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Chen L, He JN, Zhao SJ, Peng LP, Mo DC, Yin SH. Efficacy and safety of PD-1/PD-L1 inhibitors combined with standard of care for locally advanced head and neck squamous cell carcinoma: A meta-analysis of randomized controlled trials. Crit Rev Oncol Hematol 2025; 209:104668. [PMID: 39978426 DOI: 10.1016/j.critrevonc.2025.104668] [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: 01/13/2025] [Revised: 02/05/2025] [Accepted: 02/16/2025] [Indexed: 02/22/2025] Open
Abstract
OBJECTIVES Chemoradiotherapy (CRT) or radiotherapy (RT) combined with cetuximab (for cisplatin-ineligible patients) is the standard of care (SoC) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This study investigates whether adding programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICIs) to standard therapy improves survival in patients with LA-HNSCC. METHODS A comprehensive search of PubMed, Embase, and the Cochrane Library identified randomized controlled trials (RCTs) evaluating PD-1/PD-L1 inhibitors plus SoC compared with SoC alone for LA-HNSCC. The primary endpoints were progression-free survival (PFS), overall survival (OS), locoregional event-free survival (LEFS), and distant metastasis-free survival (DMFS) at the 1-year and 2-year time points, as well as the incidence of grade 3 or higher adverse events (AEs). RESULTS Four RCTs encompassing 1818 patients met the inclusion criteria. Compared with SoC alone, PD-1/PD-L1 inhibitors combined with SoC did not significantly improve 1-year or 2-year PFS, OS, LEFS, or DMFS (all p > 0.05). Subgroup analyses further showed no survival benefit at 2 years in the ICI + CRT, ICI + RT-cetuximab, anti-PD-1, or anti-PD-L1 subgroups. Additionally, there was no statistically significant difference in the incidence of grade 3 or higher AEs between the combined and SoC-only groups (p = 0.69). CONCLUSIONS These findings suggest that adding PD-1/PD-L1 inhibitors to standard therapy does not enhance 1-year or 2-year survival for patients with LA-HNSCC, and confers a similar severe safety profile.
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Affiliation(s)
- Long Chen
- ENT & HN Surgery Department, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, China; ENT & HN Surgery Department, The Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, China
| | - Jin-Nian He
- ENT & HN Surgery Department, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, China
| | - Shi-Jie Zhao
- ENT & HN Surgery Department, The Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, China
| | - Li-Ping Peng
- ENT & HN Surgery Department, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, China
| | - Dun-Chang Mo
- Radiotherapy Department, The Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, China.
| | - Shi-Hua Yin
- ENT & HN Surgery Department, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, China.
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Wei J, Zhang Y, Zheng Y, Ma C, Zhao Q, Wang Y, Miao L, Ding J. Efficacy and safety of anlotinib monotherapy or combination therapy in the treatment of patients with advanced non-small cell lung cancer: a retrospective real-world study conducted in East China. BMC Pulm Med 2025; 25:170. [PMID: 40211232 PMCID: PMC11987349 DOI: 10.1186/s12890-025-03635-8] [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: 12/03/2024] [Accepted: 03/28/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, the prognosis for advanced NSCLC remains poor. The development of resistance to standard treatments and the lack of effective therapeutic options for heavily pretreated patients underscore the urgent need for novel treatment strategies. Angiogenesis plays a pivotal role in tumor growth and metastasis, making it a critical target in cancer therapy. Anlotinib, a novel multi-target tyrosine kinase inhibitor, has demonstrated potent anti-tumor activity in patients with advanced NSCLC. METHODS The retrospective analysis was conducted on clinical data from 82 patients with advanced NSCLC who received either anlotinib monotherapy or combination therapy. Patients were divided into two groups based on different treatment modalities: anlotinib monotherapy group (30 patients) and anlotinib combination therapy group (52 patients). The anlotinib combination therapy group received anlotinib in combination with immune checkpoint inhibitors (ICIs), chemotherapy, or targeted drugs. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and adverse events. RESULTS Although the difference in ORR between the two groups was not statistically significant (P > 0.05), the DCR was notably higher in the combination therapy group compared to the monotherapy group (86.5% vs. 66.7%, P < 0.05). In the anlotinib combination therapy group, patients demonstrated a significantly longer PFS compared to those in the anlotinib monotherapy group (median PFS: 20.0 m vs. 9.3 m, P = 0.030). The PFS% at 12, 18, and 24 months in the anlotinib combination therapy group were 65.38%, 55.77%, and 28.85%, respectively, all significantly higher than in the anlotinib monotherapy group (P < 0.05). In the combination therapy regimen, anlotinib combined with ICIs significantly prolonged patients' PFS (median PFS: 25.4 m vs. 9.3 m, P < 0.05). Subgroup analysis results indicated that in subgroups of male patients, patients with a history of hypertension, patients with ≥ 3 lines of treatment, and patients without a history of anti-angiogenic therapy, the PFS in the anlotinib combination therapy group was significantly better than in the anlotinib monotherapy group (P < 0.05). Although the incidence of bleeding and skin adverse reactions was higher in the anlotinib combination therapy group compared to the monotherapy group, the difference was not statistically significant (P > 0.05). CONCLUSION Anlotinib combination therapy was associated with improved PFS in advanced NSCLC patients, with a tolerable safety profile.
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Affiliation(s)
- Jia Wei
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China
| | - Yan Zhang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China
| | - Ying Zheng
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China
| | - Chengxing Ma
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China
| | - Qi Zhao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China
| | - Yongsheng Wang
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China
| | - Liyun Miao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China
| | - Jingjing Ding
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China.
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People's Republic of China.
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Aftabi S, Barzegar Behrooz A, Cordani M, Rahiman N, Sadeghdoust M, Aligolighasemabadi F, Pistorius S, Alavizadeh SH, Taefehshokr N, Ghavami S. Therapeutic targeting of TGF-β in lung cancer. FEBS J 2025; 292:1520-1557. [PMID: 39083441 PMCID: PMC11970718 DOI: 10.1111/febs.17234] [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: 11/05/2023] [Revised: 05/22/2024] [Accepted: 07/19/2024] [Indexed: 08/02/2024]
Abstract
Transforming growth factor-β (TGF-β) plays a complex role in lung cancer pathophysiology, initially acting as a tumor suppressor by inhibiting early-stage tumor growth. However, its role evolves in the advanced stages of the disease, where it contributes to tumor progression not by directly promoting cell proliferation but by enhancing epithelial-mesenchymal transition (EMT) and creating a conducive tumor microenvironment. While EMT is typically associated with enhanced migratory and invasive capabilities rather than proliferation per se, TGF-β's influence on this process facilitates the complex dynamics of tumor metastasis. Additionally, TGF-β impacts the tumor microenvironment by interacting with immune cells, a process influenced by genetic and epigenetic changes within tumor cells. This interaction highlights its role in immune evasion and chemoresistance, further complicating lung cancer therapy. This review provides a critical overview of recent findings on TGF-β's involvement in lung cancer, its contribution to chemoresistance, and its modulation of the immune response. Despite the considerable challenges encountered in clinical trials and the development of new treatments targeting the TGF-β pathway, this review highlights the necessity for continued, in-depth investigation into the roles of TGF-β. A deeper comprehension of these roles may lead to novel, targeted therapies for lung cancer. Despite the intricate behavior of TGF-β signaling in tumors and previous challenges, further research could yield innovative treatment strategies.
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Affiliation(s)
- Sajjad Aftabi
- Department of Human Anatomy and Cell ScienceUniversity of Manitoba College of MedicineWinnipegCanada
- Paul Albrechtsen Research Institute, CancerCare ManitobaUniversity of ManitobaWinnipegCanada
- Department of Physics and AstronomyUniversity of ManitobaWinnipegCanada
| | - Amir Barzegar Behrooz
- Department of Human Anatomy and Cell ScienceUniversity of Manitoba College of MedicineWinnipegCanada
- Electrophysiology Research Center, Neuroscience InstituteTehran University of Medical SciencesIran
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of BiologyComplutense UniversityMadridSpain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC)MadridSpain
| | - Niloufar Rahiman
- Nanotechnology Research Center, Pharmaceutical Technology InstituteMashhad University of Medical SciencesIran
- Department of Pharmaceutical Nanotechnology, School of PharmacyMashhad University of Medical SciencesIran
| | - Mohammadamin Sadeghdoust
- Division of BioMedical Sciences, Faculty of MedicineMemorial University of NewfoundlandSt. John'sCanada
| | - Farnaz Aligolighasemabadi
- Department of Human Anatomy and Cell ScienceUniversity of Manitoba College of MedicineWinnipegCanada
| | - Stephen Pistorius
- Department of Human Anatomy and Cell ScienceUniversity of Manitoba College of MedicineWinnipegCanada
- Paul Albrechtsen Research Institute, CancerCare ManitobaUniversity of ManitobaWinnipegCanada
- Department of Physics and AstronomyUniversity of ManitobaWinnipegCanada
| | - Seyedeh Hoda Alavizadeh
- Nanotechnology Research Center, Pharmaceutical Technology InstituteMashhad University of Medical SciencesIran
- Department of Pharmaceutical Nanotechnology, School of PharmacyMashhad University of Medical SciencesIran
| | - Nima Taefehshokr
- Apoptosis Research CentreChildren's Hospital of Eastern Ontario Research InstituteOttawaCanada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell ScienceUniversity of Manitoba College of MedicineWinnipegCanada
- Paul Albrechtsen Research Institute, CancerCare ManitobaUniversity of ManitobaWinnipegCanada
- Faculty Academy of Silesia, Faculty of MedicineKatowicePoland
- Children Hospital Research Institute of ManitobaUniversity of ManitobaWinnipegCanada
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Su PL, Furuya N, Asrar A, Rolfo C, Li Z, Carbone DP, He K. Recent advances in therapeutic strategies for non-small cell lung cancer. J Hematol Oncol 2025; 18:35. [PMID: 40140911 PMCID: PMC11948873 DOI: 10.1186/s13045-025-01679-1] [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: 11/18/2024] [Accepted: 02/17/2025] [Indexed: 03/28/2025] Open
Abstract
The development of targeted therapy with small-molecule tyrosine kinase inhibitors and immunotherapy with immune checkpoints inhibitors has ushered in the era of precision medicine in treating lung cancer, which remains the leading cause of cancer-related deaths worldwide. Both targeted therapy and immunotherapy have significantly improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). Additionally, recent groundbreaking studies have demonstrated their efficacy in both the perioperative setting and following concurrent chemoradiotherapy in early-stage NSCLC. Despite significant advancements in first-line treatment options, disease progression remains inevitable for most patients with advanced NSCLC, necessitating the exploration and optimization of subsequent therapeutic strategies. Emerging novel agents are expanding treatment options in the first-line setting and beyond. Recently, emerging bispecific antibodies have shown enhanced efficacy. For instance, amivantamab has been approved as a treatment for epidermal growth factor receptor (EGFR)-mutant NSCLC, including those with EGFR exon 20 insertion mutations. Additionally, antibody-drug conjugates (ADCs), including HER2-targeting trastuzumab deruxtecan, TROP2-targeting ADCs, HER3-targeting patritumab deruxtecan, and MET-targeting telisotuzumab vedotin, have demonstrated promising outcomes in several clinical trials. This review summarizes the recent advancements and challenges associated with the evolving NSCLC therapeutic landscape.
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Affiliation(s)
- Po-Lan Su
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Rd., North District, Tainan, 704, Taiwan
| | - Naoki Furuya
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Alahmadi Asrar
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA
| | - Christian Rolfo
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA
| | - Zihai Li
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA
| | - David P Carbone
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA
| | - Kai He
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA.
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Moradi S, Sarikhani P, Albadr RJ, Taher WM, Alwan M, Jawad MJ, Mushtaq H, Vakilzadehian N. PD-1/PD-L1 blockade therapy with atezolizumab: a new paradigm in the treatment of non-small cell lung cancer (NSCLC). Discov Oncol 2025; 16:407. [PMID: 40140170 PMCID: PMC11947372 DOI: 10.1007/s12672-025-02076-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 03/05/2025] [Indexed: 03/28/2025] Open
Abstract
Now, platinum-based chemotherapy is used as the first-line treatment for advanced non-small cell lung cancer (NSCLC). Interestingly, a combination of immune checkpoint inhibitors, such as mepolizumab, with other targeted therapies and chemotherapy help to make a significant improvement. Atezolizumab, a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1), blocks PD-1 activation and results in T-cell activity against tumor cells. As the second-line treatment of advanced or metastatic NSCLC, atezolizumab plus chemotherapy was approved in 2017 concerning the clinical benefit of the phase III OAK trials. Atezolizumab, compared with docetaxel, remarkably increased overall survival (OS) and showed promising efficacy and tolerability in the treatment of advanced NSCLC.Research on atezolizumab's application in neoadjuvant (pre-surgery) and adjuvant (post-surgery) contexts is ongoing. It is now undergoing trials to assess its efficacy in these settings, which may broaden its place in the NSCLC therapy spectrum and enhance long-term results. This paper briefly summarizes the clinical data of atezolizumab therapy alone or in combination with other therapeutics for NSCLC therapy.
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Affiliation(s)
- Samaneh Moradi
- Departments of Internal Medical, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Pedram Sarikhani
- Medicine Department, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
| | | | | | - Niyousha Vakilzadehian
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Tehran, Tehran, Iran
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Dong S, Li X, Huang Q, Li Y, Li J, Zhu X, Xue C, Chen R, Zeng Y, Wu J, Zhong Y, Hu S. Resistance to immunotherapy in non-small cell lung cancer: Unraveling causes, developing effective strategies, and exploring potential breakthroughs. Drug Resist Updat 2025; 81:101215. [PMID: 40081220 DOI: 10.1016/j.drup.2025.101215] [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: 08/21/2024] [Revised: 02/13/2025] [Accepted: 02/16/2025] [Indexed: 03/15/2025]
Abstract
Over the last two decades, advancements in deciphering the intricate interactions between oncology and immunity have fueled a meteoric rise in immunotherapy for non-small cell lung cancer, typified by an explosive growth of immune checkpoint inhibitors. However, resistance to immunotherapy remains inevitable. Herein we unravel the labyrinthine mechanisms of resistance to immunotherapy, characterized by their involvement of nearly all types of cells within the body, beyond the extrinsic cancer cells, and importantly, such cells are not only (inhibitory or excitatory, or both) signal recipients but also producers, acting in a context-dependent manner. At the molecular level, these mechanisms underlie genetic and epigenetic aberrations, which are regulated by or regulate various protein kinases, growth factors, and cytokines with inherently dynamic and spatially heterogeneous properties. Additionally, macroscopic factors such as nutrition, comorbidities, and the microbiome within and around organs or tumor cells are involved. Therefore, developing therapeutic strategies combined with distinct action informed by preclinical, clinical, and real-world evidence, such as radiotherapy, chemotherapy, targeted therapy, antibody-drug conjugates, oncolytic viruses, and cell-based therapies, may stand as a judicious reality, although the ideality is to overcome resistance point-by-point through a novel drug. Notably, we highlight a realignment of treatment aims, moving the primary focus from eliminating cancer cells -- such as through chemotherapy and radiotherapy -- to promoting immune modulation and underscore the value of regulating various components within the host macro- or micro-environment, as their effects, even if seemingly minimal, can cumulatively contribute to visible clinical benefit when applied in combination with ICIs. Lastly, this review also emphasizes the current hurdles scattered throughout preclinical and clinical studies, and explores evolving directions in the landscape of immunotherapy for NSCLC.
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Affiliation(s)
- Shuang Dong
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Xiaoyu Li
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Qing Huang
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Yuanxiang Li
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | | | - Xianmin Zhu
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Chang Xue
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Runzhi Chen
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Yuan Zeng
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Jingyi Wu
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Yi Zhong
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China.
| | - Sheng Hu
- Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China.
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Wang R, Liu Y, Liu M, Zhang M, Li C, Xu S, Tang S, Ma Y, Wu X, Fei W. Combating tumor PARP inhibitor resistance: Combination treatments, nanotechnology, and other potential strategies. Int J Pharm 2025; 669:125028. [PMID: 39638266 DOI: 10.1016/j.ijpharm.2024.125028] [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: 09/04/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi) have demonstrated significant potential in cancer treatment, particularly in tumors with breast cancer susceptibility gene (BRCA) mutations and other DNA repair deficiencies. However, the development of resistance to PARPi has become a major challenge in their clinical application. The emergence of drug resistance leads to reduced efficacy of the PARPi over time, impacting long-term treatment outcomes and survival rates. PARPi resistance in tumors often arises as cells activate alternative DNA repair pathways or evade the effect of PARPi, diminishing therapeutic effectiveness. Consequently, overcoming resistance is crucial for maintaining treatment efficacy and improving patient prognosis. This paper reviews the strategies to overcome PARPi resistance through combination treatment and nanotechnology therapy. We first review the current combination therapies with PARPi, including anti-angiogenic therapies, radiotherapies, immunotherapies, and chemotherapies, and elucidate their mechanisms for overcoming PARPi resistance. Additionally, this paper focuses on the application of nanotechnology in improving the effectiveness of PARPi and overcoming drug resistance. Subsequently, this paper presents several promising strategies to tackle PARPi resistance, including but not limited to: structural modifications of PARPi, deployment of gene editing systems, implementation of "membrane lipid therapy," and modulation of cellular metabolism in tumors. By integrating these strategies, this research will provide comprehensive approaches to overcome the resistance of PARPi in cancer treatment and offer guidance for future research and clinical practice.
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Affiliation(s)
- Rong Wang
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yunxi Liu
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Mingqi Liu
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Meng Zhang
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Chaoqun Li
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Shanshan Xu
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Sangsang Tang
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yidan Ma
- YiPeng Subdistrict Community Healthcare Center, Hangzhou 311225, China
| | - Xiaodong Wu
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Weidong Fei
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
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Wang Q, Zhong J, Wang Y, Bao J, Li S, Yang L. Efficacy of Combined PD-1 Inhibitor and Bevacizumab in Unresectable Liver Metastasis of MSI-H Colorectal Cancer: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2025; 26:e946757. [PMID: 39789783 PMCID: PMC11730553 DOI: 10.12659/ajcr.946757] [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: 10/02/2024] [Revised: 01/02/2025] [Accepted: 12/16/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Programmed death 1 (PD-1) inhibitors have demonstrated limited effectiveness in patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC). Recent studies suggest that their efficacy can be enhanced when combined with anti-angiogenic agents. CASE REPORT We present a case of a 25-year-old woman with CRC harboring a KRAS mutation and MSI-H status, along with initially unresectable liver metastases. Despite receiving first-line chemotherapy combined with bevacizumab, her disease progressed. Subsequently, she was treated with a combination of a PD-1 inhibitor and bevacizumab as second-line therapy. This approach resulted in a partial response, ultimately leading to a pathological complete response after resection of the liver metastases. The patient continued with the combination therapy for over a year and showed no serious treatment-related adverse events. Postoperative follow-up imaging confirmed the absence of tumor recurrence or metastasis, and the patient remained in remission. CONCLUSIONS This case highlights the potential of combining immune checkpoint inhibitors with anti-angiogenic agents in treating patients with MSI-H metastatic CRC, particularly those with initially unresectable liver metastases. Although further research is warranted to validate this therapeutic strategy, our findings support the use of this combination as a viable option for achieving pathological complete response and improving outcomes in this patient population. Comprehensive clinical studies are needed to optimize conversion therapy regimens and enhance the likelihood of success in treating patients with MSI-H CRC with advanced disease.
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Affiliation(s)
- Qifan Wang
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Jie Zhong
- Oncology Center, The Fifth Hospital Affiliated to Wenzhou Medical University & Lishui Central Hospital, Lishui, Zhejiang, PR China
| | - Yi Wang
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Jun Bao
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Sheng Li
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
| | - Liu Yang
- Colorectal Center, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, PR China
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Wu S, Ho C, Yang JC, Yu S, Lin Y, Lin S, Liao B, Yang C, Lin Y, Yu C, Chuang Y, Liao W, Yap KY, Kou WS, Shih J. Atezolizumab, bevacizumab, pemetrexed and platinum for EGFR-mutant NSCLC patients after EGFR TKI failure: A phase II study with immune cell profile analysis. Clin Transl Med 2025; 15:e70149. [PMID: 39715697 PMCID: PMC11666332 DOI: 10.1002/ctm2.70149] [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: 09/22/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) remains a significant hurdle for patients with EGFR-mutated non-small cell lung cancer (NSCLC), particularly those lacking the EGFRT790M. IMpower 150 study demonstrated promising efficacy for a combination of immune-chemotherapy and bevacizumab in patients with EGFR-mutated NSCLC. METHODS This open-label, single-arm, phase II trial evaluated the efficacy and immune cell profile of the modified regimen combining atezolizumab, bevacizumab (7.5 mg/kg) and chemotherapy in patients with EGFR-mutated NSCLC following TKI failure. The primary endpoint was objective response rate (ORR). The re-biopsy tissue specimens and serial peripheral blood samples were collected to analyse the immune cell profile and tumour microenvironments. RRESULTS 22 EGFR-mutant NSCLC patients participated in this study. The ORR was 42.9%, with a disease control rate (DCR) of 100%. Median progression-free survival (PFS) was 6.3 months. Patients with programmed death-ligand 1 (PD-L1) expression ≥1% exhibited significantly higher ORR (75 vs. 23.1%; p = .032) and longer PFS (14.0 vs. 6.1 months; p = .022) compared with those with PD-L1 expression < 1%. Grade ≥ 3 adverse events occurred in 40.9% of patients. Higher peritumour nature killer (NK) cell infiltration and lower peripheral helper T cell counts before treatment were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ myelod-derived suppressor cells (MDSCs) increased, while regulatory T cells decreased. CONCLUSION This modified combination regimen may be a promising therapeutic option for EGFR-mutant NSCLC patients with TKI resistance, especially those with PD-L1-positive tumours. Furthermore, immune cell profiling may aid in identifying patients who may benefit from this approach. KEY POINTS The combination regimen yielded promising efficacy in NSCLC patients after EGFR-TKI resistance, particularly those with PD-L1-positive tumours. Higher peritumour NK cell and lower peripheral helper T cell were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ MDSC increased, but Treg cells decreased.
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Affiliation(s)
- Shang‐Gin Wu
- Department of Internal MedicineNational Taiwan University Cancer CenterTaipeiTaiwan
- Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
| | - Chao‐Chi Ho
- Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
| | - James Chih‐Hsin Yang
- Department of OncologyNational Taiwan University Cancer CenterTaipeiTaiwan
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
- Graduate Institute of OncologyCancer Research CenterNational Taiwan UniversityTaipeiTaiwan
| | - Shu‐Han Yu
- Institute of BiotechnologyNational Taiwan UniversityTaipeiTaiwan
| | - Yen‐Feng Lin
- Center for Neuropsychiatric ResearchNational Health Research InstitutesMiaoliTaiwan
- Department of Public Health & Medical HumanitiesSchool of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Institute of Behavioral MedicineCollege of MedicineNational Cheng Kung UniversityTainanTaiwan
| | - Shu‐Chin Lin
- Center for Neuropsychiatric ResearchNational Health Research InstitutesMiaoliTaiwan
| | - Bin‐Chi Liao
- Department of OncologyNational Taiwan University Cancer CenterTaipeiTaiwan
- Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
| | - Ching‐Yao Yang
- Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
| | - Yen‐Ting Lin
- Department of Internal MedicineNational Taiwan University Cancer CenterTaipeiTaiwan
- Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
| | - Chong‐Jen Yu
- Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
- Department of Internal MedicineNational Taiwan University Hospital Hsinchu BranchHsinchuTaiwan
| | - Ya‐Ting Chuang
- Department of Medical ResearchNational Taiwan University HospitalTaipeiTaiwan
| | - Wei‐Yu Liao
- Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
| | - Kah Yi Yap
- Institute of BiotechnologyNational Taiwan UniversityTaipeiTaiwan
| | - Weng Si Kou
- Institute of BiotechnologyNational Taiwan UniversityTaipeiTaiwan
| | - Jin‐Yuan Shih
- Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
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10
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Yadav R, Khatkar R, Yap KCH, Kang CYH, Lyu J, Singh RK, Mandal S, Mohanta A, Lam HY, Okina E, Kumar RR, Uttam V, Sharma U, Jain M, Prakash H, Tuli HS, Kumar AP, Jain A. The miRNA and PD-1/PD-L1 signaling axis: an arsenal of immunotherapeutic targets against lung cancer. Cell Death Discov 2024; 10:414. [PMID: 39343796 PMCID: PMC11439964 DOI: 10.1038/s41420-024-02182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/21/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system's response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host's miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.
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Affiliation(s)
- Ritu Yadav
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Rinku Khatkar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Kenneth C-H Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chloe Yun-Hui Kang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Juncheng Lyu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rahul Kumar Singh
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Surojit Mandal
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Adrija Mohanta
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Rajiv Ranjan Kumar
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Vivek Uttam
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Uttam Sharma
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| | | | | | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Aklank Jain
- Non-Coding RNA and Cancer Biology Laboratory, Department of Zoology, Central University of Punjab, Bathinda, Punjab, India.
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11
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Guo G, Zhang Z, Zhang J, Wang D, Xu S, Liu G, Gao Y, Mei J, Yan Z, Zhao R, Wang M, Li T, Bu X. Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis. Cancer Immunol Immunother 2024; 73:193. [PMID: 39105794 PMCID: PMC11303371 DOI: 10.1007/s00262-024-03774-7] [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: 05/08/2024] [Accepted: 07/05/2024] [Indexed: 08/07/2024]
Abstract
OBJECTIVE Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION This trial is registered with ClinicalTrials.gov, NCT05540275.
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Affiliation(s)
- Guangzhong Guo
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Ziyue Zhang
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Jiubing Zhang
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Dayang Wang
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Sensen Xu
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Guanzheng Liu
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yushuai Gao
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Jie Mei
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Zhaoyue Yan
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Ruijiao Zhao
- Department of Pathology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Meiyun Wang
- Department of Radiology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Tianxiao Li
- Henan Provincial Neurointerventional Engineering Research Center, Henan International Joint Laboratory of Cerebrovascular Disease, Henan Engineering Research Center of Cerebrovascular Intervention Innovation, Zhengzhou, Henan, China
- Department of Cerebrovascular Disease, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Zhengzhou, Henan, China
| | - Xingyao Bu
- Department of Neurosurgery, Juha International Center for Neurosurgery, Glioma Clinical Diagnosis and Treatment Center of Henan Province, Glioma Engineering Research Center for Precision Diagnosis and Treatment of Henan Province, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China.
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12
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Dong C, Hui K, Gu J, Wang M, Hu C, Jiang X. Plasma sPD-L1 and VEGF levels are associated with the prognosis of NSCLC patients treated with combination immunotherapy. Anticancer Drugs 2024; 35:418-425. [PMID: 38386011 DOI: 10.1097/cad.0000000000001576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2024]
Abstract
The clinical significance of plasma soluble programmed cell death ligand 1 (sPD-L1) and vascular endothelial growth factor (VEGF) for non-small cell lung cancer (NSCLC) treated with the combination of anti-angiogenic therapy and anti-PD-L1 antibody (Ab) remain unknown. This study aimed to explore the association between plasma sPD-L1 and VEGF levels and the prognosis of NSCLC patients treated with the combination of Envafolimab and Endostar. Peripheral blood samples were collected from 24 NSCLC patients at baseline and after 6 weeks of treatment and were detected for sPD-L1 and VEGF levels. Both baseline and posttreatment sPD-L1 were significantly higher in progressive disease (PD) group than in controlled disease (CD) group (median: 77.5 pg/ml vs. 64.6 pg/ml, P = 0.036, median: 8451 pg/ml vs. 5563 pg/ml, P = 0.012). In multivariate analysis, lower baseline sPD-L1 levels were significantly associated with longer progression-free survival (PFS) (HR = 6.834, 95% CI: 1.350-34.592, P = 0.020). There were significantly higher posttreatment VEGF levels in PD group compared with CD group (median: 323.7 pg/ml vs. 178.5 pg/ml, P = 0.009). Higher posttreatment VEGF levels were significantly associated with shorter PFS in multivariate analysis (HR = 5.911, 95% CI: 1.391-25.122, P = 0.016). Plasma sPD-L1 and VEGF levels are associated with the clinical response and prognosis of NSCLC patients treated with the combination of PD-L1 inhibitors and anti-angiogenetic therapy.
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Affiliation(s)
- Changhong Dong
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu Province, China
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13
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Yamaguchi T, Shimizu J, Shigematsu F, Watanabe N, Hasegawa T, Horio Y, Inaba Y, Fujiwara Y. Atezolizumab and nintedanib in patients with non-small cell lung cancer and interstitial lung disease. J Thorac Dis 2024; 16:3371-3380. [PMID: 38883641 PMCID: PMC11170387 DOI: 10.21037/jtd-24-45] [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: 01/07/2024] [Accepted: 03/29/2024] [Indexed: 06/18/2024]
Abstract
In patients with non-small cell lung cancer (NSCLC), pre-existing interstitial lung disease (ILD) is a risk factor for the development of pneumonitis induced by immune checkpoint inhibitors (ICIs). Anti-fibrotic agents, including nintedanib, reduce the potential for acute exacerbation of idiopathic pulmonary fibrosis (IPF). However, whether nintedanib can reduce the potential for ICI-induced pneumonitis is unknown. From among 140 patients with NSCLC treated with atezolizumab monotherapy at our institution, we retrospectively investigated 4 patients with pre-existing ILD treated concurrently with nintedanib. On computed tomography (CT), a usual interstitial pneumonia (UIP) pattern was present in one patient, probable UIP pattern in one patient, and indeterminate for UIP pattern in two patients. Of those four patients with pre-existing ILD, two achieved a partial response to ICI treatment, with response durations of 8.1 and 7.6 months. The other two patients experienced progressive disease. Notable adverse events included the development of non-symptomatic grade 1 pneumonitis in the patient with a probable UIP pattern and grade 3 lower gastrointestinal hemorrhage in another patient. None of the patients experienced a worsening of respiratory symptoms. In patients with NSCLC and pre-existing ILD, nintedanib might reduce the potential for ICI-induced pneumonitis and enhance the antitumor effect.
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Affiliation(s)
- Teppei Yamaguchi
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Junichi Shimizu
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Fumie Shigematsu
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Naohiro Watanabe
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takaaki Hasegawa
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yoshitsugu Horio
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yoshitaka Inaba
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yutaka Fujiwara
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
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14
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Frentzas S, Austria Mislang AR, Lemech C, Nagrial A, Underhill C, Wang W, Wang ZM, Li B, Xia Y, Coward JIG. Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors. J Immunother Cancer 2024; 12:e008037. [PMID: 38642937 PMCID: PMC11033648 DOI: 10.1136/jitc-2023-008037] [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] [Accepted: 03/12/2024] [Indexed: 04/22/2024] Open
Abstract
BACKGROUND Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. METHODS Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer. CONCLUSIONS Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted. TRIAL REGISTRATION NUMBER NCT04047290.
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Affiliation(s)
- Sophia Frentzas
- Department of Medical Oncology, Monash Health, Melbourne, Victoria, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
| | - Anna Rachelle Austria Mislang
- Icon (Adelaide) Cancer Centre, Kurralta Park, South Australia, Australia
- Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
| | - Charlotte Lemech
- Scientia Clinical Research Ltd, Sydney, New South Wales, Australia
| | - Adnan Nagrial
- Blacktown Cancer and Haematology Centre, Blacktown Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Craig Underhill
- Border Medical Oncology and Haematology Research Unit, Albury-Wodonga Regional Cancer Centre, Albury Wodonga, New South Wales, Australia
- University of New South Wales, Rural Medical School, Albury Campus, Sydney, New South Wales, Australia
| | | | | | | | - Yu Xia
- Akeso Biopharma, Inc, Zhongshan, China
| | - Jermaine I G Coward
- Icon Cancer Centre, Brisbane, Queensland, Australia
- Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia
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15
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Dong C, Hu C, Jiang Y, Hui K, Jiang X. Case report: Envafolimab combined with Endostar in the treatment of advanced non-small cell lung cancer with malignant pleural effusion. Front Oncol 2024; 14:1368059. [PMID: 38638859 PMCID: PMC11024318 DOI: 10.3389/fonc.2024.1368059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/21/2024] [Indexed: 04/20/2024] Open
Abstract
Malignant pleural effusion (MPE) is one of the common complications of lung cancer. The quality of life and prognoses for MPE patients are significantly compromised. Controlling the production of MPE can relieve patients' symptoms, improve their quality of life, and prolong their survival. This article presents a case of advanced non-small cell lung cancer (NSCLC) with MPE and negative driver genes. The patient received envafolimab and Endostar in combination, resulting in a complete reduction of MPE and durable clinical benefits. The exploratory use of this treatment method improved the quality of life of this patient and has the potential to prolong the survival of this patient.
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Affiliation(s)
| | | | | | - Kaiyuan Hui
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China
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16
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Wang J, Peng J, Chen Y, Nasser MI, Qin H. The role of stromal cells in epithelial-mesenchymal plasticity and its therapeutic potential. Discov Oncol 2024; 15:13. [PMID: 38244071 PMCID: PMC10799841 DOI: 10.1007/s12672-024-00867-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 01/15/2024] [Indexed: 01/22/2024] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a critical tumor invasion and metastasis process. EMT enables tumor cells to migrate, detach from their original location, enter the circulation, circulate within it, and eventually exit from blood arteries to colonize in foreign sites, leading to the development of overt metastases, ultimately resulting in death. EMT is intimately tied to stromal cells around the tumor and is controlled by a range of cytokines secreted by stromal cells. This review summarizes recent research on stromal cell-mediated EMT in tumor invasion and metastasis. We also discuss the effects of various stromal cells on EMT induction and focus on the molecular mechanisms by which several significant stromal cells convert from foes to friends of cancer cells to fuel EMT processes via their secretions in the tumor microenvironment (TME). As a result, a better knowledge of the role of stromal cells in cancer cells' EMT may pave the path to cancer eradication.
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Affiliation(s)
- Juanjing Wang
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmaceutical Science, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Junmei Peng
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmaceutical Science, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Yonglin Chen
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The Hengyang Key Laboratory of Cellular Stress Biology, Institute of Cytology and Genetics, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, People's Republic of China
- Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, China
| | - M I Nasser
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
| | - Hui Qin
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- The Hengyang Key Laboratory of Cellular Stress Biology, Institute of Cytology and Genetics, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
- Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, School of Basic Medical Sciences, University of South China, Hengyang, 421001, Hunan, China.
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Curkovic NB, Bai K, Ye F, Johnson DB. Incidence of Cutaneous Immune-Related Adverse Events and Outcomes in Immune Checkpoint Inhibitor-Containing Regimens: A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 16:340. [PMID: 38254829 PMCID: PMC10814132 DOI: 10.3390/cancers16020340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are used to treat many cancers, and cutaneous immune-related adverse events (cirAEs) are among the most frequently encountered toxic effects. Understanding the incidence and prognostic associations of cirAEs is of importance as their uses in different settings, combinations, and tumor types expand. To evaluate the incidence of cirAEs and their association with outcome measures across a variety of ICI regimens and cancers, we performed a systematic review and meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) ICIs, both alone and in combination with chemotherapy, antiangiogenic agents, or other ICIs in patients with melanoma, renal cell carcinoma, non-small cell lung cancer, and urothelial carcinoma. Key findings of our study include variable cirAE incidence among tumors and ICI regimens, positive association with increased cirAE incidence and response rate, as well as significant association between increased vitiligo incidence and overall survival. Across 174 studies, rash, pruritis, and vitiligo were the most reported cirAEs, with incidences of 16.7%, 18.0%, and 6.6%, respectively. Higher incidence of cirAEs was associated with ICI combination regimens and with CTLA-4-containing regimens, particularly with higher doses of ipilimumab, as compared to PD-1/L1 monotherapies. Outcome measures including response rate and progression-free survival were positively correlated with incidence of cirAEs. The response rate and incidence of pruritis, vitiligo, and rash were associated with expected rises in incidence of 0.17% (p = 0.0238), 0.40% (p = 0.0010), and 0.18% (p = 0.0413), respectively. Overall survival was positively correlated with the incidence of pruritis, vitiligo, and rash; this association was significant for vitiligo (p = 0.0483). Our analysis provides benchmark incidence rates for cirAEs and links cirAEs with favorable treatment outcomes at a study level across diverse solid tumors and multiple ICI regimens.
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Affiliation(s)
- Nina B. Curkovic
- School of Medicine, Vanderbilt University, Nashville, TN 37232, USA
| | - Kun Bai
- Vanderbilt Ingram Cancer Center, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Fei Ye
- Vanderbilt Ingram Cancer Center, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Douglas B. Johnson
- Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
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Meng Y, Liu H, Zhu H, Zhang W, Sun D, Han X, Liu Y, Luo G. RCAd-LTH-shPD-L1, a double-gene recombinant oncolytic adenovirus with enhanced antitumor immunity, increases lymphocyte infiltration and reshapes the tumor microenvironment. J Immunother Cancer 2024; 12:e007171. [PMID: 38212125 PMCID: PMC10806565 DOI: 10.1136/jitc-2023-007171] [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] [Accepted: 12/21/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND With the successful development of modern immunotherapy, immune checkpoint inhibitors (ICIs) are currently considered potential therapeutic options for patients with cancer. However, the therapeutic potential of ICIs in human cancer is mainly limited by their systemic toxicity and low response rate, which suggests the necessity of local drug delivery with an effective vector and reshaping the immunosuppressive tumor microenvironment (TME) to enhance ICI therapy. Here, we constructed a novel double-gene recombinant oncolytic adenovirus named RCAd-LTH-shPD-L1 based on the RCAd virus platform armed with a DNA fragment encoding an anti-VEGF antibody and shRNA to inhibit PD-L1 expression. METHODS The correct assembly of RCAd-LTH-shPD-L1 was characterized by analyzing its secretion, antigen specificity, and replication using western blotting, ELISA and quantitative PCR, respectively. The in vitro effects of RCAd-LTH-shPD-L1 on cell proliferation, vasculogenic, and cell migration were assessed. Antitumor effects and therapeutic mechanisms were evaluated in vivo using immunodeficient and humanized immune system mouse models. The TME was studied by ELISA, immunohistochemistry and flow cytometry. RESULTS RCAd-LTH-shPD-L1 cells secreted anti-VEGF antibodies and inhibited the expression of PD-L1 in cancer cells. Moreover, RCAd-LTH-shPD-L1 exerted a specific cytotoxic effect on human cancer cells, but not on murine cancer cells or normal human cells. RCAd-LTH-shPD-L1 elicited a more potent antitumor effect in an immunodeficient mouse model and a humanized immune system mouse model than RCAd-shPD-L1, as demonstrated by the significant decrease in tumor growth. Furthermore, RCAd-LTH-shPD-L1 modulated the TME, which led to lymphocyte infiltration and alteration of their immune phenotype, as characterized by downregulation of anoxic factor HIF-1α and angiogenesis marker CD31, upregulation of cytokine such as IFN-γ, IL-6 and IL-12. CONCLUSIONS In summary, our data demonstrated that the localized delivery of anti-VEGF antibodies and shPD-L1 by engineered RCAd-LTH-shPD-L1 is a highly effective and safe strategy for cancer immunotherapy. Moreover, the data underscore the potential of combining local virotherapy and anti-angiogenic therapy with ICIs as an effective TME therapy for poorly infiltrating tumors.
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Affiliation(s)
- Yuan Meng
- Institute of Health Science, China Medical University, Shenyang, China
| | - Haotian Liu
- Institute of Health Science, China Medical University, Shenyang, China
| | - Haoran Zhu
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Wanrong Zhang
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Dong Sun
- Bionce Biotechnology Co., Ltd, Nanjing, China
| | - Xuefei Han
- Bionce Biotechnology Co., Ltd, Nanjing, China
| | - Ying Liu
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, China
| | - Guangzuo Luo
- Institute of Health Science, China Medical University, Shenyang, China
- Bionce Biotechnology Co., Ltd, Nanjing, China
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Mai Y, Su J, Yang C, Xia C, Fu L. The strategies to cure cancer patients by eradicating cancer stem-like cells. Mol Cancer 2023; 22:171. [PMID: 37853413 PMCID: PMC10583358 DOI: 10.1186/s12943-023-01867-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/21/2023] [Indexed: 10/20/2023] Open
Abstract
Cancer stem-like cells (CSCs), a subpopulation of cancer cells, possess remarkable capability in proliferation, self-renewal, and differentiation. Their presence is recognized as a crucial factor contributing to tumor progression and metastasis. CSCs have garnered significant attention as a therapeutic focus and an etiologic root of treatment-resistant cells. Increasing evidence indicated that specific biomarkers, aberrant activated pathways, immunosuppressive tumor microenvironment (TME), and immunoevasion are considered the culprits in the occurrence of CSCs and the maintenance of CSCs properties including multi-directional differentiation. Targeting CSC biomarkers, stemness-associated pathways, TME, immunoevasion and inducing CSCs differentiation improve CSCs eradication and, therefore, cancer treatment. This review comprehensively summarized these targeted therapies, along with their current status in clinical trials. By exploring and implementing strategies aimed at eradicating CSCs, researchers aim to improve cancer treatment outcomes and overcome the challenges posed by CSC-mediated therapy resistance.
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Affiliation(s)
- Yansui Mai
- Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jiyan Su
- Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Chuan Yang
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Chenglai Xia
- Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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20
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He D, Wang L, Xu J, Zhao J, Bai H, Wang J. Research advances in mechanism of antiangiogenic therapy combined with immune checkpoint inhibitors for treatment of non-small cell lung cancer. Front Immunol 2023; 14:1265865. [PMID: 37915579 PMCID: PMC10618022 DOI: 10.3389/fimmu.2023.1265865] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/26/2023] [Indexed: 11/03/2023] Open
Abstract
Immunotherapy has changed the treatment strategy of non-small cell lung cancer (NSCLC) in recent years, among which anti-PD-1/PD-L1 antibodies are the most used. However, the majority of patients with NSCLC do not derive benefit from immune checkpoint inhibitors (ICIs). Vascular abnormalities are a hallmark of most solid tumors and facilitate immune evasion. Thus, combining antiangiogenic therapies might increase the effectiveness of anti-PD-1/PD-L1 antibodies. In this paper, the mechanisms of anti-angiogenic agents combined with anti-PD-1/PD-L1 antibodies are illustrated, moreover, relevant clinical studies and predictive immunotherapeutic biomarkers are summarized and analyzed, in order to provide more treatment options for NSCLC patients.
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Affiliation(s)
| | | | | | | | - Hua Bai
- Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jie Wang
- Chinese Academy of Medical Sciences (CAMS) Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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21
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Zheng Y, Dong H, Yu Y, Hu Z, Xue C, Zhang X, Cui H. Treatment-related adverse events of immune checkpoint inhibitors combined with angiogenesis inhibitors in advanced lung cancer: A systematic review and meta-analysis. Int Immunopharmacol 2023; 123:110785. [PMID: 37598630 DOI: 10.1016/j.intimp.2023.110785] [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: 02/20/2023] [Revised: 07/06/2023] [Accepted: 08/08/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) with angiogenesis inhibitors have been used to treat advanced lung cancer. Their associated treatment-related adverse events (trAEs) are currently considered acceptable; however, no conclusion has been reached. We aimed to summarize the trAEs caused by ICIs combined with angiogenesis inhibitors in patients with advanced lung cancer. METHODS Pulled studies met the following criteria: patients with advanced lung cancer who received treatment involving ICIs combined with angiogenesis inhibitors (with or without chemotherapy) in interventional or observational studies. Results included the type and number of trAEs or immune-related adverse events (irAEs), treatment-associated discontinuation and mortality, overall survival (OS), and progression-free survival (PFS). PROSPERO CRD42022337656. RESULTS The study enrolled 32 trials involving 2313 patients who had 7768 any-grade trAEs and 1078 grade ≥3 trAEs. The pooled incidences were 87.33% (95% confidence interval [CI]: 79.49-93.65; I2 = 94.04%) for any-grade trAEs, and 38.63% (95% CI: 28.28-49.50; I2 = 95.61%) for grade ≥3 trAEs. There were 132 kinds of any-grade trAEs involving 18 systems, and 99 kinds of grade ≥3 trAEs involving 16 systems. For all trAEs, we observed significant differences in the line of therapy, trial design, therapy combination, and types of angiogenesis inhibitors (all P < 0.05). The rate of trAEs increased with dosage and frequency of medication. Pooled incidences of discontinuation and mortality were 10.64% and 0.81%, respectively. Nearly 647 patients experienced irAEs, including 636 any-grade irAEs and 154 grade ≥3 irAEs. CONCLUSIONS Overall, the incidence of trAEs caused by ICIs combined with angiogenesis inhibitors is generally acceptable. These trAEs have a wide spectrum nearly covering the full range of adverse events. Grade ≥3 trAEs are more closely associated with angiogenesis inhibitors than any grade. However, treatment-associated mortality remains concerning.
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Affiliation(s)
- Yumin Zheng
- Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Huijing Dong
- Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Yixuan Yu
- Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Zixin Hu
- Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Chongxiang Xue
- Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Xu Zhang
- Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, People's Republic of China.
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Zhang J, Zou Z, Tan J, Shi J, Yang H, Wang H, Zhou J, Xue J. Efficacy and Safety Analysis of Immune Checkpoint Inhibitors plus Angiogenesis Inhibitors for the Treatment of Advanced Driver-negative NSCLC in Elderly Patients: A Retrospective Study. J Cancer 2023; 14:1623-1634. [PMID: 37325057 PMCID: PMC10266243 DOI: 10.7150/jca.83719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/17/2023] [Indexed: 06/17/2023] Open
Abstract
Background and Objective: Immune checkpoint inhibitors (ICIs) combined with angiogenesis inhibitors may have synergistic effects in elderly patients with advanced driver-negative NSCLC, but its true efficacy remains unclear. In addition, chemotherapy tolerance in elderly NSCLC patients is poor, and the precise identification of the population that may benefit from ICIs combined with angiogenesis inhibitors is also the focus of current research. Methods: We retrospectively compared the efficacy and safety of ICIs combined with or without antiangiogenic agents in elderly patients with advanced driver-gene negative NSCLC ≥65 years of age in the Cancer Center of Suzhou Hospital Affiliated to Nanjing Medical University. The primary endpoint was PFS. Secondary endpoints were OS, ORR, and immune-related adverse events (irAEs). Results: A total of 36 patients in the IA group (immune checkpoint inhibitors plus angiogenesis inhibitors group) and 43 patients in the NIA group (immune checkpoint inhibitors without angiogenesis inhibitors group) were enrolled in the study between January 1, 2019 and December 31, 2021. The median follow-up time for patients in the IA group and NIA group was 18.2 months (95%CI: 14 - 22.5 months) and 21.4 months (95%CI: 16.7 -26.1 months), respectively. The median PFS and median OS were longer in the IA group compared to the NIA group (8.1 months vs 5.3 months; HR for PFS: 0.778, 95%CI: 0.474-1.276, P=0.32; NA vs 30.9 months; HR for OS: 0.795, 95%CI: 0.396-1.595, P=0.519). There were no significant differences in median PFS and median OS between the two groups. Subgroup analysis showed that patients in the IA group had significantly longer PFS in the subgroup with PD-L1 expression ≥50% (P=0.017), and the association between different groups and disease progression was still different in the two subgroups (P for interaction = 0.002). There was no significant difference in ORR between the two groups (23.3% vs 30.5%, P=0.465). The incidence of irAEs in the IA group was lower than that in the NIA group (39.5% vs 19.4%, P=0.05), and the cumulative incidence of treatment interruptions due to irAEs was significantly reduced (P=0.045). Conclusion: In elderly patients with advanced driver-negative NSCLC, the addition of antiangiogenic agents to ICIs therapy did not provide significant clinical benefit, but the incidence of irAEs and treatment interruptions due to irAEs was significantly reduced. In the subgroup analysis, we found that the clinical benefit of this combination therapy was observed in patients with PD-L1 expression ≥50%, which warrants further exploration.
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Affiliation(s)
- Jian Zhang
- Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, China
| | - Zhonghua Zou
- Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, China
| | - Jie Tan
- Department of Medical Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, China
| | - Jianping Shi
- Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, China
| | - Hui Yang
- Department of Medical Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, China
| | - Hao Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, China
| | - Jundong Zhou
- Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, China
| | - Jing Xue
- Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215001, China
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23
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Li B, Jin J, Guo D, Tao Z, Hu X. Immune Checkpoint Inhibitors Combined with Targeted Therapy: The Recent Advances and Future Potentials. Cancers (Basel) 2023; 15:2858. [PMID: 37345194 PMCID: PMC10216018 DOI: 10.3390/cancers15102858] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 06/23/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer and have been widely approved for use in the treatment of diverse solid tumors. Targeted therapy has been an essential part of cancer treatment for decades, and in most cases, a special drug target is required. Numerous studies have confirmed the synergistic effect of combining ICIs with targeted therapy. For example, triple therapy of PD-L1 inhibitor atezolizumab plus BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib has been approved as the first-line treatment in advanced melanoma patients with BRAFV600 mutations. However, not all combinations of ICIs and targeted therapy work. Combining ICIs with EGFR inhibitors in non-small-cell lung cancer (NSCLC) with EGFR mutations only triggered toxicities and did not improve efficacy. Therefore, the efficacies of combinations of ICIs and different targeted agents are distinct. This review firstly and comprehensively covered the current status of studies on the combination of ICIs mainly referring to PD-1 and PD-L1 inhibitors and targeted drugs, including angiogenesis inhibitors, EGFR/HER2 inhibitors, PARP inhibitors and MAPK/ERK signaling pathway inhibitors, in the treatment of solid tumors. We discussed the underlying mechanisms, clinical efficacies, side effects, and potential predictive biomarkers to give an integrated view of the combination strategy and provide perspectives for future directions in solid tumors.
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Affiliation(s)
- Bin Li
- Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (B.L.); (J.J.); (D.G.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Juan Jin
- Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (B.L.); (J.J.); (D.G.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Duancheng Guo
- Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (B.L.); (J.J.); (D.G.)
| | - Zhonghua Tao
- Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (B.L.); (J.J.); (D.G.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xichun Hu
- Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; (B.L.); (J.J.); (D.G.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Provencio M, Ortega AL, Coves-Sarto J, Calvo V, Marsé-Fabregat R, Dómine M, Guirado M, Carcereny E, Fernández N, Álvarez R, Blanco R, León-Mateos L, Sánchez-Torres JM, Sullivan IG, Cobo M, Sánchez-Hernández A, Massuti B, Sierra-Rodero B, Mártinez-Toledo C, Serna-Blasco R, Romero A, Cruz-Bermúdez A. Atezolizumab Plus Bevacizumab as First-line Treatment for Patients With Metastatic Nonsquamous Non-Small Cell Lung Cancer With High Tumor Mutation Burden: A Nonrandomized Controlled Trial. JAMA Oncol 2023; 9:344-353. [PMID: 36520426 PMCID: PMC9856905 DOI: 10.1001/jamaoncol.2022.5959] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Importance Antiangiogenic drug combinations with anti-programmed cell death 1 protein and anti-programmed cell death 1 ligand 1 (PD-L1) agents are a novel treatment option for lung cancer. However, survival remains limited, and the activity of these combinations for tumors with high tumor mutation burden (TMB) is unknown. Objective To assess the clinical benefits and safety of atezolizumab plus bevacizumab for patients with high-TMB advanced nonsquamous non-small cell lung cancer (NSCLC). Design, Setting, and Participants This multicenter, single-arm, open-label, phase 2 nonrandomized controlled trial (Atezolizumab Plus Bevacizumab in First-Line NSCLC Patients [TELMA]) included treatment-naive patients aged 18 years or older with confirmed stage IIIB-IV nonsquamous NSCLC with TMB of 10 or more mutations/megabase and no EGFR, ALK, STK11, MDM2, or ROS1 alterations. From May 2019 through January 2021, patients were assessed at 13 sites in Spain, with follow-up until February 28, 2022. Interventions Participants were given atezolizumab, 1200 mg, plus bevacizumab, 15 mg/kg, on day 1 of each 21-day cycle. Treatment was continued until documented disease progression, unacceptable toxic effects, patient withdrawal, investigator decision, or death. Main Outcomes and Measures The primary end point was 12-month progression-free survival (PFS) rate (according to Response Evaluation Criteria in Solid Tumours, version 1.1 criteria); PFS was defined as the time from enrollment to disease progression or death. Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results A total of 307 patients were assessed for trial eligibility, of whom 266 were ineligible for enrollment. Of the 41 patients enrolled, 3 did not fulfill all inclusion criteria and were excluded. The remaining 38 patients (28 [73.7%] male; mean [SD] age, 63.7 [8.3] years) constituted the per-protocol population. The 12-month PFS rate was 51.3% (95% CI, 34.2%-66.0%), which met the primary end point. The 12-month overall survival (OS) rate was 72.0% (95% CI, 54.1%-83.9%). The median PFS was 13.0 months (95% CI, 7.9-18.0 months), and the median OS was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control. The median time to response was 2.8 months (IQR, 2.8-3.58 months), with a median duration of response of 11.7 months (range, 3.57-22.4 months; the response was ongoing at cutoff). Of 16 responses, 8 (50.0%) were ongoing. Most adverse events were grade 1 or 2. For atezolizumab, the most common adverse events were fatigue (6 [15.8%]) and pruritus (6 [15.8%]). For bevacizumab, they were hypertension (10 [26.3%]) and proteinuria (4 [10.5%]). Drug discontinuation occurred in 2 patients receiving atezolizumab (5.3%) and 3 patients receiving bevacizumab (7.9%). PD-L1 levels were not associated with response, PFS, or OS. Conclusions and Relevance These findings suggest that atezolizumab with bevacizumab is a potential treatment for high-TMB nonsquamous NSCLC. Trial Registration ClinicalTrials.gov Identifier: NCT03836066.
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Affiliation(s)
- Mariano Provencio
- Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Ana Laura Ortega
- Medical Oncology Department, Hospital Universitario de Jaén, Jaén, Spain
| | - Juan Coves-Sarto
- Medical Oncology Department, Hospital Universitari Son Llàtzer, Palma de Mallorca, Spain
| | - Virginia Calvo
- Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Raquel Marsé-Fabregat
- Medical Oncology Department, Hospital Universitari Son Espases, Palma de Mallorca, Spain
| | - Manuel Dómine
- Cancer Research Area, Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, Madrid, Spain
| | - María Guirado
- Medical Oncology Department, Hospital General Universitario de Elche General de Elche, Elche, Spain
| | - Enric Carcereny
- Medical Oncology Department, Catalan Institute of Oncology, Hospital Universitari Germans Trias i Pujol, Badalona Applied Research Group in Oncology, Germans Trias i Pujol Research Institute, Badalona, Spain
| | - Natalia Fernández
- Medical Oncology Department, Hospital Universitario Lucus Augusti, Lugo, Spain
| | | | | | - Luis León-Mateos
- Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain
| | | | | | - Manuel Cobo
- Hospital Universitario Regional de Málaga, Málaga, Spain
| | | | - Bartomeu Massuti
- Medical Oncology Department, Hospital General Universitario de Elche, Alicante, Spain
| | - Belen Sierra-Rodero
- Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | | | - Roberto Serna-Blasco
- Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Atocha Romero
- Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Alberto Cruz-Bermúdez
- Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
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25
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Ricciuti B, Awad MM. Atezolizumab Plus Bevacizumab in TMB-High Non-Small Cell Lung Cancers-The Hunt for Predictive Biomarkers to Optimize Treatment Selection. JAMA Oncol 2023; 9:353-354. [PMID: 36520420 DOI: 10.1001/jamaoncol.2022.5801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Biagio Ricciuti
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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Fu S, Huang H, Shang K, Tu G, Zhong P, Li S, Zhu X, Peng S, Liu Y, Lu Z, Chen L. Efficacy and safety of immune checkpoint inhibitors combined with recombinant human endostatin and chemotherapy as the first-line treatment of advanced non-small-cell lung cancer. Future Oncol 2023; 19:147-158. [PMID: 36779488 DOI: 10.2217/fon-2022-0861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2023] Open
Abstract
Background: To assess the efficacy and safety of combination of PD-1 inhibitors, recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: A total of 100 patients with advanced NSCLC were retrospectively reviewed and analyzed (58 in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy; 42 in the group receiving Rh-endostatin and chemotherapy). The primary end point was progression-free survival. Results: Patients in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy had significantly improved progression-free survival (10.2 vs 6.5 months; p < 0.001) and objective response rate (67.2 vs 42.9%; p = 0.015), with acceptable toxicity. Conclusion: Our study showed the superiority of combination therapy of PD-1 inhibitors and Rh-endostatin as first-line treatment for advanced NSCLC.
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Affiliation(s)
- Silv Fu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.,Department of Radiotherapy, Jiangxi Cancer Hospital, Nanchang, 330029, China
| | - Hongxiang Huang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Kai Shang
- Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Ganjie Tu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.,Department of Radiotherapy, Jiangxi Cancer Hospital, Nanchang, 330029, China
| | - Peiyuan Zhong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Siling Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Xie Zhu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Sujuan Peng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yangyang Liu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Zhihui Lu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Li Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
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Hu X, Wang L, Shang B, Wang J, Sun J, Liang B, Su L, You W, Jiang S. Immune checkpoint inhibitor-associated toxicity in advanced non-small cell lung cancer: An updated understanding of risk factors. Front Immunol 2023; 14:1094414. [PMID: 36949956 PMCID: PMC10025397 DOI: 10.3389/fimmu.2023.1094414] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/20/2023] [Indexed: 03/08/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs), such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, etc, have revolutionized cancer treatment strategies, including non-small cell lung cancer (NSCLC). While these immunotherapy agents have achieved durable clinical benefits in a subset of NSCLC patients, they bring in a variety of immune-related adverse events (irAEs), which involve cardiac, pulmonary, gastrointestinal, endocrine and dermatologic system damage, ranging from mild to life-threatening. Thus, there is an urgent need to better understand the occurrence of irAEs and predict patients who are susceptible to those toxicities. Herein, we provide a comprehensive review of what is updated about the clinical manifestations, mechanisms, predictive biomarkers and management of ICI-associated toxicity in NSCLC. In addition, this review also provides perspective directions for future research of NSCLC-related irAEs.
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Affiliation(s)
- Xiangxiao Hu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lina Wang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Respiratory and Critical Care Medicine, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bin Shang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junren Wang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jian Sun
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Bin Liang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lili Su
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Wenjie You
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- *Correspondence: Wenjie You, ; Shujuan Jiang,
| | - Shujuan Jiang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Wenjie You, ; Shujuan Jiang,
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Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L, Wang S. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol 2022; 13:964442. [PMID: 36177034 PMCID: PMC9513184 DOI: 10.3389/fimmu.2022.964442] [Citation(s) in RCA: 257] [Impact Index Per Article: 85.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Programmed cell death protein-1 (PD-1) is a checkpoint receptor expressed on the surface of various immune cells. PD-L1, the natural receptor for PD-1, is mainly expressed in tumor cells. Studies have indicated that PD-1 and PD-L1 are closely associated with the progression of human cancers and are promising biomarkers for cancer therapy. Moreover, the interaction of PD-1 and PD-L1 is one of the important mechanism by which human tumors generate immune escape. This article provides a review on the role of PD-L1/PD-1, mechanisms of immune response and resistance, as well as immune-related adverse events in the treatment of anti-PD-1/PD-L1 immunotherapy in human cancers. Moreover, we summarized a large number of clinical trials to successfully reveal that PD-1/PD-L1 Immune-checkpoint inhibitors have manifested promising therapeutic effects, which have been evaluated from different perspectives, including overall survival, objective effective rate and medium progression-free survival. Finally, we pointed out the current problems faced by PD-1/PD-L1 Immune-checkpoint inhibitors and its future prospects. Although PD-1/PD-L1 immune checkpoint inhibitors have been widely used in the treatment of human cancers, tough challenges still remain. Combination therapy and predictive models based on integrated biomarker determination theory may be the future directions for the application of PD-1/PD-L1 Immune-checkpoint inhibitors in treating human cancers.
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Affiliation(s)
- Qing Tang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yun Chen
- Department of Organ Transplantation, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaojuan Li
- Institute of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shunqin Long
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yao Shi
- Department of Cerebrovascular Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yaya Yu
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Wanyin Wu
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
| | - Sumei Wang
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Clinical and Basic Research Team of Traditional Chinese Medicine (TCM) Prevention and Treatment of Non small cell lung cancer (NSCLC), Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Wanyin Wu, ; Ling Han, ; Sumei Wang,
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Mizuno T, Katsuya Y, Sato J, Koyama T, Shimizu T, Yamamoto N. Emerging PD-1/PD-L1 targeting immunotherapy in non-small cell lung cancer: Current status and future perspective in Japan, US, EU, and China. Front Oncol 2022; 12:925938. [PMID: 36091105 PMCID: PMC9459234 DOI: 10.3389/fonc.2022.925938] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Non-small cell lung cancer (NSCLC), one of the deadliest types of cancers worldwide, has been the target of immunotherapy due to its high immune antigenicity. With the addition of immune-checkpoint inhibitors (ICIs), including anti-PD-1/PD-L1 antibodies, as an indispensable and powerful regimen for the treatment of this lethal disease, the median survival time for patients with stage IV NSCLC is approximately 2 years. In contrast, the response rate to ICIs remains less than 50%, even if the patients are selected using biomarkers such as PD-L1. Pharmaceutical companies have begun to develop additional anti-PD-1/PD-L1 antibodies to overcome resistance and are devising further immunotherapy combinations. More than 20 anti-PD-1/PD-L1antibodies have been approved or are currently in development. Numerous combination therapies are under development, and several combination therapies have provided positive results in randomized controlled trials. This review aimed to examine the current status of approved and investigational anti-PD-1/PD-L1antibodies for NSCLC in Japan, the United States, the European Union, and China. Further, this review discusses the challenges and future perspectives for developing new ICIs in alignment with the global developments in Japan.
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Affiliation(s)
- Takaaki Mizuno
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Yuki Katsuya
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Jun Sato
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Takafumi Koyama
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Toshio Shimizu
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Noboru Yamamoto
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
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Guo Q, Liu L, Chen Z, Fan Y, Zhou Y, Yuan Z, Zhang W. Current treatments for non-small cell lung cancer. Front Oncol 2022; 12:945102. [PMID: 36033435 PMCID: PMC9403713 DOI: 10.3389/fonc.2022.945102] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/06/2022] [Indexed: 12/12/2022] Open
Abstract
Despite improved methods of diagnosis and the development of different treatments, mortality from lung cancer remains surprisingly high. Non-small cell lung cancer (NSCLC) accounts for the large majority of lung cancer cases. Therefore, it is important to review current methods of diagnosis and treatments of NSCLC in the clinic and preclinic. In this review, we describe, as a guide for clinicians, current diagnostic methods and therapies (such as chemotherapy, chemoradiotherapy, targeted therapy, antiangiogenic therapy, immunotherapy, and combination therapy) for NSCLC.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, China
| | - Liwei Liu
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zelong Chen
- Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Artificial Intelligence and IoT Smart Medical Engineering Research Center of Henan Province, Zhengzhou, China
| | - Yannan Fan
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, China
| | - Yang Zhou
- Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Ziqiao Yuan
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
- *Correspondence: Wenzhou Zhang, ; Ziqiao Yuan,
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, China
- *Correspondence: Wenzhou Zhang, ; Ziqiao Yuan,
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31
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Kawachi H, Tamiya M, Taniguchi Y, Yokoyama T, Yokoe S, Oya Y, Imaji M, Okabe F, Kanazu M, Sakata Y, Uematsu S, Tanaka S, Arai D, Saito G, Kobe H, Miyauchi E, Okada A, Hara S, Kumagai T. Efficacy of Immune Checkpoint Inhibitor With or Without Chemotherapy for Non–Squamous Non-Small Cell Lung Cancer with Malignant Pleural Effusion: A Retrospective Multicenter Cohort Study. JTO Clin Res Rep 2022; 3:100355. [PMID: 35769388 PMCID: PMC9234704 DOI: 10.1016/j.jtocrr.2022.100355] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 11/04/2022] Open
Abstract
Introduction Malignant pleural effusion (MPE) is associated with poor treatment outcome in patients with NSCLC receiving immune checkpoint inhibitors (ICIs). ICIs and chemotherapy (ICI/Chemo) combination therapy is currently the standard therapy for NSCLC, and some ICI/Chemo regimens for nonsquamous (non-Sq) NSCLC contain bevacizumab (BEV), which is effective for controlling MPE and may enhance immune response. This study aimed to determine the optimal first-line treatment for this clinical population. Methods We retrospectively enrolled consecutive patients with non-Sq NSCLC with MPE who received ICI/Chemo or pembrolizumab monotherapy. Treatment outcomes were analyzed in patients with programmed death-ligand 1 (PD-L1) tumor proportion score more than or equal to 50% who were administered ICI/Chemo or pembrolizumab monotherapy (PD-L1 high cohort) and in patients with any PD-L1 status, treated with ICI/Chemo with or without BEV (ICI/Chemo cohort). We used propensity score matching (PSM) to reduce bias. Results PD-L1 high and ICI/Chemo cohorts included 143 and 139 patients, respectively. In PD-L1 high cohort, 37 patients received ICI/Chemo. With PSM, the median progression-free survival was significantly longer in the ICI/Chemo group than in the pembrolizumab group (11.1 versus 3.9 mo, respectively, p = 0.0409). In the ICI/Chemo cohort, 23 patients received BEV. With PSM, no significant difference occurred in median progression-free survival between BEV and non-BEV groups (6.1 versus 7.4 mo, p = 0.9610). Conclusion ICI/Chemo seemed more effective than pembrolizumab monotherapy for patients with non-Sq NSCLC with MPE. Nevertheless, the synergistic effect of BEV with ICI/Chemo may be limited. Further studies are needed to clarify the key factor in the tumor-induced immunosuppression environment in these patients.
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