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Philips TJ, Erickson BK, Thomas SN. Opportunities for predictive proteogenomic biomarkers of drug treatment sensitivity in epithelial ovarian cancer. Front Oncol 2025; 14:1503107. [PMID: 39839766 PMCID: PMC11746003 DOI: 10.3389/fonc.2024.1503107] [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: 09/28/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025] Open
Abstract
Genomic analysis has played a significant role in the identification of driver mutations that are linked to disease progression and response to drug treatment in ovarian cancer. A prominent example is the stratification of epithelial ovarian cancer (EOC) patients with homologous recombination deficiency (HRD) characterized by mutations in DNA damage repair genes such as BRCA1/2 for treatment with PARP inhibitors. However, recent studies have shown that some epithelial ovarian tumors respond to PARP inhibitors irrespective of their HRD or BRCA mutation status. An exclusive focus on the genome overlooks the significant insight that can be gained from other biological analytes, including proteins, which carry out cellular functions. Proteogenomics is the integration of genomics, transcriptomics, epigenomics and proteomics data. This review paper provides novel insight into the role of proteogenomics as an analytical approach to identify predictive biomarkers of drug treatment response in epithelial ovarian cancer. Proteogenomic analysis can facilitate the identification of predictive biomarkers of drug treatment response, consequently greatly improving the stratification of patients with EOC for treatment towards a goal of personalized medicine.
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Affiliation(s)
- Trudy J. Philips
- Molecular Pharmacology and Therapeutics Graduate Program, University of Minnesota School of Medicine, Minneapolis, MN, United States
| | - Britt K. Erickson
- Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota School of Medicine, Minneapolis, MN, United States
| | - Stefani N. Thomas
- Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, MN, United States
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Wang H, Jin Y, Liu P, Zhou J, Fan N, Li M. Immune checkpoint inhibitor-related pneumonitis following discontinuation of pembrolizumab in a patient with advanced lung adenocarcinoma: a case report and literature review. BMC Pulm Med 2024; 24:597. [PMID: 39623374 PMCID: PMC11613465 DOI: 10.1186/s12890-024-03424-9] [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: 07/22/2024] [Accepted: 11/28/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Checkpoint inhibitor-related pneumonitis (CIP) is a rare but serious complication of immune checkpoint inhibitors (ICIs). While it typically occurs within the first few months of treatment, its onset after ICI discontinuation is relatively uncommon. This report presents a case of CIP occurring 2.5 months after cessation of pembrolizumab and reviews the existing literature on CIP after discontinuation of ICIs. CASE PRESENTATION A 77-year-old female with stage IV right lung adenocarcinoma (T4N2M1a) developed pneumonitis 2.5 months after discontinuation of pembrolizumab (following 26 months of initial treatment). Initially suspected as community-acquired pneumonia, the patient received antiviral and antibiotic therapy with progressive deterioration. Microbiological investigations yielded negative results, and consultation suggested lung cancer recurrence. PET-CT revealed heightened metabolic activity in the lungs. Percutaneous lung biopsy demonstrated organizing pneumonia, and NGS testing of biopsy tissue showed no pathogenic organisms. Combined with CT findings and the patient's history of pembrolizumab use, the diagnosis of checkpoint inhibitor-related pneumonitis (CIP) was established. Short-term steroid therapy resulted in significant improvement. CONCLUSIONS Integration of clinical presentation, imaging findings, and medication history is crucial for diagnosis. This case underscores the need for vigilance for CIP even after discontinuing ICI therapy. Although this report provides insights into CIP after discontinuation based on a single case and a literature review, further studies involving larger cohorts are warranted to better understand the post-treatment risk of CIP.
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Affiliation(s)
- Huan Wang
- Department of Oncology, Cangzhou Fifth Hospital (People's Hospital of Qingxian), Cangzhou, China
| | - Yuzhen Jin
- Department of Respiratory and Critical Care Medicine, Cangzhou Fifth Hospital (People's Hospital of Qingxian), Cangzhou, China
| | - Peng Liu
- Department of Respiratory and Critical Care Medicine, Cangzhou Fifth Hospital (People's Hospital of Qingxian), Cangzhou, China
| | - Jie Zhou
- Department of Oncology, Cangzhou Fifth Hospital (People's Hospital of Qingxian), Cangzhou, China
| | - Na Fan
- Department of Respiratory and Critical Care Medicine, Cangzhou Fifth Hospital (People's Hospital of Qingxian), Cangzhou, China
| | - Mengjie Li
- Department of Respiratory and Critical Care Medicine, Cangzhou Fifth Hospital (People's Hospital of Qingxian), Cangzhou, China.
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Cheema PK, Iafolla MAJ, Abdel-Qadir H, Bellini AB, Chatur N, Chandok N, Comondore VR, Cunningham M, Halperin I, Hu AB, Jaskolka D, Darvish-Kazem S, Khandaker MH, Kitchlu A, Sachdeva JS, Shapera S, Woolnough NRJ, Nematollahi M. Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors. Curr Oncol 2024; 31:6356-6383. [PMID: 39451777 PMCID: PMC11506662 DOI: 10.3390/curroncol31100473] [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: 09/17/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.
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Affiliation(s)
- Parneet K. Cheema
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Marco A. J. Iafolla
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Husam Abdel-Qadir
- Women’s College Hospital Research Institute, Toronto, ON M5S 1B2, Canada;
- Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2N2, Canada
| | - Andrew B. Bellini
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Nazira Chatur
- Division of Gastroenterology, Faculty of Medicine, Vancouver General Hospital (Sanders), University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
| | - Natasha Chandok
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Vikram R. Comondore
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Morven Cunningham
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 2C4, Canada;
| | - Ilana Halperin
- Division of Endocrinology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
| | - Anne B. Hu
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Diana Jaskolka
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Saeed Darvish-Kazem
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Masud H. Khandaker
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Abhijat Kitchlu
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada;
| | - Jasdip S. Sachdeva
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Shane Shapera
- Department of Medicine, University of Toronto, Toronto, ON M5G 2N2, Canada;
| | - Nicholas R. J. Woolnough
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Massey Nematollahi
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
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Zeng Y, Huang J, Pang J, Pan S, Wu Y, Jie Y, Li X, Chong Y. The occurrence of immune-related adverse events is an independent risk factor both for serum HBsAg increase and HBV reactivation in HBsAg-positive cancer patients receiving PD-1 inhibitor combinational therapy. Front Immunol 2024; 15:1330644. [PMID: 38558804 PMCID: PMC10979302 DOI: 10.3389/fimmu.2024.1330644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. OBJECTIVE To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. METHODS A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. RESULTS With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. CONCLUSION PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.
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Affiliation(s)
- Yingfu Zeng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiwei Huang
- Department of Pharmacy, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiahui Pang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shufang Pan
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yusheng Jie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xinhua Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yutian Chong
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Nukaya T, Takahara K, Yoshizawa A, Saruta M, Yano Y, Ohno T, Uchimoto T, Fukuokaya W, Adachi T, Yamazaki S, Tokushige S, Nishimura K, Tsujino T, Nakamori K, Yamamoto S, Iwatani K, Urabe F, Mori K, Yanagisawa T, Tsuduki S, Hirasawa Y, Hashimoto T, Komura K, Inamoto T, Miki J, Kimura T, Ohno Y, Azuma H, Shiroki R. Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. Clin Genitourin Cancer 2024; 22:76-83. [PMID: 37880020 DOI: 10.1016/j.clgc.2023.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 09/24/2023] [Accepted: 09/25/2023] [Indexed: 10/27/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors can cause various immune-related adverse events (irAEs). This study aimed to evaluate the association between the incidence of irAEs and oncological outcomes of metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as first-line therapy. PATIENTS AND METHODS We retrospectively analyzed data from 69 patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy between September 2018 and September 2021 at 4 institutions. Cox regression analyses were performed to investigate the important factors affecting overall survival (OS) in patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy. RESULTS During observation with a median follow-up of 9.1 months, the median OS was not reached, while the median progression-free survival was 6.0 months. Patients with irAEs had significantly prolonged OS and progression-free survival than those without irAEs (p = .012 and .002, respectively). Multivariate analysis showed that 3 independent factors, including C-reactive protein (CRP), irAEs, and performance status (PS), were significantly associated with OS (p = .04, .02, and .01, respectively). The patients were subsequently divided into 3 groups as follows: group 1, 20 patients with all 3 independent OS predictors; group 2, 18 patients with irAE predictors alone or 2 positive independent OS predictors (irAEs + CRP or irAEs + PS); group 3, 31 patients with 3 negative independent S predictors. OS varied significantly among the 3 groups (p = .004). CONCLUSION The appearance of irAEs could predict OS in patients with mRCC treated with nivolumab plus ipilimumab as the first-line therapy.
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Affiliation(s)
- Takuhisa Nukaya
- Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Kiyoshi Takahara
- Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan..
| | - Atsuhiko Yoshizawa
- Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Masanobu Saruta
- Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Yusuke Yano
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Takaya Ohno
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Taizo Uchimoto
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Wataru Fukuokaya
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Adachi
- Department of Urology, Tokyo Medical University, Tokyo, Japan
| | - Shogo Yamazaki
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Satoshi Tokushige
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Kazuki Nishimura
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Takuya Tsujino
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Keita Nakamori
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Shutaro Yamamoto
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Kosuke Iwatani
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Fumihiko Urabe
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Keiichiro Mori
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takafumi Yanagisawa
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shunsuke Tsuduki
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yosuke Hirasawa
- Department of Urology, Tokyo Medical University, Tokyo, Japan
| | | | - Kazumasa Komura
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Teruo Inamoto
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Jun Miki
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshio Ohno
- Department of Urology, Tokyo Medical University, Tokyo, Japan
| | - Haruhito Azuma
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Ryoichi Shiroki
- Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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Washino S, Shirotake S, Takeshita H, Inoue M, Miura Y, Hyodo Y, Kagawa M, Izumi K, Oyama M, Kawakami S, Saito K, Matsuoka Y, Taniuchi S, Shintani A, Miyagawa T. Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. Int J Clin Oncol 2023; 28:1651-1658. [PMID: 37658926 DOI: 10.1007/s10147-023-02406-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 08/21/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab. MATERIALS AND METHODS This retrospective study included patients who received nivolumab plus ipilimumab at six centres, institutions, or hospitals between September 2018 and February 2022. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used. RESULTS This study included 129 patients with a median follow-up of 12.3 months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165-0.648, p = 0.001; HR 0.334, 95% CI 0.151-0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235-1.097, p = 0.085 or HR 0.245, 95% CI 0.110-0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316-1.036, p = 0.085 or HR 0.267, 95% CI 0.113-0.628, p = 0.002) compared with those who experienced single or zero irAE. CONCLUSIONS Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab.
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Affiliation(s)
- Satoshi Washino
- Department of Urology, Jichi Medical University Saitama Medical Center, 1-847, Amanuma-cho, Omiya-ku, Saitama, Saitama, 330-8503, Japan.
- Musashino Study Group, Saitama, Japan.
| | - Suguru Shirotake
- Department of Uro-Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan
- Musashino Study Group, Saitama, Japan
| | - Hideki Takeshita
- Department of Urology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama, 350-8550, Japan
- Musashino Study Group, Saitama, Japan
| | - Masaharu Inoue
- Department of Urology, Saitama Cancer Center, 818, Ina-machi, Kitaadati-gun, Komuro, Saitama, 362-0806, Japan
- Musashino Study Group, Saitama, Japan
| | - Yuji Miura
- Department of Medical Oncology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
- Musashino Study Group, Saitama, Japan
| | - Yoji Hyodo
- Department of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Saitama, 343-0845, Japan
- Musashino Study Group, Saitama, Japan
| | - Makoto Kagawa
- Department of Urology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama, 350-8550, Japan
- Musashino Study Group, Saitama, Japan
| | - Keita Izumi
- Department of Urology, Saitama Cancer Center, 818, Ina-machi, Kitaadati-gun, Komuro, Saitama, 362-0806, Japan
- Musashino Study Group, Saitama, Japan
| | - Masafumi Oyama
- Department of Uro-Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Satoru Kawakami
- Department of Urology, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama, 350-8550, Japan
| | - Kazutaka Saito
- Department of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Saitama, 343-0845, Japan
| | - Yoh Matsuoka
- Department of Urology, Saitama Cancer Center, 818, Ina-machi, Kitaadati-gun, Komuro, Saitama, 362-0806, Japan
| | - Satsuki Taniuchi
- Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, Osaka, 545-8585, Japan
| | - Ayumi Shintani
- Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, Osaka, 545-8585, Japan
| | - Tomoaki Miyagawa
- Department of Urology, Jichi Medical University Saitama Medical Center, 1-847, Amanuma-cho, Omiya-ku, Saitama, Saitama, 330-8503, Japan
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Wang S, Iyer R, Han X, Wei J, Li N, Cheng Y, Zhou Y, Gao Q, Zhang L, Yan M, Sun Z, Fang D. CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1-positive regulator for tumor immune evasion. J Clin Invest 2023; 133:e167728. [PMID: 38038129 PMCID: PMC10688982 DOI: 10.1172/jci167728] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 09/27/2023] [Indexed: 12/02/2023] Open
Abstract
Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α. Moreover, ATXN3 functioned as a deubiquitinase of the AP-1 transcription factor JunB, indicating that ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ- and hypoxia-induced PD-L1 expression and consequently enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Furthermore, tumoral ATXN3 suppression improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy. Importantly, ATXN3 expression was increased in human lung adenocarcinoma and melanoma, and its levels were positively correlated with PD-L1 as well as its transcription factors IRF1 and HIF-2α. Collectively, our study identifies what we believe to be a previously unknown deubiquitinase, ATXN3, as a positive regulator for PD-L1 transcription and provides a rationale for targeting ATXN3 to sensitize checkpoint blockade antitumor immunotherapy.
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Affiliation(s)
- Shengnan Wang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Radhika Iyer
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Xiaohua Han
- Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Juncheng Wei
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Na Li
- College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Yang Cheng
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Yuanzhang Zhou
- College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Qiong Gao
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Ming Yan
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- Department of Oral Maxillofacial Head and Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China
| | - Zhaolin Sun
- College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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8
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Zou Y, Ren X, Zhang H, Wang Y, Wang H, Bai R, Zhang Z, Sun G, Xu L. Efficacy and safety of durvalumab + chemotherapy vs. atezolizumab + chemotherapy in the treatment of small‑cell lung cancer: a retrospective comparative cohort study. J Thorac Dis 2023; 15:3339-3349. [PMID: 37426159 PMCID: PMC10323594 DOI: 10.21037/jtd-23-588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 06/16/2023] [Indexed: 07/11/2023]
Abstract
Background Durvalumab and atezolizumab have recently been approved in extensive small cell lung cancer (SCLC) with moderate median overall survival (OS) improvements. However, only limited data exist regarding the impact of immunotherapy in real-world SCLC patients. This study sought to assess the efficacy and safety of atezolizumab plus chemotherapy and durvalumab plus chemotherapy in the treatment of SCLC in a real-world setting. Methods A retrospective cohort study of all patients treated for SCLC with chemotherapy with PD-L1 inhibitor, at 3 centers in China between February 1, 2020 and April 30, 2022. Patient characteristics, adverse-events and survival analyses were conducted. Results A total of 143 patients were enrolled in this study, 100 were treated with durvalumab and the remainder with atezolizumab. The baseline characteristics of the two groups were fundamentally balanced before using PD-L1 inhibitors (P>0.05). The median OS (mOS) of the patients who received durvalumab or atezolizumab as the first-line treatment were 22.0 and 10.0 months, respectively (P=0.03). Survival analysis of patients with brain metastasis (BM) revealed that the median progression-free survival (mPFS) of patients without BM treated with durvalumab plus chemotherapy (5.5 months) was longer than that of those with BM (4.0 months) (P=0.03). In contrast, in the atezolizumab plus chemotherapy regimen, BM did not affect survival. In addition, the addition of radiotherapy to treatment with PD-L1 inhibitors in combination with chemotherapy has a tendency to improve long-term survival. As for safety analysis, there was no significant difference in the incidence of immune-related adverse events (IRAEs) during PD-L1 inhibitor therapy between the 2 groups (P>0.05). And during treatment with immunochemotherapy, radiotherapy was not associated with the development of IRAE (P=0.42) but increased the risk of immune-related pneumonitis (P=0.026). Conclusions The implication of this study for clinical practice is a preference for durvalumab in first-line immunotherapy for SCLC. In addition, appropriate radiotherapy during treatment with PD-L1 inhibitors in combination with chemotherapy may prolong long-term survival, but the occurrence of immune-related pneumonitis should be vigilant. Data from this study are limited and the baseline characteristics of the two populations still need to be more finely classified.
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Affiliation(s)
- Yuxia Zou
- Department of Respiratory Oncology, The Anhui Provincial Cancer Hospital/The First Affiliated Hospital of University of Science and Technology of China (USTC) West District, Hefei, China
| | - Xueru Ren
- Department of Respiratory Oncology, The Anhui Provincial Cancer Hospital/The First Affiliated Hospital of University of Science and Technology of China (USTC) West District, Hefei, China
| | - Huanhuan Zhang
- Department of Respiratory Oncology, The Anhui Provincial Cancer Hospital/The First Affiliated Hospital of University of Science and Technology of China (USTC) West District, Hefei, China
| | - Yuenan Wang
- Department of Respiratory Oncology, The Anhui Provincial Cancer Hospital/The First Affiliated Hospital of University of Science and Technology of China (USTC) West District, Hefei, China
| | - Hanqi Wang
- Department of Respiratory Oncology, The Anhui Provincial Cancer Hospital/The First Affiliated Hospital of University of Science and Technology of China (USTC) West District, Hefei, China
| | - Rubing Bai
- Department of Respiratory Oncology, The Anhui Provincial Cancer Hospital/The First Affiliated Hospital of University of Science and Technology of China (USTC) West District, Hefei, China
| | - Zhihong Zhang
- Department of Respiratory Oncology, The Anhui Provincial Cancer Hospital/The First Affiliated Hospital of University of Science and Technology of China (USTC) West District, Hefei, China
| | - Gengyun Sun
- Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ling Xu
- Department of Interventional Pulmonary Diseases, The Anhui Chest Hospital, Hefei, China
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9
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Nikoo M, Hassan ZF, Mardasi M, Rostamnezhad E, Roozbahani F, Rahimi S, Mohammadi J. Hepatocellular carcinoma (HCC) immunotherapy by anti-PD-1 monoclonal antibodies: A rapidly evolving strategy. Pathol Res Pract 2023; 247:154473. [PMID: 37207558 DOI: 10.1016/j.prp.2023.154473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/21/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world, with a high relapse rate. Delayed symptom onset observed in 70-80% of patients leads to diagnosis in advanced stages commonly associated with chronic liver disease. Programmed cell death protein 1 (PD-1) blockade therapy has recently emerged as a promising therapeutic option in the clinical management of several advanced malignancies, including HCC, due to the activation of exhausted tumor-infiltrating lymphocytes and improved outcomes of T-cell function. However, many people with HCC do not respond to PD-1 blockade therapy, and the diversity of immune-related adverse events (irAEs) restricts their clinical utility. Therefore, numerous effective combinatory strategies, including combinations with anti-PD-1 antibodies and other therapeutic methods ranging from chemotherapy to targeted therapies, are evolving to improve therapeutic outcomes and evoke synergistic anti-tumor impressions in patients with advanced HCC. Unfortunately, combined therapy may have more side effects than single-agent treatment. Nonetheless, identifying appropriate predictive biomarkers can aid in managing potential immune-related adverse events by distinguishing patients who respond best to PD-1 inhibitors as single agents or in combination strategies. In the present review, we summarize the therapeutic potential of PD-1 blockade therapy for advanced HCC patients. Besides, a glimpse of the pivotal predictive biomarkers influencing a patient's response to anti-PD-1 antibodies will be provided.
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Affiliation(s)
- Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Mahsa Mardasi
- Biotechnology Department, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University G. C., Evin, Tehran, Iran
| | - Elmira Rostamnezhad
- Department of Molecular Genetics, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Fatemeh Roozbahani
- Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sahel Rahimi
- Industrial and Environmental Biotechnology Department, National Institute of Genetic Engineering and Biotechnology(NIGEB), Tehran, Iran
| | - Javad Mohammadi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
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10
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Shek D, Gloss B, Lai J, Ma L, Zhang HE, Carlino MS, Mahajan H, Nagrial A, Gao B, Read SA, Ahlenstiel G. Identification and Characterisation of Infiltrating Immune Cells in Malignant Pleural Mesothelioma Using Spatial Transcriptomics. Methods Protoc 2023; 6:mps6020035. [PMID: 37104017 PMCID: PMC10146955 DOI: 10.3390/mps6020035] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/16/2023] [Accepted: 03/21/2023] [Indexed: 03/31/2023] Open
Abstract
Increasing evidence strongly supports the key role of the tumour microenvironment in response to systemic therapy, particularly immune checkpoint inhibitors (ICIs). The tumour microenvironment is a complex tapestry of immune cells, some of which can suppress T-cell immunity to negatively impact ICI therapy. The immune component of the tumour microenvironment, although poorly understood, has the potential to reveal novel insights that can impact the efficacy and safety of ICI therapy. Successful identification and validation of these factors using cutting-edge spatial and single-cell technologies may enable the development of broad acting adjunct therapies as well as personalised cancer immunotherapies in the near future. In this paper we describe a protocol built upon Visium (10x Genomics) spatial transcriptomics to map and characterise the tumour-infiltrating immune microenvironment in malignant pleural mesothelioma. Using ImSig tumour-specific immune cell gene signatures and BayesSpace Bayesian statistical methodology, we were able to significantly improve immune cell identification and spatial resolution, respectively, improving our ability to analyse immune cell interactions within the tumour microenvironment.
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11
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Cortijo-Cascajares S, Cercós-Lletí AC, Ortiz-Pérez S, Caro-Teller JM, Ferrari-Piquero JM. Analysis of immune-mediated reactions in patients with non-small cell lung cancer treated with nivolumab and its association with effectiveness. J Oncol Pharm Pract 2023; 29:290-298. [PMID: 34907812 DOI: 10.1177/10781552211067429] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To study immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients treated with nivolumab, as well as to assess whether these reactions could be predictors of further effectiveness of therapy. METHODS Retrospective, observational and longitudinal study. All NSCLC patients who received nivolumab between February 2015-May 2020 were included. In terms of safety, irAEs and their severity were registered and to evaluate the effectiveness, overall survival (OS) and progression free survival (PFS) were calculated. RESULTS 75 patients were included. 32 patients (43%) were reported irAES. Mainly the irAEs affected the skin (36%). Followed by pneumonitis (20%), gastrointestinal reactions (12%), endocrine (12%) and hepatitis (12%). Regarding severity, 92% were moderate. The median PFS was 9.49 months on the group with irAEs versus 1.99 months on the group without irAEs group (p < 0.0001). The median OS was 17.44 months versus 7.67 months respectively (p = 0.0001). According to the incidence of irAEs developed ( = > 2 vs. 1 vs. 0), the median PFS was 20.53 versus 5.35 versus 1.99 months respectively (p < 0.0001). The median OS was 23.41 versus 15.80 versus 7.67 months, respectively (p = 0.0002). CONCLUSION In a significant number of patients irAEs occur, generally of grade 1-2 severity, affecting mainly the skin, lungs and gastrointestinal system. We confirm that the development of irAEs in patients with NSCLC treated with nivolumab is a strong predictor of treatment effectiveness in both PFS and OS, with statistically significant results. On those patients who experience two or more immunorelated adverse events the greatest benefit has been observed.
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Affiliation(s)
| | | | - Sara Ortiz-Pérez
- Department of Pharmacy, 16473Hospital Universitario 12 de Octubre, Madrid, Spain
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12
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Ohsawa M, Hamai Y, Emi M, Ibuki Y, Kurokawa T, Yoshikawa T, Hirohata R, Kitasaki N, Okada M. Real-world clinical outcomes of nivolumab and taxane as a second- or later-line therapy for recurrent or unresectable advanced esophageal squamous cell carcinoma. Front Oncol 2023; 13:1126536. [PMID: 37139161 PMCID: PMC10151017 DOI: 10.3389/fonc.2023.1126536] [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: 12/18/2022] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
Background Nivolumab is approved in Japan as a second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC) resistant to fluoropyrimidine and platinum-based drugs. It is also used in adjuvant and primary postoperative therapies. This study aimed to report real-world data on nivolumab use for esophageal cancer treatment. Methods In total, 171 patients with recurrent or unresectable advanced ESCC who received nivolumab (n = 61) or taxane (n = 110) were included. We collected real-world data of patients treated with nivolumab as a second- or later-line therapy and evaluated treatment outcomes and safety. Results Median overall survival was longer and progression-free survival (PFS) was significantly longer (p = 0.0172) in patients who received nivolumab than in patients who received taxane as a second- or later-line therapy. Furthermore, subgroup analysis for second-line treatment only showed the superiority of nivolumab in increasing the PFS rate (p = 0.0056). No serious adverse events were observed. Conclusions In real-world practice, nivolumab was safer and more effective than taxane in patients with ESCC with diverse clinical profiles who did not meet trial eligibility criteria, including those with poor Eastern Cooperative Oncology Group performance status, comorbidities, and receiving multiple treatments.
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13
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Liu W, Luo Z, Liu Y, Sun B. Current landscape and tailored management of immune-related adverse events. Front Pharmacol 2023; 14:1078338. [PMID: 36950013 PMCID: PMC10025325 DOI: 10.3389/fphar.2023.1078338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Unprecedented advances have been made in immune checkpoint inhibitors (ICIs) in the treatment of cancer. However, the overall benefits from ICIs are impaired by the increasing incidence of immune-related adverse events (irAEs). Although several factors and mechanisms have been proposed in the development of irAEs, there is still incomprehensive understanding of irAEs. Therefore, it is urgent to identify certain risk factors and biomarkers that predict the development of irAEs, as well as to understand the underlying mechanisms of these adverse events. Herein, we comprehensively summarize the state-of-the-art knowledge about clinical features and the related risk factors of irAEs. Particularly, we also discuss relevant mechanisms of irAEs and address the mechanism-based strategies, aiming to develop a tailored management approach for irAEs.
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Affiliation(s)
- Wenhui Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Zhiying Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yiping Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Bao Sun,
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14
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Li G, Gong S, Wang N, Yao X. Toxic epidermal necrolysis induced by sintilimab in a patient with advanced non-small cell lung cancer and comorbid pulmonary tuberculosis: A case report. Front Immunol 2022; 13:989966. [PMID: 36090976 PMCID: PMC9459224 DOI: 10.3389/fimmu.2022.989966] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/08/2022] [Indexed: 11/27/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have had a revolutionary effect on the treatment of patients with advanced non-small cell lung cancer (NSCLC), especially squamous cell lung cancer. However, ICIs may cause associated immune-related adverse events (ir-AEs). No case of sintilimab-induced toxic epidermal necrolysis (TEN) has been reported. In this report, we discussed a patient with advanced NSCLC and comorbid pulmonary tuberculosis who underwent immunotherapy and chemotherapy as neoadjuvant therapy and anti-tuberculosis therapy concurrently. Partial response (PR) of the tumor was achieved after three cycles of neoadjuvant therapy without cutaneous toxicities. Video-assisted thoracoscopic surgery (VATS) left lower lobectomy was performed successfully. Sintilimab and chemotherapy were administered as adjuvant therapy, after which the patient suffered severe TEN that rapidly progressed to cover >50% of the skin. TEN was associated with extensive rashes of the trunk and pruritus. With history of sintilimab use, clinical symptoms, and physical examination, TEN was diagnosed. Intravenous methylprednisolone and oral prednisone were administered until the patient totally recovered from the cutaneous toxicities caused by sintilimab. Monitoring of such rare but severe cutaneous toxicities is essential in patients who are treated with sintilimab.
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Affiliation(s)
- Gang Li
- Department of Thoracic Surgery, The Public Health Clinical Center of Chengdu, Chengdu, China
| | - Sheng Gong
- Department of Thoracic Surgery, The Public Health Clinical Center of Chengdu, Chengdu, China
| | - Ning Wang
- Department of Public Health, Chengdu Medical College, Chengdu, China
| | - Xiaojun Yao
- Department of Thoracic Surgery, The Public Health Clinical Center of Chengdu, Chengdu, China
- *Correspondence: Xiaojun Yao,
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15
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Yan YD, Zhao Y, Zhang C, Fu J, Su YJ, Cui XL, Ma EL, Liu BL, Gu ZC, Lin HW. Toxicity spectrum of immunotherapy in advanced lung cancer: A safety analysis from clinical trials and a pharmacovigilance system. EClinicalMedicine 2022; 50:101535. [PMID: 35812997 PMCID: PMC9256649 DOI: 10.1016/j.eclinm.2022.101535] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND With the increased use of immune checkpoint inhibitors (ICIs) in advanced lung cancer, adverse events (AEs), particularly immune-related AEs (irAEs), have garnered considerable interest. We conducted a comprehensive assessment of the toxicity profile in advanced lung cancer using multi-source medical data. METHODS First, we systematically searched the PubMed, Embase, and Cochrane Library databases (from inception to 10 August 2021) for relevant randomised controlled trials (RCTs) involving ICI-based treatments for advanced lung cancer. The primary outcomes were treatment-related AEs and irAEs, including events that were assigned grade 1-5 and 3-5. The secondary outcomes were grade 5 AEs and irAEs (grade 1-5 and grade 3-5) in specific organs. Network comparisons were conducted for 11 treatments, including chemotherapy (CT), ICI monotherapy (three regimens: programmed death-1 receptor [PD-1] inhibitors, programmed death ligand-1 [PD-L1] inhibitors, and cytotoxic T lymphocyte-associated antigen [CTLA-4] inhibitors), dual-ICI combination therapy (two regimens), and treatment using one or two ICI drugs administered in combination with CT (five regimens). We also conducted a disproportionality analysis by extracting reports of various irAEs associated with ICIs from the FDA Adverse Event Reporting System (FAERS) database. The reporting odds ratios and fatality proportions of different irAEs were calculated and compared. PROSPERO: CRD42021268650. FINDINGS Overall, 41 RCTs involving 23,121 patients with advanced lung cancer were included. Treatments containing chemotherapy increased the risk of treatment-related AEs compared to ICI-based regimens without chemotherapy. Concerning irAEs, PD-L1 + CTLA-4 + CT was associated with the highest risk of grade 1-5 irAEs, followed by two regimens of dual ICI combination, three regimens of ICI monotherapy, and three regimens of one ICI combined with CT. For 3-5 irAEs, CTLA-4 accounted for most AEs. Detailed comparisons of ICI-based treatment options provided irAE profiles based on specific organs/systems and AE severity. Insights from the FAERS database revealed that signals corresponding to pneumonitis, colitis, thyroiditis, and hypophysitis were observed across all ICI regimens. Further analyses of the outcomes indicated that myocarditis (163 of 367, 44.4%), pneumonitis (1610 of 4497, 35.8%), and hepatitis (290 of 931, 31.1%) had high fatality rates. INTERPRETATION Included RCTs showed heterogeneity in a few clinical factors, and reports derived from the FAERS database might have involved inaccurate data. Our results can be used as a basis for improving clinical treatment strategies and designing preventive methods for ICI treatment in advanced lung cancer. FUNDING This study was supported by the Research Project of Drug Clinical Comprehensive Evaluation and Drug Treatment Pathway (SHYXH-ZP-2021-001, SHYXH-ZP-2021-006), Clinical Research Innovation and Cultivation Fund of Ren Ji Hospital (RJPY-LX-008), Ren Ji Boost Project of National Natural Science Foundation of China (RJTJ-JX-001), and Shanghai "Rising Stars of Medical Talent" Youth Development Program - Youth Medical Talents - Clinical Pharmacist Program (SHWJRS (2019) 072).
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Affiliation(s)
- Yi-Dan Yan
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Drug Clinical Comprehensive Evaluation Group, Shanghai Pharmaceutical Association, Shanghai 200040, China
| | - Ying Zhao
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Chi Zhang
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Drug Clinical Comprehensive Evaluation Group, Shanghai Pharmaceutical Association, Shanghai 200040, China
| | - Jie Fu
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Ying-Jie Su
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Drug Clinical Comprehensive Evaluation Group, Shanghai Pharmaceutical Association, Shanghai 200040, China
| | - Xiang-Li Cui
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Er-Li Ma
- Drug Clinical Comprehensive Evaluation Group, Shanghai Pharmaceutical Association, Shanghai 200040, China
| | - Bing-Long Liu
- Drug Clinical Comprehensive Evaluation Group, Shanghai Pharmaceutical Association, Shanghai 200040, China
| | - Zhi-Chun Gu
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Drug Clinical Comprehensive Evaluation Group, Shanghai Pharmaceutical Association, Shanghai 200040, China
- Corresponding author at: Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
| | - Hou-Wen Lin
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
- Corresponding author.
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16
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Janicka N, Sałek A, Sawińska M, Kuchar E, Wiela-Hojeńska A, Karłowicz-Bodalska K. Effects of Non-Opioid Analgesics on the Cell Membrane of Skin and Gastrointestinal Cancers. Int J Mol Sci 2022; 23:ijms23137096. [PMID: 35806101 PMCID: PMC9266389 DOI: 10.3390/ijms23137096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 02/05/2023] Open
Abstract
Skin and gastrointestinal cancer cells are the target of research by many scientists due to the increasing morbidity and mortality rates around the world. New indications for drugs used in various conditions are being discovered. Non-opioid analgesics are worth noting as very popular, widely available, relatively cheap medications. They also have the ability to modulate the membrane components of tumor cells. The aim of this review is to analyze the impact of diclofenac, ibuprofen, naproxen, acetylsalicylic acid and paracetamol on skin and gastrointestinal cancers cell membrane. These drugs may affect the membrane through topical application, at the in vitro and in vivo level after oral or parenteral administration. They can lead to up- or downregulated expression of receptors, transporters and other molecules associated with plasma membrane. Medications may also alter the lipid bilayer composition of membrane, resulting in changes in its integrity and fluidity. Described modulations can cause the visualization of cancer cells, enhanced response of the immune system and the initiation of cell death. The outcome of this is inhibition of progression or reduction of tumor mass and supports chemotherapy. In conclusion, non-opioid analgesics may be used in the future as adjunctive therapy for the treatment of these cancers.
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Affiliation(s)
- Natalia Janicka
- Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (N.J.); (A.S.); (M.S.)
| | - Agnieszka Sałek
- Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (N.J.); (A.S.); (M.S.)
| | - Magdalena Sawińska
- Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (N.J.); (A.S.); (M.S.)
| | - Ernest Kuchar
- Department of Pediatrics with Clinical Assessment Unit, Medical University of Warsaw, 02-091 Warsaw, Poland;
| | - Anna Wiela-Hojeńska
- Department of Clinical Pharmacology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Katarzyna Karłowicz-Bodalska
- Department of Drugs Form Technology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland
- Correspondence:
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Farshidpour M, Hutson W. Immune Checkpoint Inhibitors Induced Hepatotoxicity; Gastroenterologists' Perspectives. Middle East J Dig Dis 2022; 14:244-253. [PMID: 36619143 PMCID: PMC9489307 DOI: 10.34172/mejdd.2022.279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 01/10/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have promising clinical activity and are essential medications for patients with several malignancies. However, by deranging the immune system, these novel agents could lead to immune-related adverse events (IRAEs). Hepatotoxicity with checkpoint inhibitors usually results in acute hepatitis or drug-induced liver injury. METHODS: This review article discusses the recent clinical evidence available regarding checkpoint inhibitor-induced hepatitis and reviews an approach to their diagnosis and management. CONCLUSION: ICIs have improved patients' outcomes with different forms of malignancy; however, ICIs-related liver damage is a clinically significant entity in these patients. All patients should be monitored carefully for IRAEs while undergoing treatment with ICIs.
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Affiliation(s)
- Maham Farshidpour
- Loma Linda University Transplantation Institute,Corresponding Author: Maham Farshidpour, MD Loma Linda University Transplant Institute 197 E Caroline St, Suite 1400, San Bernardino, CA 92408 Tel: + 909 558 3636 Fax: + 909 337 2222
| | - William Hutson
- West Virginia University - Department of Medicine Section of Gastroenterology & Hepatology
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A Guide to Implementing Immune Checkpoint Inhibitors within a Cancer Program: Experience from a Large Canadian Community Centre. Curr Oncol 2022; 29:869-880. [PMID: 35200573 PMCID: PMC8870472 DOI: 10.3390/curroncol29020074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/31/2022] [Accepted: 02/01/2022] [Indexed: 11/25/2022] Open
Abstract
The increased use of immune checkpoint inhibitors across cancer programs has created the need for standardized patient assessment, education, monitoring, and management of immune-related adverse events (irAEs). At William Osler Health System in Brampton, Ontario, a practical step-wise approach detailing the implementation of cancer immunotherapy in routine practice was developed. The approach focuses on four key steps: (1) identification of patient educators; (2) development of patient education materials; (3) development of patient monitoring tools; (4) involvement and education of multidisciplinary teams. Here, we provide an in-depth description of what was included in each step and how we integrated the different elements of the program. For each step, resources, tools, and materials that may be useful for patients, healthcare providers, and multidisciplinary teams were developed or modified based on existing materials. At our centre, the program led to improved patient comprehension of irAEs, the ability to act on symptoms (patient self-efficacy), and low rates of emergency room visits at first presentation for irAEs. We recognize that centres may need to tailor the approaches to their institutional policies and encourage centres to adapt and modify the forms and tools according to their needs and requirements.
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Checkpoint Inhibition in Bladder Cancer: Clinical Expectations, Current Evidence, and Proposal of Future Strategies Based on a Tumor-Specific Immunobiological Approach. Cancers (Basel) 2021; 13:cancers13236016. [PMID: 34885126 PMCID: PMC8656785 DOI: 10.3390/cancers13236016] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary In contrast with other strategies, immunotherapy is a treatment aimed at empowering the patient’s immune system in order to increase immunity and the response against cancer. Recently, a new class of drugs, immune checkpoint inhibitors, has shown potential in increasing treatment chances for patients with bladder cancers, improving their survival. However, predicting the response to immune checkpoint inhibition is important, since only a group of patients develop a good response. Biomarkers to predict the response to checkpoint inhibition must identify tumors’ and patients’ specific profiles. This study reviews the current knowledge on this most relevant clinical topic, focusing on bladder cancer, going from basic science to ongoing clinical trials and available clinical evidence. Finally, a critical analysis of published data is provided, and an original panel of biomarkers, able to select the right patients for treatments, based on patient-specific immune profiling, is proposed. Abstract In contrast with other strategies, immunotherapy is the only treatment aimed at empowering the immune system to increase the response against tumor growth. Immunotherapy has a role in the treatment of bladder cancer (BC) due to these tumors’ high tumor mutational burden (TMB) and mostly prominent immune infiltrate. The therapy or combination has to be adjusted to the tumor’s immunobiology. Recently, a new class of immunotherapeutic agents, immune checkpoint inhibitors (ICI), has shown potential in increasing treatment chances for patients with genitourinary cancers, improving their oncological outcomes. The clinical efficacy of ICI has been shown in both the first-line treatment of cisplatin-ineligible patients, with programmed death ligand 1 (PD-L1)-positive tumors (atezolizumab, pembrolizumab), and in second-line settings, for progression after platinum-based chemotherapy (atezolizumab, pembrolizumab, and nivolumab for FDA and EMA; durvalumab and avelumab for FDA alone). Predicting the response to ICI is important since only a subset of patients undergoing ICI therapy develop a concrete and lasting response. Most of the patients require a different therapy or therapy combination to achieve tumor control. The cancer immunity cycle provides a conceptual framework to assist therapy selection. Biomarkers to predict response to ICI must identify where the cancer immunity cycle is disrupted. We reviewed the current knowledge on ICI treatment in BC, going from basic science to current data and available clinical evidence. Secondly, a critical analysis of published data is provided, and an original panel of biomarkers able to predict response to ICI treatment, based on tumor-specific immune profiling, is proposed.
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20
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Kim W, Cho YA, Kim DC, Jo AR, Min KH, Lee KE. Factors Associated with Thyroid-Related Adverse Events in Patients Receiving PD-1 or PD-L1 Inhibitors Using Machine Learning Models. Cancers (Basel) 2021; 13:cancers13215465. [PMID: 34771631 PMCID: PMC8582564 DOI: 10.3390/cancers13215465] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/28/2021] [Accepted: 10/28/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Although immune checkpoint inhibitors have a potential role in thyroid-related complications, no study has investigated factors associated with such adverse events. This study aims to explore the factors associated with thyroid-related adverse events in patients with anti-PD-1/PD-L1 agents by training predictive models utilizing various machine learning approaches. The results of this study could be used to develop individually tailored intervention strategies to prevent immune checkpoint inhibitor-induced thyroid-related outcomes. Abstract Targets of immune checkpoint inhibitors (ICIs) regulate immune homeostasis and prevent autoimmunity by downregulating immune responses and by inhibiting T cell activation. Although ICIs are widely used in immunotherapy because of their good clinical efficacy, they can also induce autoimmune-related adverse events. Thyroid-related adverse events are frequently associated with anti-programmed cell death 1 (PD-1) or anti-programmed cell death-ligand 1 (PD-L1) agents. The present study aims to investigate the factors associated with thyroid dysfunction in patients receiving PD-1 or PD-L1 inhibitors and to develop various machine learning approaches to predict complications. A total of 187 patients were enrolled in this study. Logistic regression analysis was conducted to investigate the association between such factors and adverse events. Various machine learning methods were used to predict thyroid-related complications. After adjusting for covariates, we found that smoking history and hypertension increase the risk of thyroid dysfunction by approximately 3.7 and 4.1 times, respectively (95% confidence intervals (CIs) 1.338–10.496 and 1.478–11.332, p = 0.012 and 0.007). In contrast, patients taking opioids showed an approximately 4.0-fold lower risk of thyroid-related complications than those not taking them (95% CI 1.464–11.111, p = 0.007). Among the machine learning models, random forest showed the best prediction, with an area under the receiver operating characteristic of 0.770 (95% CI 0.648–0.883) and an area under the precision-recall of 0.510 (95%CI 0.357–0.666). Hence, this study utilized various machine learning models for prediction and showed that factors such as smoking history, hypertension, and opioids are associated with thyroid-related adverse events in cancer patients receiving PD-1/PD-L1 inhibitors.
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Affiliation(s)
- Woorim Kim
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea; (W.K.); (K.-H.M.)
| | - Young-Ah Cho
- College of Pharmacy, Gyeongsang National University, Jinju 52828, Korea;
- The Prime Hospital, 305 Nabulo, Jinju 52828, Korea
| | - Dong-Chul Kim
- Department of Pathology, Gyeongsang National University Hospital, Jinju 52828, Korea;
| | - A-Ra Jo
- Department of Nursing education, Gyeongsang National University Hospital, Jinju 52828, Korea;
| | - Kyung-Hyun Min
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea; (W.K.); (K.-H.M.)
| | - Kyung-Eun Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea; (W.K.); (K.-H.M.)
- Correspondence: ; Tel.: +82-43-261-3590; Fax: +82-43-268-2732
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21
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Nemoto Y, Ishihara H, Nakamura K, Tachibana H, Fukuda H, Yoshida K, Kobayashi H, Iizuka J, Shimmura H, Hashimoto Y, Tanabe K, Kondo T, Takagi T. Efficacy and safety of immune checkpoint inhibitors in elderly patients with metastatic renal cell carcinoma. Int Urol Nephrol 2021; 54:47-54. [PMID: 34704214 DOI: 10.1007/s11255-021-03042-y] [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: 07/19/2021] [Accepted: 10/13/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE To clarify the efficacy and safety profile of immune checkpoint inhibitors (ICIs) for elderly patients with metastatic renal cell carcinoma (mRCC). METHODS We retrospectively evaluated 149 mRCC patients treated with nivolumab monotherapy as subsequent therapy (n = 89) and nivolumab plus ipilimumab as first-line therapy (n = 60) at 5 affiliated institutions. The patients were divided according to age: > 70 (elderly) vs. ≤ 70 years (young). Efficacy was analyzed by comparing progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) between elderly and young patients. Safety was assessed by comparing the incidence rates of immune-related adverse events (irAEs). RESULTS In the nivolumab monotherapy group, 34/89 patients (38%) were classified as elderly. There was no significant difference in PFS (p = 0.607), OS (p = 0.383), ORR (p = 0.0699), or DCR (p = 0.881) between elderly and young patients. In the nivolumab plus ipilimumab group, 20/60 patients (33%) were classified as elderly. There was no significant difference in PFS (p = 0.995), OS (p = 0.714), ORR (p = 0.763), or DCR (p = 1.000) between the two groups. The incidence rate of irAEs was not significantly different in the nivolumab (any grade: p = 0.121; grade ≥ 3: p = 0.542) or in the nivolumab plus ipilimumab (any grade: p = 0.666; grade ≥ 3: p = 0.576) group; a higher rate of gastrointestinal irAEs was observed in elderly than in young patients (any grade 15% vs. 3%). CONCLUSIONS The efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab were comparable between elderly and young patients. Thus, chronological age alone should not be a contraindication in the use of ICIs for mRCC.
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Affiliation(s)
- Yuki Nemoto
- Department of Urology, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi, Saitama, Japan.,Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Hiroki Ishihara
- Department of Urology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.
| | - Kazutaka Nakamura
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.,Department of Urology, Tokiwakai Jyoban Hospital, 57 Kaminodai, Jyoban Kamiyunagayamachi, Iwaki, Fukushima, Japan
| | - Hidekazu Tachibana
- Department of Urology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.,Department of Urology, Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama, Japan
| | - Hironori Fukuda
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Kazuhiko Yoshida
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Hirohito Kobayashi
- Department of Urology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan
| | - Junpei Iizuka
- Department of Urology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan
| | - Hiroaki Shimmura
- Department of Urology, Tokiwakai Jyoban Hospital, 57 Kaminodai, Jyoban Kamiyunagayamachi, Iwaki, Fukushima, Japan
| | - Yasunobu Hashimoto
- Department of Urology, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi, Saitama, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Tsunenori Kondo
- Department of Urology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
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22
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Paderi A, Gambale E, Botteri C, Giorgione R, Lavacchi D, Brugia M, Mazzoni F, Giommoni E, Bormioli S, Amedei A, Pillozzi S, Matucci Cerinic M, Antonuzzo L. Association of Systemic Steroid Treatment and Outcome in Patients Treated with Immune Checkpoint Inhibitors: A Real-World Analysis. Molecules 2021; 26:5789. [PMID: 34641331 PMCID: PMC8510096 DOI: 10.3390/molecules26195789] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/15/2021] [Accepted: 09/15/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Immune-related adverse events (irAEs) are inflammatory side effects, which can occur during immune-checkpoint(s) inhibitors (ICIs) therapy. Steroids are the first-line agents to manage irAEs because of their immunosuppressive properties. However, it is still debated whether or when steroids can be administered without abrogating the therapeutic efforts of immunotherapy. METHODS We retrospectively evaluated 146 patients with metastatic non-small cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC) treated with ICIs. We assessed the progression-free survival (PFS) of patients treated with steroids due to an irAE compared to a no-steroid group. RESULTS The early treatment with steroid (within the first 30 days from the beginning of immunotherapy) was not related to a shorter PFS (p = 0.077). Interestingly, patients who were treated with steroids after 30 days from the start of immunotherapy had significantly longer PFS (p = 0.017). In a multivariate analysis, treatment with steroids after 30 days was an independent prognostic factor for PFS (HR: 0.59 [95% CI 0.36-0.97], p = 0.037). CONCLUSIONS This retrospective study points out that early systemic steroids administration to manage irAEs might not have a detrimental effect on patient clinical outcome in NSCLC, melanoma and RCC patients.
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Affiliation(s)
- Agnese Paderi
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Elisabetta Gambale
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Cristina Botteri
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Roberta Giorgione
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Daniele Lavacchi
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Marco Brugia
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Francesca Mazzoni
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Elisa Giommoni
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Susanna Bormioli
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (S.B.); (A.A.); (M.M.C.)
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (S.B.); (A.A.); (M.M.C.)
| | - Serena Pillozzi
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
| | - Marco Matucci Cerinic
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (S.B.); (A.A.); (M.M.C.)
| | - Lorenzo Antonuzzo
- Medical Oncology Unit, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy; (A.P.); (E.G.); (C.B.); (R.G.); (D.L.); (M.B.); (F.M.); (E.G.); (S.P.)
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; (S.B.); (A.A.); (M.M.C.)
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23
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Kato T, Okada R, Furusawa A, Inagaki F, Wakiyama H, Furumoto H, Okuyama S, Fukushima H, Choyke PL, Kobayashi H. Simultaneously Combined Cancer Cell- and CTLA4-Targeted NIR-PIT Causes a Synergistic Treatment Effect in Syngeneic Mouse Models. Mol Cancer Ther 2021; 20:2262-2273. [PMID: 34518299 DOI: 10.1158/1535-7163.mct-21-0470] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/12/2021] [Accepted: 09/01/2021] [Indexed: 11/16/2022]
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that utilizes antibody-IRDye700DX (IR700) conjugates. The clinical use of NIR-PIT has recently been approved in Japan for patients with inoperable head and neck cancer targeting human epidermal growth factor receptor (hEGFR). Previously, cytotoxic T-lymphocyte antigen 4 (CTLA4)-targeted NIR-PIT has been shown to strongly inhibit tumor progression and prolonged survival was seen in different tumor models due to enhanced T-cell-mediated antitumor immunity. In this study, combined NIR-PIT targeting CTLA4 expressing cells and cancer cells was investigated in four tumor models including a newly established hEGFR-expressing murine oropharyngeal cancer cell (mEERL-hEGFR). While single molecule-targeted therapy (NIR-PIT targeting hEGFR or CTLA4) did not inhibit tumor progression in poorly immunogenic mEERL-hEGFR tumor, dual (CTLA4/hEGFR)-targeted NIR-PIT significantly suppressed tumor growth and prolonged survival resulting in a 38% complete response rate. After the dual-targeted NIR-PIT, depletion of CTLA4 expressing cells, which were mainly regulatory T cells (Tregs), and an increase in the CD8+/Treg ratio in the tumor bed were observed, suggesting enhanced host antitumor immunity. Furthermore, dual-targeted NIR-PIT showed antitumor immunity in distant untreated tumors of the same type. Thus, simultaneous cancer cell-targeted NIR-PIT and CTLA4-targeted NIR-PIT is a promising new cancer therapy strategy, especially in poorly immunogenic tumors where NIR-PIT monotherapy is suboptimal.
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Affiliation(s)
- Takuya Kato
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Ryuhei Okada
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Aki Furusawa
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Fuyuki Inagaki
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Hiroaki Wakiyama
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Hideyuki Furumoto
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Shuhei Okuyama
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Hiroshi Fukushima
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Peter L Choyke
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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24
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Nuzzo PV, Pond GR, Abou Alaiwi S, Nassar AH, Flippot R, Curran C, Kilbridge KL, Wei XX, McGregor BA, Choueiri T, Harshman LC, Sonpavde G. Conditional immune toxicity rate in patients with metastatic renal and urothelial cancer treated with immune checkpoint inhibitors. J Immunother Cancer 2021; 8:jitc-2019-000371. [PMID: 32234849 PMCID: PMC7174062 DOI: 10.1136/jitc-2019-000371] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2020] [Indexed: 12/31/2022] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs. Methods We identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method. Results A total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p<0.001), first-line ICI therapy (p=0.011), and PD-1 inhibitor therapy (p=0.007) were all significantly associated with irAE development. Conclusions This study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted.
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Affiliation(s)
- Pier Vitale Nuzzo
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Gregory R Pond
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Sarah Abou Alaiwi
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Amin H Nassar
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Ronan Flippot
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Catherine Curran
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kerry L Kilbridge
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Xiao X Wei
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Bradley A McGregor
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Toni Choueiri
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Lauren C Harshman
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Guru Sonpavde
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
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25
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Ikeda T, Ishihara H, Nemoto Y, Tachibana H, Fukuda H, Yoshida K, Takagi T, Iizuka J, Hashimoto Y, Ishida H, Kondo T, Tanabe K. Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Urol Oncol 2021; 39:735.e9-735.e16. [PMID: 34172370 DOI: 10.1016/j.urolonc.2021.05.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/06/2021] [Accepted: 05/06/2021] [Indexed: 01/11/2023]
Abstract
OBJECTIVES Evidence regarding the prognostic impact of immune-related adverse events (irAEs) remains limited in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as a first-line systemic therapy. Thus, we investigated the association between irAE development and oncological outcomes during nivolumab plus ipilimumab therapy. METHODS We retrospectively evaluated 46 patients with mRCC who were treated with nivolumab plus ipilimumab at our hospital and its affiliated institutions. The associations between irAE development and progression-free survival (PFS), overall survival (OS), and objective response rates (ORRs) were assessed after treatment initiation. RESULTS A total of 60 irAEs occurred in 33 patients (72%), with 24 grade ≥ 3 irAEs developed in 20 patients (43%). PFS was significantly longer in patients with irAEs than that in patients without irAEs (P < 0.0001); however, OS was not different (P = 0.571). Multivariable analysis further revealed that the development of irAEs was an independent predictor of a longer PFS (hazard ratio: 0.18, P = 0.0005). A landmark analysis for the initial four cycles of nivolumab plus ipilimumab administration also showed that PFS was significantly longer in patients with irAEs than that in patients without irAEs (P = 0.0386). The ORRs were also higher in patients with irAEs (P = 0.0064). Furthermore, in 22 patients (48%) who discontinued nivolumab plus ipilimumab treatment, the 6-month PFS rate was 87%. CONCLUSION This multi-institutional study showed that irAE development was significantly associated with PFS but not with OS in patients treated with nivolumab plus ipilimumab as a first-line therapy. The development of irAEs may be used as a surrogate prognostic marker for PFS in this treatment regimen.
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Affiliation(s)
- Takashi Ikeda
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan; Department of Urology, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi City, Saitama 332-8558, Japan
| | - Hiroki Ishihara
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
| | - Yuki Nemoto
- Department of Urology, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi City, Saitama 332-8558, Japan
| | - Hidekazu Tachibana
- Department of Urology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo 116-8567, Japan
| | - Hironori Fukuda
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Kazuhiko Yoshida
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Toshio Takagi
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Junpei Iizuka
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Yasunobu Hashimoto
- Department of Urology, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi City, Saitama 332-8558, Japan
| | - Hideki Ishida
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Tsunenori Kondo
- Department of Urology, Tokyo Women's Medical University Medical Center East, 2-1-10 Nishiogu, Arakawa-ku, Tokyo 116-8567, Japan
| | - Kazunari Tanabe
- Department of Urology, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Jacob JB, Jacob MK, Parajuli P. Review of immune checkpoint inhibitors in immuno-oncology. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2021; 91:111-139. [PMID: 34099106 DOI: 10.1016/bs.apha.2021.01.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Tumor cells predominantly express self-antigens and overcoming self-tolerance is the primary challenge to effective immunotherapy. Tumors also express ligands for co-inhibitory molecules on immune cells, in order to suppress anti-tumor immunity. Over a decade ago, the first antibodies generated to block the co-inhibitory molecule CTLA-4 was tested in patients with metastatic melanoma. Results from this landmark trial have informed not only the current landscape of checkpoint blockade but also the way in which immunotherapy trial outcomes are determined. Antibodies targeting PD-1 and its ligand, PD-L1, soon followed and use of these checkpoint inhibitors (ICIs) have expanded exponentially. ICI treatment has shown long-lasting clinical benefit in several tumor types and patients refractory to other treatments can often respond to ICI therapy. On the other hand, in some tumor types, the response to ICI is short-lived and tumors eventually recur. Current clinical trials are focused on enhancing anti-tumor effects through combinations of multiple ICIs with agents which cause tumor death, particularly in solid tumors, in order to enhance antigen presentation. It is also important to define which patients will respond to therapy with ICIs as over half of all patients suffer from immune-related adverse events (irAE), some of which are severe and long-lasting.
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Affiliation(s)
- Jennifer B Jacob
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.
| | - Mark K Jacob
- Michigan State University School of Human Medicine, East Lansing, MI, United States
| | - Prahlad Parajuli
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
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Chen J, Wang J, Xu H. Comparison of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with extensive-stage small cell lung cancer: A systematic review and network meta-analysis. Medicine (Baltimore) 2021; 100:e25180. [PMID: 33847617 PMCID: PMC8051984 DOI: 10.1097/md.0000000000025180] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/25/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND In recent years, immune checkpoint inhibitors (ICIs) including atezolizumab, durvalumab, pembrolizumab, and nivolumab have reported their efficacy and safety profile in patients with extensive-stage small cell lung cancer (ES-SCLC). However, given the diverse efficacy and inconsistent safety among the ICIs, with the absence of head-to-head researches designed to evaluate the efficacy among them, it might bring with confusion on selection in clinical practice. OBJECTIVES The present systematic review and network meta-analysis was performed to conduct indirect comparisons on efficacy and safety profile among ICIs, including atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC. DESIGN Several databases were retrieved with established criteria until June 20, 2020, with the main MeSH Terms and their similarities. Hazard ratios of overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) of disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were compared indirectly with network meta-analysis. DATA SOURCES Medline, Cochrane library, and Embase. ELIGIBILITY CRITERIA Prospective, randomized, controlled clinical studies, which reported PFS, OS, and AEs. DATA EXTRACTION AND SYNTHESIS Clinical characteristics were extracted by the 2 authors independently. Comparisons of HRs were calculated for PFS and OS by random effect model. ORR, DCR, and AEs were presented with ORs. Based on surface under the cumulative ranking curve, and forest plots, efficacy and safety of the treatments were ranked, with predicted histogram described. RESULTS In total, there were 4 studies including 1547 patients who met the eligibility criteria and enrolled. For indirect comparisons, no significant difference on PFS was observed between atezolizumab and durvalumab (HR 0.96, 95% CI, 0.72-1.29), or between atezolizumab and pembrolizumab (HR 1.05, 95% CI, 0.78-1.43), or between atezolizumab and nivolumab (HR 1.18, 95% CI, 0.79-1.79), or between durvalumab and pembrolizumab (HR 1.10, 95% CI, 0.84-1.43). or between durvalumab and nivolumab (HR 1.23, 95% CI, 0.83-1.82), or between pembrolizumab and nivolumab (HR 1.12, 95% CI, 0.76-1.66), nor significant difference on OS observed between atezolizumab and durvalumab (HR 0.93, 95% CI, 0.67-1.30), or between atezolizumab and pembrolizumab (HR 0.88, 95% CI, 0.62-1.24), or between atezolizumab and nivolumab (HR 1.04, 95% CI, 0.66-1.66), or between durvalumab and pembrolizumab (HR 0.94, 95% CI, 0.70-1.25), or between durvalumab and nivolumab (HR 1.12, 95% CI, 0.73-1.71), or between pembrolizumab and nivolumab (HR 1.19, 95% CI, 0.77-1.84). However, durvalumab was shown statistical superiority on ORR when compared with atezolizumab (HR 0.79, 95% CI, 0.64-0.98), also with significantly higher risk on immune-related AEs when compared with atezolizumab (OR 0.22, 95% CI, 0.10-0.50), and pembrolizumab (OR 3.12, 95% CI, 1.27-7.64). CONCLUSIONS Results of the study revealed that there was no statistical difference on PFS or OS among agents of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC. However, durvalumab was shown superiority on ORR when compared with atezolizumab, also with significantly higher risk on immune-related AEs.
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Affiliation(s)
| | | | - Hui Xu
- Medical Department, Quzhou People's Hospital, Quzhou, Zhejiang, China
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Nadal R, Clara JA, Valderrama BP, Bellmunt J. Current Therapy for Metastatic Urothelial Carcinoma. Hematol Oncol Clin North Am 2021; 35:469-493. [PMID: 33958146 DOI: 10.1016/j.hoc.2021.02.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Urothelial carcinoma (UC) is a highly lethal malignancy in the metastatic state. Platinum-based chemotherapy regimens have been the backbone treatment for patients with advanced UC in the first-line setting. However, a large subset of patients are suboptimal candidates for these combinations owing to poor renal function and/or other comorbidities. Patients who are unable to tolerate or who progress after frontline platinum chemotherapy face a poor outcome. Recent insights into UC biology and immunology are being translated into new therapies for metastatic UC (mUC) including immune checkpoint inhibitors (ICIs), erdafitinib, a FGFR inhibitor, and antibody drug conjugates (ADC) such enfortumab vedotin.
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Affiliation(s)
- Rosa Nadal
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes, National Institutes of Health, 10 Center Drive, Room 3E-5330, Bethesda, MD 20892, USA
| | - Joseph A Clara
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institutes, National Institutes of Health, 10 Center Drive, Room 3E-5330, Bethesda, MD 20892, USA
| | - Begoña P Valderrama
- Hospital Universitario Virgen del Rocio, Avenida Manuel Siurot, s/n, Sevilla 41001, Spain
| | - Joaquim Bellmunt
- Department of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, KS 118, Boston, MA 02215, USA.
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Zam W, Ali L. Immune checkpoint inhibitors in the treatment of cancer. ACTA ACUST UNITED AC 2021; 17:103-113. [PMID: 33823768 DOI: 10.2174/1574884716666210325095022] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Immunotherapy drugs, known as immune checkpoint inhibitors (ICIs), work by blocking checkpoint proteins from binding with their partner proteins. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) that showed potent immune-modulatory effects through their function as negative regulators of T cell activation. METHODS In view of the rapid and extensive development of this research field, we conducted a comprehensive review of the literature and update on the use of CTLA-4, PD-1 and PD-L1 targeted therapy in the treatment of several types of cancer including melanoma, non-small-cell lung carcinoma, breast cancer, hepatocellular carcinoma, hodgkin lymphoma, cervical cancer, head and neck squamous cell carcinoma. RESULTS Based on the last updated list released on March 2019, seven ICIs are approved by the FDA including ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and cemiplimab. CONCLUSION This review also highlighted the most common adverse effects caused by ICIs and which affect people in different ways.
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Affiliation(s)
- Wissam Zam
- Department of Analytical and Food Chemistry, Faculty of Pharmacy, Al-Wadi International University, Homs. Syrian Arab Republic
| | - Lina Ali
- Department of Analytical and Food Chemistry, Faculty of Pharmacy, Tartous University, Tartous. Syrian Arab Republic
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Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy. Case Rep Nephrol 2021; 2021:6640154. [PMID: 33728076 PMCID: PMC7939740 DOI: 10.1155/2021/6640154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/04/2021] [Accepted: 02/20/2021] [Indexed: 01/05/2023] Open
Abstract
A 65-year-old male patient with metastatic CCRCC developed steroid-dependent, grade 3 AIN secondary to nivolumab weeks after its initiation that resulted in 3 hospitalizations with acute renal failure. The patient was started on MM and his AIN was successfully controlled after a 2-year period of follow-up. Refractory renal AIN resulting from PD-1 inhibitor use is rare, and its successful treatment with mofetil mycophenolate with a 2-year follow-up in a patient with metastatic CCRCC has not been reported. This case is important because not only was his renal irAEs controlled but also long-term treatment with MM did not result in progression of metastatic disease.
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Araujo-Castro M, Pascual-Corrales E, Molina-Cerrillo J, Alonso-Gordoa T. Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance. Biomedicines 2021; 9:biomedicines9030304. [PMID: 33809752 PMCID: PMC8002272 DOI: 10.3390/biomedicines9030304] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/02/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.
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Affiliation(s)
- Marta Araujo-Castro
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Ramón y Cajal Health Research Institute (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
- Correspondence:
| | - Eider Pascual-Corrales
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Ramón y Cajal Health Research Institute (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (J.M.-C.); (T.A.-G.)
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, Ramón y Cajal Health Research Institute (IRYCIS), Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (J.M.-C.); (T.A.-G.)
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Chen C, Wu B, Zhang C, Xu T. Immune-related adverse events associated with immune checkpoint inhibitors: An updated comprehensive disproportionality analysis of the FDA adverse event reporting system. Int Immunopharmacol 2021; 95:107498. [PMID: 33725634 DOI: 10.1016/j.intimp.2021.107498] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUNDS Immune-related adverse events were reported in patients treated with immune checkpoint inhibitors (ICIs). However, with the increasing number of immune-related adverse events (irAEs), the differences of each immune checkpoint inhibitor regimen had not been fully assessed. METHODS Disproportionality analysis was used in data mining of the suspected adverse events after ICIs administration based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019. The onset time and fatality proportion of ICI-associated irAEs were further evaluated. RESULTS A total of 32,441 reports of ICI-associated irAEs were gathered. This study showed that all ICI regimens generated lung toxicity and endocrine toxicity signals. Colitis, pneumonitis and interstitial lung disease were the most common ICI-associated irAEs. Five regimens including durvalumab monotherapy, ipilimumab monotherapy, ipilimumab plus nivolumab, ipilimumab plus pembrolizumab, durvalumab plus tremelimumab were associated with irAEs. Anti-PD-1 agents generated more signals of ocular toxicities than anti-PD-L1 agents, while anti-PD-L1 agents reported more signals of hematologic toxicities. Anti-CTLA-4 agents showed more signals of gastrointestinal toxicities compared with anti-PD-1 or anti-PD-L1 agents. The highest fatality proportion of lung toxicities with durvalumab monotherapy, hematological toxicities with avelumab monotherapy, renal and skin toxicities with cemiplimab monotherapy were found. CONCLUSION Our results demonstrated that each ICI regimen had different characteristics of irAEs. Pembrolizumab had the highest fatality proportion. Ipilimumab plus pembrolizumab had the shortest median time to onset irAEs. Further studies were expected to assess whether there were clinically relevant differences exist among ICIs.
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Affiliation(s)
- Chen Chen
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
| | - ChenYu Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Ting Xu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
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Boussios S, Sheriff M, Rassy E, Moschetta M, Samartzis EP, Hallit R, Sadauskaite A, Katsanos KH, Christodoulou DK, Pavlidis N. Immuno-oncology: a narrative review of gastrointestinal and hepatic toxicities. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:423. [PMID: 33842644 PMCID: PMC8033350 DOI: 10.21037/atm-20-7361] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Vaccines, cytokines, and adoptive cellular therapies (ACT) represent immuno-therapeutic modalities with great development potential, and they are currently approved for the treatment of a limited number of advanced malignancies. The most up-to-date knowledge on the regulation of the anti-cancer immune response has recently led to the development and approval of inhibitors of immune checkpoints, which have produced unprecedented clinical activity in several hard to treat solid malignancies. However, severe adverse events (AEs) represent a limitation to the use of these drugs. Currently approved checkpoint inhibitors block cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand (PD-L1), resulted in increased survival of patients with several solid and hematologic malignancies. The most common treatment AEs associated with these drugs are fatigue, rash, and auto-immune/inflammatory reactions. Many of the immune-related AEs are reversible and the strategies for their management include supportive care either with or without treatment withdrawal; nevertheless, in severe cases, hospitalization and treatment with immune suppressants, and/or immunomodulators may be required. Steroid therapy is a critical component of the treatment algorithm; nevertheless, the associated immunosuppression may compromise the antitumor response. This article provides a comprehensive and narrative review of luminal gastrointestinal and hepatic complications, including recommendations for their investigation and management.
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Affiliation(s)
- Stergios Boussios
- King's College London, Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, SE1 9RT, London, UK.,Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, ME7 5NY, Gillingham, Kent, UK.,AELIA Organization, 9th Km Thessaloniki - Thermi, Thessaloniki, Greece
| | - Matin Sheriff
- Department of Urology, Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent, ME7 5NY, UK
| | - Elie Rassy
- Department of Cancer Medicine, Gustave Roussy Institut, Villejuif, France.,Department of Hematology-Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon
| | - Michele Moschetta
- CHUV, Lausanne University Hospital, Rue du Bugnon 21 CH-1011, Lausanne, Switzerland
| | - Eleftherios P Samartzis
- Department of Gynecology, University Hospital Zurich, Frauenklinikstrasse 10, CH-8091 Zurich, Switzerland
| | - Rachel Hallit
- Gastroenterology Department, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris and University of Paris, Paris, France
| | - Agne Sadauskaite
- Department of Pharmacy, Medway NHS Foundation Trust, Gillingham, Kent, UK
| | - Konstantinos H Katsanos
- Department of Gastroenterology, University Hospital of Ioannina, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Dimitrios K Christodoulou
- Department of Gastroenterology, University Hospital of Ioannina, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
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Shore N. Diagnosis and Management of Checkpoint Inhibitor Side Effects in Patients with Bladder Cancer: the Urologist’s Perspective. Bladder Cancer 2020. [DOI: 10.3233/blc-200362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
From 2016 through the present day, we have witnessed extraordinarily rapid advances and regulatory approvals of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway, which has significantly improved survival among patients with advanced and metastatic urothelial carcinoma (mUC). Although these agents usually are well tolerated, their unique mechanism of action may enhance cytotoxic T-cell mediated immunity, evoking unique side effects that differ from conventional chemotherapy or molecularly targeted agents. The most common immune-related adverse events (irAEs) are dermatitis, colitis, pneumonitis, thyroid dysfunction, and transaminitis, but any organ system permeated by the lymphatic vasculature can be affected; also, neuropathies and arthralgias may occur. Immune-mediated events of any grade require prompt recognition and appropriate management to mitigate the risk of irAE exacerbation. Most patients with mild (grade 1) irAEs may continue checkpoint inhibitor treatment with careful monitoring. For grade 2 irAEs, it is appropriate to suspend treatment, initiate corticosteroid therapy, and only resume treatment if the irAE resolves to < grade 1. Events classified as > grade 3 may require permanent treatment cessation and high-dose corticosteroid therapy. In clinical trials of PD-1/PD-L1 inhibitors across multiple cancer types, approximately 15% of patients with mUC developed irAEs requiring corticosteroid therapy. Training physicians and nurse providers and counseling patients regarding the early recognition of irAEs are mandatory to ensure timely irAE detection and optimized patient management. Hence, operationalizing an advanced bladder cancer clinic requires collaboration and coordination amongst urologists, medical and radiation oncologists, and other medical specialists who participate in the increasingly multimodal and multidisciplinary care of patients with bladder cancer.
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Affiliation(s)
- Neal Shore
- Carolina Urologic Research Center Atlantic Urology Clinics Myrtle Beach, SC, USA
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The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:284. [PMID: 33317597 PMCID: PMC7734811 DOI: 10.1186/s13046-020-01749-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023]
Abstract
The enthusiasm for immune checkpoint inhibitors (ICIs), an efficient tumor treatment model different from traditional treatment, is based on their unprecedented antitumor effect, but the occurrence of immune-related adverse events (irAEs) is an obstacle to the prospect of ICI treatment. IrAEs are a discrete toxicity caused by the nonspecific activation of the immune system and can affect almost all tissues and organs. Currently, research on biomarkers mainly focuses on the gastrointestinal tract, endocrine system, skin and lung. Several potential hypotheses concentrate on the overactivation of the immune system, excessive release of inflammatory cytokines, elevated levels of pre-existing autoantibodies, and presence of common antigens between tumors and normal tissues. This review lists the current biomarkers that might predict irAEs and their possible mechanisms for both nonspecific and organ-specific biomarkers. However, the prediction of irAEs remains a major clinical challenge to screen and identify patients who are susceptible to irAEs and likely to benefit from ICIs.
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Chen FW, Liu AF, Srivastava A, Buchbinder E, Grover S. Checkpoint inhibitor induced esophagitis with documented resolution on infliximab. CURRENT PROBLEMS IN CANCER: CASE REPORTS 2020. [DOI: 10.1016/j.cpccr.2020.100029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Cho SY, Huff DT, Jeraj R, Albertini MR. FDG PET/CT for Assessment of Immune Therapy: Opportunities and Understanding Pitfalls. Semin Nucl Med 2020; 50:518-531. [PMID: 33059821 PMCID: PMC8201415 DOI: 10.1053/j.semnuclmed.2020.06.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Immune checkpoint blockade has demonstrated the ability to modulate the immune system to produce durable responses in a wide range of cancers and has significantly impacted the standard of care. However, many cancer patients still do not respond to immune checkpoint blockade or have a limited duration of antitumor responses. Moreover, immune-related adverse events caused by immune checkpoint blockade can be severe and debilitating for some patients, limiting continuation of therapy and resulting in severe autoimmune conditions. Standard-of-care conventional anatomic imaging modalities and tumor response criteria have limitations to adequately assess tumor responses, especially early in the course of therapy, for risk-adapted clinical management to inform care of patients treated with immunotherapy. Molecular imaging with position emission tomography (PET) provides a noninvasive functional biomarker of tumor response, and of immune activation, for patients on immune-based therapies to help address these needs. 18F-FDG (FDG) PET/CT is readily available clinically and a number of studies have evaluated the use of this agent for assessment of prognosis, treatment response and immune activation for patients treated with immune checkpoint blockade. In this review paper, we discuss the current oncologic applications and imaging needs of cancer immunotherapy, recent studies applying FDG PET/CT for tumor response assessment, and evaluation of immune-related adverse events for improving clinical management. We largely focus on metastatic melanoma; however, we generalize where applicable to immunotherapy in other tumor types. We also briefly discuss PET imaging and quantitation as well as emerging non-FDG PET imaging radiotracers for cancer immunotherapy imaging.
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Affiliation(s)
- Steve Y Cho
- University of Wisconsin Carbone Cancer Center, Madison, WI; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
| | - Daniel T Huff
- University of Wisconsin Carbone Cancer Center, Madison, WI; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Robert Jeraj
- University of Wisconsin Carbone Cancer Center, Madison, WI; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Mark R Albertini
- University of Wisconsin Carbone Cancer Center, Madison, WI; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI; Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI
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Parmar A, Richardson M, Coyte PC, Cheng S, Sander B, Chan KKW. A cost-utility analysis of atezolizumab in the second-line treatment of patients with metastatic bladder cancer. Curr Oncol 2020; 27:e386-e394. [PMID: 32905260 PMCID: PMC7467791 DOI: 10.3747/co.27.5459] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Despite initial promising results, the IMvigor211 clinical trial failed to demonstrate an overall survival (os) benefit for atezolizumab compared with chemotherapy as second-line treatment for metastatic bladder cancer (mbc). However, given lessened adverse events (aes) and preserved quality of life (qol) with atezolizumab, there might still be investment value. To evaluate that potential value, we conducted a cost-utility analysis (cua) of atezolizumab compared with chemotherapy from the perspective of the Canadian health care payer. Methods A partitioned survival model was used to evaluate atezolizumab compared with chemotherapy over a lifetime horizon (5 years). The base-case analysis was conducted for the intention-to-treat (itt) population, with additional scenario analyses for subgroups by IMvigor-defined PD-L1 status. Health outcomes were evaluated through life-year gains and quality-adjusted life-years (qalys). Cost estimates in 2018 Canadian dollars for systemic treatment, aes, and end-of-life care were incorporated. The incremental cost-effectiveness ratio (icer) was used to compare treatment strategies. Parameter and model uncertainty were assessed through sensitivity and scenario analyses. Per Canadian guidelines, cost and effectiveness were discounted at 1.5%. Results For the itt population, the expected qalys for atezolizumab and chemotherapy were 0.75 and 0.56, with expected costs of $90,290 and $8,466 respectively. The resultant icer for atezolizumab compared with chemotherapy was $430,652 per qaly. Scenario analysis of patients with PD-L1 expression levels of 5% or greater led to a lower icer ($334,387 per qaly). Scenario analysis of observed compared with expected benefits demonstrated a higher icer, with a shorter time horizon ($928,950 per qaly). Conclusions Despite lessened aes and preserved qol, atezolizumab is not considered cost-effective for the second-line treatment of mbc.
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Affiliation(s)
- A Parmar
- Odette Cancer Centre, Sunnybrook Health Sciences Centre
- Institute of Health Policy, Management and Evaluative Sciences, University of Toronto
| | - M Richardson
- Institute of Health Policy, Management and Evaluative Sciences, University of Toronto
| | - P C Coyte
- Institute of Health Policy, Management and Evaluative Sciences, University of Toronto
- Toronto Health Economics and Technology Assessment Collaboration, University Health Network
| | - S Cheng
- Odette Cancer Centre, Sunnybrook Health Sciences Centre
| | - B Sander
- Institute of Health Policy, Management and Evaluative Sciences, University of Toronto
- Toronto Health Economics and Technology Assessment Collaboration, University Health Network
- ices, University of Toronto
- Public Health Ontario
| | - K K W Chan
- Odette Cancer Centre, Sunnybrook Health Sciences Centre
- Institute of Health Policy, Management and Evaluative Sciences, University of Toronto
- Canadian Centre for Applied Research in Cancer Control, Toronto, ON
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Relationship between IL10 and PD-L1 in Liver Hepatocellular Carcinoma Tissue and Cell Lines. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8910183. [PMID: 32724815 PMCID: PMC7381951 DOI: 10.1155/2020/8910183] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 06/26/2020] [Indexed: 12/14/2022]
Abstract
Background Despite the large-scale clinical application of programmed death-ligand 1 (PD-L1) monoclonal antibody, reduction in its clinical response rate has become a gradual problem. As such, use of PD-L1 monoclonal antibody in combination with other anticarcinoma drugs has been the main strategy in improving its efficacy. Interleukin 10 (IL10) is a recognized inflammatory and immunosuppressive factor. Previous studies have suggested that there is a link between PD-L1 and IL10. Objective This study was aimed at clarifying the relationship between PD-L1 and IL10 in liver hepatocellular carcinoma (LIHC) and whether IL10 enhances the efficacy of PD-L1 inhibitor. Methods Expression levels of PD-L1 and IL10 in carcinoma and adjacent tissues were tested by immunochemistry, Western blotting, and RT-PCR. Survival duration and follow-up data of each patient were recorded. LIHC cell lines Bel7405 and MHCC 97-H were used for in vitro experiments. Exogenous IL10 and anti-IL10 were added to cell supernatant. Expression level of PD-L1 in the LIHC cell lines was determined using Western blotting and ELISA. CCK8 and transwell assays were adopted to examine the effect of PD-L1 combined with IL10 on proliferation, invasion, and metastasis of LIHC cells. Results The survival period of patients with low expression of IL10 was longer than that of patients with high expression (P = 0.01). Overexpression of PD-L1 increased the IL10 and Met levels in LIHC tissues and cell lines. IL10 downregulated the expression level of PD-L1 and enhanced the efficacy of crizotinib via the Met signaling pathway in the LIHC cells. Conclusions A combination of IL10 and PD-L1 inhibitor holds great promise as an effective treatment for LIHC.
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Deligiorgi MV, Panayiotidis MI, Trafalis DT. Endocrine adverse events related with immune checkpoint inhibitors: an update for clinicians. Immunotherapy 2020; 12:481-510. [PMID: 32345074 DOI: 10.2217/imt-2019-0132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Designated as scientific breakthrough of current decade, immune checkpoint inhibitors attenuate the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1)/ligand 1 (PD-L1) pathways, depriving cancer cells of a key strategy of evasion from immunosurveillance. The reinvigoration of immune response translates into clinical success, inevitably entwined with a novel constellation of immune-related adverse events. The present review dissects the endocrine immune-related adverse events, emphasizing their unique profile featured by unpredictable onset, irreversibility, nonspecific symptoms, wide clinical spectrum and sophisticated diagnostic work-up. Guidelines advocate individualized decision-making process guided by clinicians' judgement. Future perspective should be governed by five principles - prevention, anticipation, detection, treatment, monitoring - aiming to gain the optimal profit diminishing immunotoxicity.
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Affiliation(s)
- Maria V Deligiorgi
- Department of Pharmacology - Clinical Pharmacology Unit, National & Kapodistrian University of Athens, Faculty of Medicine, Building 16, 1st Floor: 75 Mikras Asias, 11527-Goudi, Athens, Greece
| | - Mihalis I Panayiotidis
- Department of Applied Sciences, Group of Translational Biosciences, Faculty of Health & Life Sciences, Northumbria University, Ellison Building A516, Newcastle Upon Tyne, NE1 8ST, UK
| | - Dimitrios T Trafalis
- Department of Pharmacology - Clinical Pharmacology Unit, National & Kapodistrian University of Athens, Faculty of Medicine, Building 16, 1st Floor: 75 Mikras Asias, 11527-Goudi, Athens, Greece
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Qian Q, Wu C, Chen J, Wang W. Relationship between IL-10 and PD-L1 in esophageal carcinoma tissues and IL-10 down-regulates PD-L1 expression via Met signaling pathway. J Gastrointest Oncol 2020; 11:337-355. [PMID: 32399275 DOI: 10.21037/jgo.2020.01.06] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Programmed death-ligand 1 (PD-L1) plays a critical role in host immunity in the setting of cancer progression. Interleukin 10 (IL-10) is a multi-cellular, multi-functional cytokine that regulates cell growth and differentiation and participates in inflammatory and immune responses. The purpose of this study was to clarify the relationship between PD-L1 and IL-10 and their clinical importance in esophageal carcinoma (ESCA). Methods ESCA patients (n=100) who underwent surgery with preoperative therapy were included in the study. By immuno-histochemical staining, PD-L1, IL-10 and CD8 positive cells were examined in resected specimens. The gene expression levels of PD-L1, IL-10 and Met were detected by qRT-PCR and Western blots, and differentially compared in cancer, adjacent and normal tissues. In cell experiments, the Eca109 and TE-1 cell-lines were incubated with IL-10 or anti-IL-10 antibody, and then PD-L1 and Met expression levels were compared by ELISA and Western blots. The effect of crizotinib and/or IL-10 on the proliferation, invasion and migration of esophageal squamous cell-lines was estimated by CCK8 and transwell assay. Results In tumor tissues, the mRNA and protein levels of PD-L1, IL-10 and Met were higher than those in adjacent tissues. The high expression levels of PD-L1 and IL-10 indicated a poor prognosis. IL-10 reduced the expression of PD-L1 in esophageal squamous cell-lines via Met signaling. Over-expression of PD-L1 in increased the levels of IL-10, and Met in in ESCA tissue and cell lines. The combination of crizotinib and IL-10 were more effective in inhibiting the proliferation, migration and invasion of esophageal squamous cell lines. Conclusions The combination of IL-10 and PD-L1 monoclonal antibody may have therapeutic promise in treating ESCA.
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Affiliation(s)
- Qian Qian
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Jianping Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Weibing Wang
- Chinese People's Liberation Army 904 Hospital, Changzhou 214044, China
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Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives. Diagnostics (Basel) 2020; 10:diagnostics10030146. [PMID: 32156035 PMCID: PMC7151145 DOI: 10.3390/diagnostics10030146] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/03/2020] [Accepted: 03/04/2020] [Indexed: 12/21/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers. Despite improvements in medical treatments, the prognosis for EOC remains poor, and there is an urgent need for new therapeutic strategies. Immune checkpoint inhibitors (CPIs) have dramatically improved survival of several cancers and are under evaluation in OC. Unfortunately, CPIs have shown globally unsatisfactory results. The aim of this manuscript is to critically review the results from early-phase trials with CPIs in terms of safety and activity, discuss the possible reasons for disappointing results and the new therapeutic approaches to improve patient outcomes.
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43
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Singh BP, Marshall JL, He AR. Workup and Management of Immune-Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors. Oncologist 2020; 25:197-202. [PMID: 32162824 PMCID: PMC7066712 DOI: 10.1634/theoncologist.2018-0304] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 08/19/2019] [Indexed: 12/14/2022] Open
Abstract
As the use of immune checkpoint inhibitors for several different malignancies becomes more mainstream, their side-effect profile raises new challenges. In 2011, the Food and Drug Administration approved the first checkpoint inhibitor for the treatment of advanced melanoma, and since then, checkpoint inhibitors have demonstrated efficacy in many other tumor types. Given the frequent use of immune checkpoint inhibitors in a wide range of cancers today, the diagnosis and management of their immune-mediated toxicities need special attention. One of the most common is immune-mediated colitis. Workup and management of immune-mediated colitis can be challenging and is the purpose of this review. KEY POINTS: Rate of immune mediated colitis differ from different kind of immune checkpoint inhibitor treatment. To work up immune-mediated colitis, tests to rule out infectious etiologies of diarrhea, colonoscopy and abdominal image will help to differentiate immune mediated colitis from colitis from other etiology. Patients with mild colitis can be managed with supportive therapies alone, but more severe cases may require immunomodulators such as steroid. Refractory cases may require tumor necrosis factor (TNF) inhibitors, such as infliximab in addition to steroid treatment.
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Affiliation(s)
- Bhavana Pendurthi Singh
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
| | - John L. Marshall
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
| | - Aiwu Ruth He
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical CenterWashingtonDCUSA
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Cugnet Anceau C, Abeillon J, Maillet D, Borson-Chazot F, Disse E. Les dysthyroïdies sous immunothérapie anti-cancéreuse. Bull Cancer 2020; 107:262-271. [DOI: 10.1016/j.bulcan.2019.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 10/03/2019] [Accepted: 10/17/2019] [Indexed: 10/25/2022]
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45
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Nguyen ED, Xue YK, Danesh M, Ameri A, Weng CQ, Klebanov N, Foreman RK, Nazarian RM, Demehri S, Tsao H, Kroshinsky D. A Case of Nivolumab-Induced Cutaneous Toxicity with Multiple Morphologies. Dermatopathology (Basel) 2020; 6:255-259. [PMID: 32232031 PMCID: PMC7098352 DOI: 10.1159/000505353] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/09/2019] [Indexed: 12/22/2022] Open
Abstract
Cutaneous reactions are among the most prevalent immune-related adverse events in patients treated with immunotherapy. Given that immunotherapies often act through blocking inhibitory signals on T cells, these treatments also have the potential to generate a host of immune toxicities. We report the case of a 73-year-old woman with a history of non-small cell lung cancer treated with nivolumab 10 months prior to presentation who developed painful nodules, bullae, and a scaly rash on her extremities. Four months after discontinuation of nivolumab, she noted an acute eruption of painful nodules on her extremities, followed by pink papules and tense bullae on her palms and soles. Biopsies were performed of three lesions in sites of varying morphologies. These findings were felt to be consistent with a nivolumab-induced lichenoid reaction. She was initially treated with intralesional steroid injections, topical steroid ointment, and liquid nitrogen cryotherapy with minimal improvement. As the lesions continued to progress, the patient was admitted to the hospital and started on intravenous methylprednisolone. She eventually transitioned to daily oral prednisone with a slow taper with good effect and no recurrence of lesions.
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Affiliation(s)
- Emily D Nguyen
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Yun K Xue
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Combined Dermatology Residency Training Program, Boston, Massachusetts, USA
| | - Melissa Danesh
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Combined Dermatology Residency Training Program, Boston, Massachusetts, USA
| | - Amir Ameri
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Christina Q Weng
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Combined Dermatology Residency Training Program, Boston, Massachusetts, USA
| | - Nikolai Klebanov
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ruth K Foreman
- Department of Dermatopathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rosalynn M Nazarian
- Department of Dermatopathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shadmehr Demehri
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hensin Tsao
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Daniela Kroshinsky
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Sun T, Zhang W, Li Y, Jin Z, Du Y, Tian J, Xue H. Combination Immunotherapy with Cytotoxic T-Lymphocyte-Associated Antigen-4 and Programmed Death Protein-1 Inhibitors Prevents Postoperative Breast Tumor Recurrence and Metastasis. Mol Cancer Ther 2019; 19:802-811. [PMID: 31796506 DOI: 10.1158/1535-7163.mct-19-0495] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 09/25/2019] [Accepted: 11/25/2019] [Indexed: 11/16/2022]
Abstract
Postoperative tumor recurrence and metastasis remain an extreme challenge in breast cancer. Therapies that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have provided unprecedented clinical benefits in various types of cancer. The aim of this study was to determine whether the combination of anti-CTLA-4 and anti-PD-1 could prevent postoperative breast tumor recurrence and metastasis in breast tumor-bearing mice. The results indicated that the combination of CTLA-4 and PD-1 inhibitors was more effective compared with single inhibitors for mammary tumor growth and prevention of postsurgical tumor recurrence and pulmonary metastasis (P < 0.05), which resulted in prolonged survival (P < 0.05). Analysis of the underlying mechanism revealed that anti-CTLA-4 and anti-PD-1 in combination synergistically promoted the infiltration of CD8+ and CD4+ T cells into tumors (P < 0.05 vs. single inhibitors), thus boosting the antitumor immune responses. In summary, our results revealed that combination immunotherapy with anti-CTLA-4 and anti-PD-1 may present a new, promising regimen to inhibit postoperative breast cancer relapse and lung metastasis and improve patient outcomes, which warrants further investigation in clinical settings.
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Affiliation(s)
- Ting Sun
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,CAS Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Wenjia Zhang
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,CAS Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China
| | - Yuan Li
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Zhengyu Jin
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yang Du
- CAS Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China. .,The University of Chinese Academy of Sciences, Beijing, China
| | - Jie Tian
- CAS Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, China. .,The University of Chinese Academy of Sciences, Beijing, China
| | - Huadan Xue
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
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Spiers L, Coupe N, Payne M. Toxicities associated with checkpoint inhibitors-an overview. Rheumatology (Oxford) 2019; 58:vii7-vii16. [PMID: 31816085 PMCID: PMC6900917 DOI: 10.1093/rheumatology/kez418] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 07/30/2019] [Indexed: 12/14/2022] Open
Abstract
Immunotherapy has an increasing role in the management of cancer, both in metastatic disease and as an adjuvant therapy. However, sensitization of the immune system with checkpoint inhibitors comes with a unique side effect profile. Full appreciation of this can take some time to emerge as some adverse events are rare, or can be subtle and potentially overlooked. Clinician awareness of these side effects can be particularly important in patients with pre-existing autoimmune conditions. Here we describe common symptoms and diagnostic strategies for organ-specific side effects of anti-CTLA-4 and anti-PD-1/PD-L1 immunotherapy agents.
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Affiliation(s)
- Laura Spiers
- Department of Oncology, Churchill Hospital, Oxford University Hospitals Foundation Trust, Oxford, UK
| | - Nicholas Coupe
- Department of Oncology, Churchill Hospital, Oxford University Hospitals Foundation Trust, Oxford, UK
| | - Miranda Payne
- Department of Oncology, Churchill Hospital, Oxford University Hospitals Foundation Trust, Oxford, UK
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Abstract
PURPOSE OF REVIEW This review addresses our current knowledge of immune-mediated colitis (IMC) and offers a practical guide to its management. RECENT FINDINGS Due to the similarity in clinical, endoscopic, and histologic findings between IMC and inflammatory bowel disease (IBD), gastroenterologists have tailored their approach to IMC management to that of IBD. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that augment the T-cell anti-tumor response of the immune system and have demonstrated their importance in the treatment of a wide range of malignancies. With the growing benefits of ICIs, there are immune-related adverse events (irAEs) that mirror many known autoimmune diseases. Diarrhea and IMC are the most common and severe irAEs noted. No standardized guidelines exist in the management of these irAEs.
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Affiliation(s)
- Tara Menon
- The Ohio State University Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Anita Afzali
- The Ohio State University Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Nishida T, Iijima H, Adachi S. Immune checkpoint inhibitor-induced diarrhea/colitis: Endoscopic and pathologic findings. World J Gastrointest Pathophysiol 2019; 10:17-28. [PMID: 31559106 PMCID: PMC6751508 DOI: 10.4291/wjgp.v10.i2.17] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 06/30/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
The indications of immune checkpoint inhibitors (ICPIs) for cancer treatment have rapidly expanded, and their use is increasing in clinical settings worldwide. Despite the considerable clinical benefits of ICPIs, frequent immune-related adverse events (irAEs) have become nonnegligible concerns. Among irAEs, ICPI-induced colitis/diarrhea is frequent and recognized not only by oncologists but also by gastroenterologists or endoscopists. The endoscopic findings show similarity to those of inflammatory bowel disease to a certain extent, particularly ulcerative colitis, but do not seem to be identical. The pathological findings of ICPI-induced colitis may vary among drug classes. They show acute or chronic inflammation, but it may depend on the time of colitis suggested by colonoscopy, including biopsy or treatment intervention. In the case of chronic inflammation determined by biopsy, the endoscopy findings may overlap with those of inflammatory bowel disease. Here, we provide a comprehensive review of ICPI-induced colitis based on clinical, endoscopic and pathologic findings.
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Affiliation(s)
- Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, Osaka 560-8565, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Shiro Adachi
- Department of Pathology, Toyonaka Municipal Hospital, Osaka 560-8565, Japan
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50
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Teufel A, Zhan T, Härtel N, Bornschein J, Ebert MP, Schulte N. Management of immune related adverse events induced by immune checkpoint inhibition. Cancer Lett 2019; 456:80-87. [DOI: 10.1016/j.canlet.2019.04.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/02/2019] [Accepted: 04/09/2019] [Indexed: 12/17/2022]
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