. Cost-Effectiveness of PD-L1 Testing in Non-Small Cell Lung Cancer (NSCLC) Using In Vitro Diagnostic (IVD) Versus Laboratory-Developed Test (LDT). Oncol Ther 2022; 10:391-409. [PMID: 35556235 DOI: 10.1007/s40487-022-00197-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/20/2022] [Indexed: 10/18/2022] Open
Abstract
INTRODUCTION Accurate PD-L1 testing for non-small cell lung cancer (NSCLC) maximizes the benefits of immune checkpoint inhibitor (ICI) drugs like pembrolizumab. False negative test results deny ICI treatments to eligible patients, worsening clinical and economic outcomes, while false positives increase costs by using ICI treatments without their benefits. This study evaluates the cost-effectiveness of PD-L1 testing with an in vitro diagnostic (IVD) compared to a laboratory-developed test (LDT) for allocating patients with NSCLC to treatment with either pembrolizumab or chemotherapy using the German healthcare system as a model. METHODS We developed a decision analytical model to evaluate the cost-effectiveness of PD-L1 testing with a regulatory body approved IVD compared to an LDT from the national German healthcare payer (statutory health insurance system) perspective. Accuracy of PD-L1 testing was based on data from two independent proficiency testing programs. The 1-year model was based on outcomes data from the KEYNOTE-024 clinical trial and treatment patterns reflecting current German practices. RESULTS IVDs produced accurate PD-L1 testing results in 93% (752/811) of tested cases compared to 73% (492/672) with LDTs. Most misclassifications concerned false negatives, occurring in 21% of LDTs vs 7% of IVDs. Total costs of the IVD group (48,878 €) were 196 € higher than the LDT group (48,682 €). These costs incorporate testing, first- and second-line therapy, managing treatment-related grade 3+ adverse events (AEs), and end-of-life costs for those who died within the year. Total effectiveness (percentage of patients successfully diagnosed and prescribed the correct therapy per German treatment guidelines) was 19 percentage points higher for the IVD group (88%) compared to the LDT group (69%). These differences in costs and effects lead to an incremental cost-effectiveness ratio (ICER) of 1057 €. CONCLUSION Compared to LDT technology, on-label IVD use for PD-L1 testing is only slightly more costly and substantially more effective for aligning patients with PD-L1-positive NSCLC with ICI therapy according to German practice guidelines. Given these findings, changes to testing and reimbursement policies may be considered to maximize patient outcomes in NSCLC.
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Affiliation(s)
- Jason T Hurwitz
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, 1295 N Martin, P.O. Box 210202, Tucson, AZ, 85721-0202, USA
| | - Shannon Vaffis
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, 1295 N Martin, P.O. Box 210202, Tucson, AZ, 85721-0202, USA
| | - Amy J Grizzle
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, 1295 N Martin, P.O. Box 210202, Tucson, AZ, 85721-0202, USA.
| | - Søren Nielsen
- NordiQC, Institute of Pathology, Aalborg University Hospital, P.O. Box 561, 9100, Aalborg, Denmark
| | - Andrew Dodson
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation, 5 Coldbath Square, London, EC1R 5HL, UK
| | - Suzanne Parry
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation, 5 Coldbath Square, London, EC1R 5HL, UK
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Kanji S, Morin S, Agtarap K, Purkayastha D, Thabet P, Bosse D, Wang X, Lunny C, Hutton B. Adverse Events Associated with Immune Checkpoint Inhibitors: Overview of Systematic Reviews. Drugs 2022; 82:793-809. [PMID: 35416592 DOI: 10.1007/s40265-022-01707-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recognition and management of adverse events (AEs) associated with immune checkpoint inhibitor (ICI) use by cancer patients requires expertise from multiple disciplines. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes. OBJECTIVE The primary objective of this overview of systematic reviews was to synthesize and consolidate systematic review evidence describing the incidence proportion and severity of AEs associated with various ICI therapies across different cancers. METHODS A systematic literature search of four databases was conducted to identify systematic reviews that describe the incidence proportion and severity of AEs related to ICI therapy in cancer patients. A systematic review was eligible if it included adults with cancer; on ICI alone or in combination with another ICI, chemotherapy, or targeted therapy; severity (graded according to the Common Terminology Criteria for Adverse Events) and incidence proportion of AEs and whether it reported its eligibility criteria. AEs of interest were identified through an iterative ranking exercise by key stakeholders and knowledge users. Extraction of PICOTTS elements and quality indicators (AMSTAR-2) were used to manage overlap of primary studies across systematic reviews at the outcome level. Cancer subtypes were mapped to drug class and AE severity. RESULTS Overall, 129 systematic reviews met the inclusion criteria for data mapping. Systematic reviews reported incidence proportions for more than 76 AEs, of which 34 were identified as AEs of interest. After overlap assessment, 65 systematic reviews were chosen for data extraction. The three AEs with the highest median incidence were fatigue (18.3%, interquartile range [IQR] 15.0-28.0%), diarrhea (15.3%, IQR 9.7-29.2%) and rash (14.4%, IQR 10.3-19.2%). The three AEs (high-grade) with the highest median incidence were diarrhea (1.5%, IQR 1.2-6.0%), colitis (1.3%, IQR 0.6-6.1%) and neutropenia (1.2%, IQR 0.4-3.3%). Incidence proportions of high-grade AEs were often considerably lower than all-grade AEs and combination therapy (ICI combinations or combinations of ICI with chemotherapy or targeted therapy) was responsible for some of the highest incidence proportions regardless of AE. Rare AEs and certain cancer subtypes were not well reported. CONCLUSIONS Early recognition of AEs associated with ICIs requires expertise from diverse specialists, not just oncologists. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes. PROSPERO REGISTRATION CRD42021231593.
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Affiliation(s)
- Salmaan Kanji
- The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada. .,Ottawa Hospital Research Institute, Ottawa, ON, Canada.
| | | | | | | | | | - Dominick Bosse
- The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada
| | - Xiang Wang
- The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada
| | - Carole Lunny
- St. Michaels Hospital, Unity Health Toronto, Toronto, ON, Canada.,University of British Columbia, Vancouver, BC, Canada
| | - Brian Hutton
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Tran T, Tran NGT, Ho V. Checkpoint Inhibitors and the Gut. J Clin Med 2022; 11:824. [PMID: 35160275 PMCID: PMC8836963 DOI: 10.3390/jcm11030824] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/27/2022] [Accepted: 02/01/2022] [Indexed: 12/18/2022] Open
Abstract
Checkpoint inhibitors have revolutionized treatments in modern oncology, including many conditions previously relegated to palliative therapies only. However, emerging recognition of checkpoint inhibitor-related adverse events has complicated the status of checkpoint inhibitor-related therapies. This review article discusses gastrointestinal adverse events as a result of checkpoint inhibitor therapy, as well as limitations of current guidelines, thus providing recommendations for guideline revision and future study direction.
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Affiliation(s)
- Tuan Tran
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (N.G.T.T.); (V.H.)
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Tahir IM, Rauf A, Mehboob H, Sadaf S, Alam MS, Kalsoom F, Bouyahya A, El Allam A, El Omari N, Bakrim S, Akram M, Raza SK, Emran TB, Mabkhot YN, Zengin G, Derkho M, Natalya S, Shariati MA. Prognostic significance of programmed death-1 and programmed death ligand-1 proteins in breast cancer. Hum Antibodies 2022; 30:131-150. [PMID: 35938242 DOI: 10.3233/hab-220001] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In numerous studies related to tumor prognosis, programmed death-ligand 1 (PD-L1) has been identified as a biomarker. This work aimed to determine the prognostic importance of PD-L1 in breast cancer. We searched electronic databases such as PubMed, Google scholar, home pages of publishing groups, medical, clinical, and pharmaceutical sciences journals, as well as other relevant sources to discover the importance of PD-1 and PD-L1 expression in breast cancer therapies and also recurrence. The keywords used in this search were autoimmunity, programmed cell death, PD-L1 or PD-1, and breast cancer. Our inclusion criteria included studies showing the synergy between the expression of PD-L1 and PD-1 in primary breast cancers as prognostic markers and this research was limited to humans only. We included review articles, original research, letters to the editor, case reports, and short communications in our study, published in English. We focused our work on PD-L1 mRNA expression in breast cancer cell lines. PD-L1 expression has been decisively demonstrated to be a high-risk factor for breast cancer with a bad prognosis.
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Affiliation(s)
- Imtiaz Mahmood Tahir
- College of Allied Health Professionals, Government College University, Faisalabad, Pakistan
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, KPK, Pakistan
| | - Huma Mehboob
- Department of Biochemistry, Government College Women University, Faisalabad, Pakistan
| | - Samia Sadaf
- Department of Genetic Engineering and Biotechnology, University of Chittagong, Chittagong, Bangladesh
| | - Muhammad Shaiful Alam
- Department of Pharmacy, University of Science and Technology Chittagong, Chittagong, Bangladesh
| | - Fadia Kalsoom
- College of Allied Health Professionals, Government College University, Faisalabad, Pakistan
| | - Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, Morocco
| | - Aicha El Allam
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, Morocco
| | - Nasreddine El Omari
- Laboratory of Histology, Embryology, and Cytogenetics, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
| | - Saad Bakrim
- Geo-Bio-Environment Engineering and Innovation Laboratory, Molecular Engineering, Biotechnologies and Innovation Team, Polydisciplinary Faculty of Taroudant, Ibn Zohr University, Agadir, Morocco
| | - Muhammad Akram
- Department of Eastern Medicine, Government College University Faisalabad Pakistan, Faisalabad, Pakistan
| | - Syed Kashif Raza
- College of Allied Health Professionals, Government College University, Faisalabad, Pakistan
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Yahia N Mabkhot
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Gokhan Zengin
- Department of Biology, Science Faculty, Selcuk University, Konya, Turkey
| | - Marina Derkho
- South-Urals State Agrarian University, Troitsk, Chelyabinsk Region, Russia
| | - Suray Natalya
- K.G. Razumovsky Moscow State University of Technologies and Management (The First Cossack University), Moscow, Russia
| | - Mohammad Ali Shariati
- K.G. Razumovsky Moscow State University of Technologies and Management (The First Cossack University), Moscow, Russia
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Anti-PD-1 therapy activates tumoricidic properties of NKT cells and contributes to the overall deceleration of tumor progression in a model of murine mammary carcinoma. VOJNOSANIT PREGL 2022. [DOI: 10.2298/vsp210126039j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background/Aim. Immune checkpoint therapy is a well-established therapeutic approach in the treatment of malignant diseases and is thought to be mostly based on facilitating the adaptive immune response. However, the cells of the innate immune response, such as natural killer T (NKT) cells, might also be important for a successful anti-programmed cell death protein-1 (anti-PD-1) therapy, as they initiate the antitumor immune response. The aim of this study was to investigate the influence of anti-PD-1 therapy on the immune response against tumors. Methods. For tumor induction, 4T1 cells synergic to BALB/c back-ground were used, after which mice underwent anti-PD-1 treatment. After the mice were sacrificed, NKT cells, dendritic cells (DCs), and macrophages derived from spleen and primary tumor tissue were analyzed using flow cytometry. Results. Anti-PD-1 therapy enhanced the expression of activating molecules CD69, NKp46, and NKG2D in NKT cells of the tumor and spleen. This therapy activated NKT cells directly and indirectly via DCs. Activated NKT cells acquired tumoricidic properties directly, by secreting perforin, and indirectly by stimulating M1 macrophages polarization. Conclusion. Anti-PD-1 therapy activates changes in DCs and macrophages of primary tumor tissue towards protumoricidic activity. Since anti-PD-1 therapy induces significant changes in NKT cells, DCs, and macrophages, the efficacy of the overall antitumor response is increased and has significantly decelerated tumor growth.
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Wong SK, Nebhan CA, Johnson DB. Impact of Patient Age on Clinical Efficacy and Toxicity of Checkpoint Inhibitor Therapy. Front Immunol 2021; 12:786046. [PMID: 34868071 PMCID: PMC8635107 DOI: 10.3389/fimmu.2021.786046] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/29/2021] [Indexed: 12/19/2022] Open
Abstract
The addition of immune checkpoint inhibitors (ICIs) to the therapeutic armamentarium for solid malignancies has resulted in unprecedented improvements in patient outcomes in many cancers. The landscape of ICIs continues to evolve with novel approaches such as dual immune checkpoint blockade and combination therapies with other anticancer agents including cytotoxic chemotherapies and/or antiangiogenics. However, there is significant heterogeneity seen in antitumor responses, with certain patients deriving durable benefit, others experiencing initial benefit followed by acquired resistance necessitating change in therapy, and still others who are primarily refractory to ICIs. While generally better tolerated than traditional cytotoxic chemotherapy, ICIs are associated with unique toxicities, termed immune-related adverse events (irAEs), which can be severe or even lethal. As a disease of aging, older individuals make up a large proportion of patients diagnosed with cancer, yet this population is often underrepresented in clinical trials. Because ICIs indirectly target malignant cells through T cell activation, it has been hypothesized that age-related changes to the immune system may impact the efficacy and toxicity of these drugs. In this review, we discuss differences in the clinical efficacy and toxicity of ICIs in patients at the extremes of age.
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Affiliation(s)
- Selina K Wong
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, United States
| | - Caroline A Nebhan
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, United States
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, United States
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Khan M, Zhao Z, Li X, Liao G. Anti-PD1 Therapy Plus Whole-Brain Radiation Therapy May Prolong PFS in Selected Non-Small Cell Lung Cancer Patients with Brain Metastases: A Retrospective Study. Int J Gen Med 2021; 14:8903-8918. [PMID: 34858054 PMCID: PMC8631977 DOI: 10.2147/ijgm.s333890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/06/2021] [Indexed: 12/17/2022] Open
Abstract
Background Whole-brain radiotherapy (WBRT) remains an essential modality of treatment for brain metastases (BMs) derived from non-small cell lung cancer (NSCLC) patients and anti-PD-1 therapy has demonstrated intracranial responses in these patients. We aimed to evaluate if the combination of the two treatments could yield additive efficacy. Methods A retrospective review of our institution’s database was carried out to identify NSCLC patients with BMs who had been treated with anti-PD1 therapy and/or WBRT between 2015 and 2020. Patient characteristics, main outcomes, including progression-free survival (PFS) and overall survival (OS), and factors affecting these outcomes were analyzed. SPSS 24 was used for statistical analysis. Appropriate statistical tests were employed according to the type of data. Results Overall, 21 NSCLC BM patients were identified that had received WBRT. Of these, ten had been additionally treated with anti-PD1 therapy within 30 days of WBRT initiation. Median PFS was 3 (95% CI 0.8–5.1) months with WBRT alone versus 11 (95% CI 6.3–15.6) months with combined treatment. Risk of disease progression was 71% lower with the combined approach (HR 0.29, 95% CI 0.11–0.80; p=0.016). A trend toward improved OS was also observed with the combined approach (HR 0.33, 95% CI 0.08–1.12; p=0.107). Concurrent treatment (p=0.028) and male sex (p=0.052) were associated with improved PFS, while OS was associated only with age (p=0.02). Conclusion Concurrent WBRT and anti-PD1 therapy may delay progression and improve survival in BM patients with confirmed EGFR- and ALK-negative NSCLC histology. Prospective studies are warranted to validate and elucidate on the additive effect of the two modalities.
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Affiliation(s)
- Muhammad Khan
- Department of Oncology, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, People's Republic of China.,Department of Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Zhihong Zhao
- Department of Nephrology, Shenzhen People's Hospital, Second Clinical Medicine Centre, Jinan University, Shenzhen, People's Republic of China
| | - Xianming Li
- Department of Oncology, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, People's Republic of China
| | - Guixiang Liao
- Department of Oncology, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, People's Republic of China
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Gordon J, Stainthorpe A, Jones B, Jacob I, Hertel N, Diaz J, Yuan Y, Borrill J. Non-Price-Related Determinants of Value and Access for Novel Non-small Cell Lung Cancer Treatments: A Cross-Country Review of HTA Decision Making. PHARMACOECONOMICS - OPEN 2021; 5:701-713. [PMID: 34216002 PMCID: PMC8611140 DOI: 10.1007/s41669-021-00279-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 06/05/2021] [Indexed: 06/13/2023]
Abstract
INTRODUCTION Access and funding for newly approved treatments for non-small cell lung cancer (NSCLC) are often dependent on Health Technology Assessment (HTA) involving cost-effectiveness analysis. Whilst methods used by HTA agencies share many similarities, final decisions may differ. This may be the result, not just of price considerations, but also of variation in value judgements by different agencies. The aim of this study was to review international HTA evaluations to identify determinants of value and access for NSCLC treatments. METHODS A targeted review and analysis was undertaken of published HTAs for NSCLC across HTA agencies in six countries (Australia, Canada, England, France, Ireland and Scotland). Analysis of extracted data consisted of three stages: descriptive analysis, bivariate analysis and multivariable analysis. RESULTS The analysis included 163 HTAs that assessed oncological treatments for NSCLC from 2003 to 2019. The majority of HTA decisions (67.5%) were positive. However, some evidence of heterogeneity in HTA decisions and the factors informing them were identified. The most influential factors included in the multivariate model related to the HTA agency conducting the appraisal, the year of market authorisation, treatment type and the line of treatment. CONCLUSION Heterogenous decision-making frameworks can present a challenge to developing HTA submissions. This research contributes to understanding decision-making factors and why countries make different decisions.
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Affiliation(s)
- Jason Gordon
- Health Economics and Outcomes Research Ltd, Rhymney House, Unit A Copse Walk, Cardiff Gate Business Park, Cardiff, CF23 8RB, UK.
| | - Angela Stainthorpe
- Health Economics and Outcomes Research Ltd, Rhymney House, Unit A Copse Walk, Cardiff Gate Business Park, Cardiff, CF23 8RB, UK
| | - Beverley Jones
- Health Economics and Outcomes Research Ltd, Rhymney House, Unit A Copse Walk, Cardiff Gate Business Park, Cardiff, CF23 8RB, UK
| | - Ian Jacob
- Health Economics and Outcomes Research Ltd, Rhymney House, Unit A Copse Walk, Cardiff Gate Business Park, Cardiff, CF23 8RB, UK
| | | | - Jose Diaz
- Bristol Myers Squibb, WW HEOR, Uxbridge, UK
| | - Yong Yuan
- Bristol Myers Squibb, WW HEOR, Lawrenceville, USA
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Liao G, Qian Y, Arooj S, Zhao Z, Yan M, Li Z, Yang H, Zheng T, Li G, Li X, Khan M. Radiation Plus Anti-PD-1 Therapy for NSCLC Brain Metastases: A Retrospective Study. Front Oncol 2021; 11:742971. [PMID: 34745964 PMCID: PMC8567143 DOI: 10.3389/fonc.2021.742971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 09/28/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Radiation therapy (RT) is the mainstay of brain metastases (BMs), and anti-PD-1 blockade has led to intracranial responses in non-small cell lung carcinoma (NSCLC) patients with BMs. OBJECTIVE This study aimed to evaluate the efficacy and safety of adding anti-PD-1 blockade to RT in the management of NSCLC patients with BM in terms of survival outcome. MATERIALS AND METHODS We retrospectively reviewed 70 NSCLC patients with BMs who were treated with whole brain radiation therapy (WBRT) between January 2016 and January 2021. Of the 70 patients, 29 additionally received anti-PD-1 therapy within 30 days of WBRT initiation. Baseline characteristics of the patients and efficacy outcomes such as progression-free survival (PFS) and overall survival (OS) were statistically compared using SPSS v26. Results were obtained using the Chi-square test/Fisher exact test, t-test, Kaplan-Meier, and Cox regression survival analyses. RESULTS The median survival for the entire cohort was 24 months (95% CI, 19.5-28.5). The median survival times for WBRT alone and WBRT plus anti-PD-1 therapy cohorts were 20 months (95% CI, 11.6-28.3) and 27 months (95% CI, 19.5-28.5), respectively (p=0.035). There was no statistical difference in PFS for the treatment cohorts (median PFS for WBRT alone: 7 months vs. 12 months for WBRT plus anti-PD-1, p=0.247). In EGFR wild-type subgroup (n=31), both PFS (p=0.037) and OS (p=0.012) were significantly improved. Only the treatment group (WBRT plus anti-PD-1) was a significant predictor of OS on univariate and multivariate analyses (p=0.040). There were no significant differences in adverse events among the treatment groups. CONCLUSIONS NSCLC patients with BM receiving additional anti-PD-1 therapy may derive better OS than WBRT alone without any increase in adverse events. Prospective well-designed studies are warranted to validate and elucidate the additive effects of the two modalities in this group of patients.
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Affiliation(s)
- Guixiang Liao
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
| | - Yuting Qian
- Department of Radiation Oncology, Shenzhen People's Hospital, The Second College of Jinan University, Shenzhen, China
| | - Sumbal Arooj
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
- Department of Biochemistry and Molecular Biology, University of Sialkot, Sialkot, Pakistan
| | - Zhihong Zhao
- Department of Nephrology, Shenzhen People’s Hospital, Second Clinical Medicine Centre, Jinan University, Shenzhen, China
| | - Maosheng Yan
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
| | - Zihuang Li
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
| | - Hongli Yang
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
| | - Tao Zheng
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
| | - Gang Li
- Department of Chemoradiation Oncology, The First Affiliated Hospital Of Wenzhou Medical University, Wenzhou, China
| | - Xianming Li
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
| | - Muhammad Khan
- Department of Oncology, Shenzhen People’s Hospital, The First Affiliated Hospital Of Southern University Of Science And Technology, Shenzhen, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Satouchi M, Nosaki K, Takahashi T, Nakagawa K, Aoe K, Kurata T, Sekine A, Horiike A, Fukuhara T, Sugawara S, Umemura S, Saka H, Okamoto I, Yamamoto N, Sakai H, Kishi K, Katakami N, Horinouchi H, Hida T, Okamoto H, Atagi S, Ohira T, Rong Han S, Noguchi K, Ebiana V, Hotta K. First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset. Cancer Sci 2021; 112:5000-5010. [PMID: 34543477 PMCID: PMC8645705 DOI: 10.1111/cas.15144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/31/2021] [Accepted: 09/06/2021] [Indexed: 12/24/2022] Open
Abstract
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death‐ligand 1 (PD‐L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression‐free survival by independent central review (data cut‐off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10‐0.64; one‐sided, nominal P = .001). The HR for overall survival (data cut‐off date, 15 February 2019) was 0.39 (95% CI, 0.17‐0.91; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.
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Affiliation(s)
- Miyako Satouchi
- Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan
| | - Kaname Nosaki
- Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Toshiaki Takahashi
- Division of Thoracic Oncology, Shizuoka Cancer Center, Shuntougun, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Keisuke Aoe
- Department of Medical Oncology, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan
| | - Takayasu Kurata
- Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan
| | - Akimasa Sekine
- Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan
| | - Atsushi Horiike
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | - Shunichi Sugawara
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan
| | - Shigeki Umemura
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideo Saka
- Department of Respiratory Medicine and Medical Oncology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Hiroshi Sakai
- Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan
| | - Kazuma Kishi
- Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, Tokyo, Japan
| | - Nobuyuki Katakami
- Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan
| | - Hidehito Horinouchi
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Toyoaki Hida
- Department of Thoracic Oncology, Aichi Cancer Center, Aichi, Japan
| | - Hiroaki Okamoto
- Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Shinji Atagi
- Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan
| | - Tatsuo Ohira
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | | | | | | | - Katsuyuki Hotta
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
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Zhou L, Wei X. Ocular Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Lung Cancer. Front Immunol 2021; 12:701951. [PMID: 34504488 PMCID: PMC8421677 DOI: 10.3389/fimmu.2021.701951] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/05/2021] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are novel immunotherapy-based drugs that have become increasingly popular in the treatment of lung cancer. Researchers have recognized ocular immune-related adverse events (irAEs) secondary to ICIs because of their vision-threatening characteristics. However, they are incompletely characterized and no studies have reported the ICI-related ocular irAEs in lung cancer. Therefore, we aimed to comprehensively illustrate the clinical characteristics, contributory factors, diagnosis, and management of ICI-related ocular irAEs in lung cancer, based on previously reported 79 patients. Ophthalmoplegia (40.51%), uveitis (20.25%), and dry eye (17.72%) were the most common ICI-related ocular irAEs in lung cancer. Ptosis was the most common (36.71%) and the highest mortality (23.33%) of ophthalmoplegia. Patients in Asia and patients who underwent combination therapy with programmed cell death-1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors demonstrated significantly higher frequency of ophthalmoplegia than other ocular irAEs. Most ICI-related ophthalmoplegia and uveitis in lung cancer were observed in the first 10 weeks following the initiation of ICIs. Furthermore, the onset time of dry eye and other ocular irAEs was much longer. In addition, 92.31% of the patients with ocular irAEs other than ophthalmoplegia could be remised. In conclusion, ocular irAEs secondary to ICIs in lung cancer are non-negligible, particularly ophthalmoplegia. Ethnicity and the type of ICIs play important roles in the distribution of ocular irAEs. ICI-related ophthalmoplegia in lung cancer presented with early onset and worse prognosis features, thus necessitating further attention.
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Affiliation(s)
- Lin Zhou
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Wei
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
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Lin X, Deng H, Yang Y, Wu J, Qiu G, Li S, Xie X, Liu M, Xie Z, Qin Y, Song Y, Zhou C. Peripheral Blood Biomarkers for Early Diagnosis, Severity, and Prognosis of Checkpoint Inhibitor-Related Pneumonitis in Patients With Lung Cancer. Front Oncol 2021; 11:698832. [PMID: 34327140 PMCID: PMC8313853 DOI: 10.3389/fonc.2021.698832] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
Background Checkpoint inhibitor-related pneumonitis (CIP) is a potentially fatal immune-related adverse event that occurs during treatment with immune checkpoint inhibitors (ICIs). However, the roles played by peripheral blood parameters in CIP development remain unclear. Here, we aimed to identify which blood biomarkers correlated with the development and prognosis of CIP in patients with lung cancer. Methods We conducted a retrospective analysis of 87 patients with CIP (CIP group) and 87 patients without CIP (control group). Cytokines, blood routine, lactate dehydrogenase (LDH) and albumin (ALB) were collected at baseline (before ICIs), at onset of pneumonitis (in the CIP group), and before the last dose of ICI (in the control group). We compared the baseline values and changes over time in various blood parameters between the CIP and control groups. The CIP outcomes were collected and compared according to the median values of these parameters. Results Squamous carcinoma (odds ratio [OR]: 3.02; p = 0.004) and ICI monotherapy (OR: 6.56; p = 0.004) correlated with a high risk of CIP. In the CIP group, interleukin (IL)-6 and platelet-to-lymphocyte ratio (PLR) at CIP were significantly increased relative to baseline. By contrast, IL-6 and PLR reduced over time in the control group. Significant decrease in absolute lymphocyte count (ALC) and increases in IL-10, neutrophil to lymphocyte ratio (NLR), and LDH levels were observed from baseline to CIP. No significant change in these parameters was observed in the control group relative to baseline. ALB decreased in both groups, but the decrease in the CIP group was greater (9.21% vs. 2.44%; p = 0.020). High IL-6 levels (OR: 5.23, 95% confidence interval [CI]: 1.15–23.86; p = 0.033), and low levels of ALB (OR: 0.16, 95% CI: 0.04–0.64; p = 0.009) measured at the time of CIP symptom onset were associated with severe pneumonitis. Low concentration of IL-6 (hazard ratio [HR]: 0.17, 95% CI: 0.03–0.95; p = 0.044) and high ALB levels (HR: 0.28, 95% CI: 0.08–0.94; p = 0.040) were correlated with favorable overall survival in CIP. Conclusions Increase in IL-6, IL-10, NLR, PLR, and LDH levels or reduced ALC and ALB levels were associated with the occurrence of CIP in lung cancer patients. High IL-6 and low ALB levels at onset of CIP were related to severe grade and poor prognosis of CIP.
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Affiliation(s)
- Xinqing Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Haiyi Deng
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yilin Yang
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jianhui Wu
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Guihuan Qiu
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Suyang Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiaohong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ming Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yinyin Qin
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing, China
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Brahmer JR, Abu-Sbeih H, Ascierto PA, Brufsky J, Cappelli LC, Cortazar FB, Gerber DE, Hamad L, Hansen E, Johnson DB, Lacouture ME, Masters GA, Naidoo J, Nanni M, Perales MA, Puzanov I, Santomasso BD, Shanbhag SP, Sharma R, Skondra D, Sosman JA, Turner M, Ernstoff MS. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2021; 9:e002435. [PMID: 34172516 PMCID: PMC8237720 DOI: 10.1136/jitc-2021-002435] [Citation(s) in RCA: 443] [Impact Index Per Article: 110.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2021] [Indexed: 02/06/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.
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Affiliation(s)
- Julie R Brahmer
- Department of Oncology and the Thoracic Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, Maryland, USA
| | - Hamzah Abu-Sbeih
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Paolo Antonio Ascierto
- Unit of Melanoma Cancer Immunotherapy and Innovative Therapy, National Tumour Institute IRCCS Fondazione 'G. Pascale', Napoli, Italy
| | - Jill Brufsky
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Laura C Cappelli
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Frank B Cortazar
- Massachusetts General Hospital, Boston, Massachusetts, USA
- New York Nephrology Vasculitis and Glomerular Center, Albany, New York, USA
| | - David E Gerber
- Department of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Lamya Hamad
- Department of Pharmacy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Eric Hansen
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
| | - Mario E Lacouture
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Gregory A Masters
- Department of Medicine, Helen F. Graham Cancer Center, Newark, Delaware, USA
| | - Jarushka Naidoo
- Department of Oncology and the Thoracic Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, Maryland, USA
- Department of Oncology, Beaumont Hospital Dublin, The Royal College of Surgeons of Ireland, Dublin, Ireland
| | - Michele Nanni
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Miguel-Angel Perales
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Igor Puzanov
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Bianca D Santomasso
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Satish P Shanbhag
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Cancer Specialist of North Florida, Fleming Island, Florida, USA
| | - Rajeev Sharma
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Dimitra Skondra
- Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, Illinois, USA
| | - Jeffrey A Sosman
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical Center, Chicago, Illinois, USA
| | - Michelle Turner
- Department of Oncology and the Thoracic Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, Maryland, USA
| | - Marc S Ernstoff
- Division of Cancer Treatment & Diagnosis, National Cancer Institute, Rockville, Maryland, USA
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46
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Pham J, Conron M, Wright G, Mitchell P, Ball D, Philip J, Brand M, Zalcberg J, Stirling RG. Excess mortality and undertreatment in elderly lung cancer patients: treatment nihilism in the modern era? ERJ Open Res 2021; 7:00393-2020. [PMID: 34046489 PMCID: PMC8141829 DOI: 10.1183/23120541.00393-2020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 02/15/2021] [Indexed: 12/24/2022] Open
Abstract
Treatment of elderly patients with lung cancer is significantly hindered by concerns about treatment tolerability, toxicity and limited clinical trial data in the elderly; potentially giving rise to treatment nihilism amongst clinicians. This study aims to describe survival in elderly patients with lung cancer and explore potential causes for excess mortality. Patients diagnosed with lung cancer in the Victorian Lung Cancer Registry between 2011–2018 were analysed (n=3481). Patients were age-categorised and compared using Cox-regression modelling to determine mortality risk, after adjusting for confounding. Probability of being offered cancer treatments was also determined, further stratified by disease stage. The eldest patients (≥80 years old) had significantly shorter median survival compared with younger age groups (<60 years: 2.0 years; 60–69 years: 1.5 years; 70–79 years: 1.6 years; ≥80 years: 1.0 years; p<0.001). Amongst those diagnosed with stage 1 or 2 lung cancer, there was no significant difference in adjusted-mortality between age groups. However, in those diagnosed with stage 3 or 4 disease, the eldest patients had an increased adjusted-mortality risk of 28% compared with patients younger than 60 years old (p=0.005), associated with markedly reduced probability of cancer treatment, after controlling for sex, performance status, comorbidities and histology type (OR 0.24, compared with <60 years old strata; p<0.001). Compared to younger patients, older patients with advanced-stage lung cancer have a disproportionately higher risk of mortality and lower likelihood of receiving cancer treatments, even when performance status and comorbidity are equivalent. These healthcare inequities could be indicative of widespread treatment nihilism towards elderly patients. Treatment strongly determines lung cancer survival, yet nihilism may threaten treatment provision and survival outcomes. Older patients in this cohort had reduced multidisciplinary presentation, less treatment (OR 0.24) and 28% increased mortality risk.https://bit.ly/2ZGotj0
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Affiliation(s)
- Jonathan Pham
- Dept of Respiratory Medicine, The Alfred Hospital, Melbourne, Australia
| | - Matthew Conron
- Dept of Respiratory Medicine, St Vincent's Hospital, Melbourne, Australia
| | - Gavin Wright
- Victorian Comprehensive Cancer Centre, Melbourne, Australia.,Dept of Surgery, University of Melbourne, Melbourne, Australia
| | - Paul Mitchell
- Olivia Newton-John Cancer Wellness and Research Centre, Melbourne, Australia
| | - David Ball
- Division of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,The Sir Peter MacCallum Dept of Oncology, The University of Melbourne, Parkville, Australia
| | - Jennifer Philip
- Dept of Palliative Care, St Vincent's Hospital, Melbourne, Australia.,Dept of Medicine, University of Melbourne, Melbourne, Australia
| | - Margaret Brand
- Dept of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - John Zalcberg
- Dept of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Rob G Stirling
- Dept of Respiratory Medicine, The Alfred Hospital, Melbourne, Australia.,Dept of Medicine, Monash University, Melbourne, Australia
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47
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Combination of the EP and Anti-PD-1 Pathway or Anti-CTLA-4 for the Phase III Trial of Small-Cell Lung Cancer: A Meta-Analysis. JOURNAL OF ONCOLOGY 2021; 2021:6662344. [PMID: 34122547 PMCID: PMC8166470 DOI: 10.1155/2021/6662344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 03/31/2021] [Accepted: 05/10/2021] [Indexed: 12/09/2022]
Abstract
The morbidity and mortality of lung cancer remain one of the highest among multiple cancers, respectively. Small-Cell Lung Cancer (SCLC) accounts for around 10%-15% of all lung cancers. Approximately two-thirds of the diagnosed SCLCs are in extensive stage (ES). Decades later, we still rely on the same traditional regimen with etoposide and platinum (EP) as the mainstay of treatment with poor prognosis. This meta-analysis aims to assess the effect of adding Immune Checkpoint Inhibitors (CPIs) such as (ipilimumab, atezolizumab, pembrolizumab, and durvalumab) to the traditional EP regimen for small-cell lung cancer extensive stage (ES-SCLC). We searched through PubMed looking for studies that compare between EP and CPIs, with EP alone, and only Phase III randomized controlled trials were considered eligible for this study. A total of 3645 papers were the results of the initial search, and only 4 studies met our criteria. Each investigator extracted the data independently using the PRISMA MODEL (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Each author used a prespecified sheet. The primary endpoint was to calculate OS (overall survival) and PFS (progression-free survival) hazard ratios for both arms. We found that adding EP plus CPIs increased both OS (HR, 95% CI 0.80 [0.70, 0.93], P = 0.0001, I 2 = 49%) and PFS (HR95% CI 0.81 [0.74, 0.88], P < 0.00001, I 2 = 0%). On the other hand, ORR (overall response rate) was not affected by the addition of CPIs to EP compared to EP alone, and the same was true for adverse events. To conclude, CTLA-4 alone is not encouraging, but PD-1/PD-L1 adds survival benefits. A combined treatment regimen shows to be more effective, improving overall survival rate Durvalumab and atezolizumab showed improvement for OS, but pembrolizumab and ipilimumab did not show a significant increase of OS over EP; however, pembrolizumab showed significant prolongation of the disease-free period.
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Hagiwara S, Watanabe T, Kudo M, Minaga K, Komeda Y, Kamata K, Kimura M, Hayashi H, Nakagawa K, Ueshima K, Minami Y, Aoki T, Takita M, Morita M, Cishina H, Ida H, Park AM, Nishida N. Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease. Sci Rep 2021; 11:9242. [PMID: 33927311 PMCID: PMC8085223 DOI: 10.1038/s41598-021-88824-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 04/16/2021] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
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Affiliation(s)
- Satoru Hagiwara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Yoriaki Komeda
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Masatomo Kimura
- Department of Pathology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Masahiro Takita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Masahiro Morita
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Hirokazu Cishina
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Hiroshi Ida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Ah-Mee Park
- Department of Microbiology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
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Glode AE, May MB. Immune checkpoint inhibitors: Significant advancements in non-small cell lung cancer treatment. Am J Health Syst Pharm 2021; 78:769-780. [PMID: 33580648 DOI: 10.1093/ajhp/zxab041] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE This article explores the efficacy, toxicity, place in therapy, and considerations for use of recently approved immune checkpoint inhibitors (ICIs) in the treatment of non-small cell lung cancer (NSCLC). SUMMARY Lung cancer is the leading cause of cancer mortality in the United States and is responsible for more cancer-related deaths than breast, prostate, and colorectal cancer combined. The landscape for lung cancer treatment is evolving with the approval of new and exciting novel therapies. Within the last decade numerous ICIs have been approved for use in the management of the most common subtype of lung cancer, NSCLC. The ICI agents currently approved by the Food and Drug Administration (FDA) for use in NSCLC include ipilimumab, pembrolizumab, nivolumab, durvalumab, and atezolizumab. These agents are approved for specific indications; therefore, they are not interchangeable. This review focuses on the landmark trials that led to each FDA-approved indication, as well as common toxicities seen with use of these agents. It also discusses the use of ICIs in special populations and unique considerations prior to initiation of treatment with these novel therapies in a patient with NSCLC. CONCLUSION ICIs can provide a breakthrough treatment option for the management of NSCLC and are rapidly being adopted into clinical practice. It is important to be familiar with appropriate selection of an ICI therapy option for each patient based on approved indication, unique considerations, and anticipated toxicities.
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Affiliation(s)
- Ashley E Glode
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
| | - Megan B May
- Department of Pharmacy, Baptist Health Lexington, Lexington, KY, USA
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Ehlert K, Hansjuergens I, Zinke A, Otto S, Siebert N, Henze G, Lode H. Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma. J Immunother Cancer 2021; 8:jitc-2020-000540. [PMID: 32414861 PMCID: PMC7239695 DOI: 10.1136/jitc-2020-000540] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Neuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than 50% of patients present with widespread (stage M) or refractory disease. In these patients, event-free and overall survival was improved by the addition of the anti-disialoganglioside antibody dinutuximab beta (DB) following multimodal conventional therapy. However, the prognosis of patients with refractory/relapsed NB remains poor. In the past decade, immunotherapy approaches with checkpoint inhibitors were approved for patients with certain malignant diseases such as melanoma or Hodgkin lymphoma. In preclinical models, DB resulted in an upregulation of the programmed cell death protein 1 (PD-1) checkpoint in NB cell lines and a combined treatment of DB with a murine anti-PD-1 checkpoint inhibitor showed a synergistic effect in a NB mouse model. CASE PRESENTATIONS Two patients were admitted with refractory metastatic NB. In the 4-year-old girl, NB was diagnosed in 2013. She completed her first-line therapy with a first remission in 2015, but suffered a relapse in 2017. Treatment with chemotherapy and DB resulted in progressive disease after transient improvement. In the 17-year-old young man, NB was first diagnosed in April 2010. After two local relapses in 2011 and 2014, a metastatic relapse and a large abdominal tumor bulk were found in 2018. Despite transient improvement with multimodal therapy, progressive metastatic disease was observed in May 2019. Both patients had a satisfactory quality of life. Therefore, treatment with DB and nivolumab was performed-in the girl from October 2018 until August 2019, in the young man since June 2019. Tolerance to treatment was excellent. The girl continues to be in complete remission 6 months after therapy was stopped. In the young man, the soft tissue lesions disappeared completely, the skeletal lesions regressed substantially after 9 months of his still ongoing treatment. CONCLUSIONS The combination of DB with the checkpoint inhibitor nivolumab led to complete and a very good partial remission in two patients with relapsed/refractory NB. Prospective trials are warranted to clarify the role of this novel approach in a larger number of patients.
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Affiliation(s)
- Karoline Ehlert
- Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany
| | - Ina Hansjuergens
- Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany
| | - Andreas Zinke
- Department of Nuclear Medicine, Greifswald University Medicine, Greifswald, Germany
| | - Sylke Otto
- Institute for Diagnostic Radiology, Greifswald University Medicine, Greifswald, Germany
| | - Nikolai Siebert
- Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany
| | - Guenter Henze
- Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany.,Department of Pediatric Oncology and Hematology, Charité University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Holger Lode
- Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany
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