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Kälble F, Leonhard J, Zeier M, Zivanovic O, Schaier M, Steinborn A. Exhaustion of CD8 pos central memory regulatory T cell differentiation is involved in renal allograft rejection. Front Immunol 2025; 16:1532086. [PMID: 39925813 PMCID: PMC11802571 DOI: 10.3389/fimmu.2025.1532086] [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: 11/21/2024] [Accepted: 01/03/2025] [Indexed: 02/11/2025] Open
Abstract
Background The role of regulatory CD8pos T cells (CD8pos Tregs) and cytotoxic CD8pos responder T cells (CD8pos Tresps) in maintaining stable graft function in kidney transplant recipients (KTR) remains largely unclear. The pathogenesis of graft deterioration in case of rejection involves the exhaustive differentiation of both CD8pos T cell subsets, but the causal mechanisms have not yet been identified. Methods In this study, we separately investigated the differentiation of CD8posTregs/Tresps in 134 stable KTR with no evidence of renal graft rejection, in 41 KTR diagnosed with biopsy-confirmed rejection at enrolment and in 5 patients who were unremarkable at enrolment, but developed rejection within three years of enrolment. We were investigating whether changed differentiation of CCR7posCD45RAposCD31pos recent thymic emigrant (RTE) cells via CD45RAnegCD31pos memory (CD31pos memory) cells (pathway 1), via direct proliferation (pathway 2), or via CCR7posCD45RA+CD31neg resting mature naïve (MN) cells (pathway 3) into CD45RAnegCD31neg memory (CD31neg memory) cells affects the CD8pos Treg/Tresp ratio or identifies a CD8pos Treg/Tresp subset that predicts or confirms renal allograft rejection. Results We found that RTE Treg differentiation via pathway 1 was age-independently increased in KTR, who developed graft rejection during the follow-up period, leading to abundant MN Treg and central memory Treg (CM Treg) production and favoring a strongly increased CD8pos Treg/Tresp ratio. In KTR with biopsy-confirmed rejection at the time of enrolment, an increased differentiation of RTE Tregs into CCR7negCD45RAposCD31neg terminally differentiated effector memory (CD31neg TEMRA Tregs) and CD31pos memory Tregs was observed. CD31neg memory Treg production was maintained by alternative differentiation of resting MN Tregs, resulting in increased effector memory Treg (EM Treg) production, while the CD8pos Treg/Treg ratio was unaffected. An altered differentiation of CD8pos Tresps was not observed, shifting the Treg/Tresp ratio in favor of Tregs. Conclusions Our results show that exhaustive CD8pos Treg differentiation into CM Tregs may lead to future rejection, with a shift towards EM Treg production and an accumulation of CD31neg TEMRA Tregs in KTR with current rejection.
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Affiliation(s)
- Florian Kälble
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Jonas Leonhard
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Oliver Zivanovic
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
| | - Matthias Schaier
- Department of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Andrea Steinborn
- Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
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2
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Herrmann SM, Abudayyeh A, Gupta S, Gudsoorkar P, Klomjit N, Motwani SS, Karam S, Costa E Silva VT, Khalid SB, Anand S, Kala J, Leaf DE, Murakami N, Rashidi A, Wanchoo R, Kitchlu A. Diagnosis and management of immune checkpoint inhibitor-associated nephrotoxicity: a position statement from the American Society of Onco-nephrology. Kidney Int 2025; 107:21-32. [PMID: 39455026 DOI: 10.1016/j.kint.2024.09.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/09/2024] [Accepted: 09/13/2024] [Indexed: 10/28/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer and are now the backbone of therapy for several malignancies. However, ICIs can cause a spectrum of kidney immune-related adverse events including acute kidney injury (AKI), most commonly manifesting as acute interstitial nephritis (AIN), although glomerular disease and electrolyte disturbances have also been reported. In this position statement by the American Society of Onco-nephrology (ASON), we summarize the incidence and risk factors for ICI-AKI, pathophysiological mechanisms, and clinicopathologic features of ICI-AKI. We also discuss novel diagnostic approaches and promising biomarkers for ICI-AKI. From expert panel consensus, we provide clinical practice points for the initial assessment and diagnosis of ICI-AKI, management and immunosuppressive therapy, and consideration for rechallenge with ICI following AKI episodes. In addition, we explore ICI use in special populations, such as kidney transplant recipients, and propose key areas of focus for future research and clinical investigation.
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Affiliation(s)
- Sandra M Herrmann
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
| | - Ala Abudayyeh
- Section of Nephrology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Shruti Gupta
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Department of Medical Oncology, Dana-Farber Cancer Institute. Harvard Medical School, Boston, Massachusetts, USA
| | | | - Nattawat Klomjit
- Department of Medicine, Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, Minnesota, USA
| | - Shveta S Motwani
- Department of Medical Oncology, Dana-Farber Cancer Institute. Harvard Medical School, Boston, Massachusetts, USA
| | - Sabine Karam
- Department of Medicine, Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, Minnesota, USA; Department of Internal Medicine, Division of Nephrology and Hypertension, American University of Beirut, Beirut, Lebanon
| | - Verônica T Costa E Silva
- Serviço de Nefrologia, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil; Laboratório de Investigação Médica (LIM) 16, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Sheikh B Khalid
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Shuchi Anand
- Department of Medicine (Nephrology), Stanford University, Stanford, California, USA
| | - Jaya Kala
- Division of Renal Diseases and Hypertension, University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas, USA
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Arash Rashidi
- Division of Nephrology and Hypertension, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Rimda Wanchoo
- Division of Kidney Diseases and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Great Neck, New York, USA
| | - Abhijat Kitchlu
- Department of Medicine, Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
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3
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Struckmeier AK, Gosau M, Smeets R. Cutaneous squamous cell carcinoma in solid organ transplant recipients: Current therapeutic and screening strategies. Transplant Rev (Orlando) 2024; 38:100882. [PMID: 39348772 DOI: 10.1016/j.trre.2024.100882] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/23/2024] [Accepted: 09/23/2024] [Indexed: 10/02/2024]
Abstract
Solid organ transplant recipients (SOTRs) are particularly prone to developing malignancies, often manifesting multiple tumors and tumors with a heightened susceptibility to metastasis, resulting in much lower survival rates when compared to the general population. Among these, cutaneous squamous cell carcinoma (CSCC) respresent a major challenge in terms of morbidity and mortality following organ transplantation. The management of post-transplant CSCC requires expertise from various disciplines, including dermatology, maxillofacial surgery, transplant medicine, radiation oncology, and medical oncology. Furthermore, the unique behaviors and prevalence of tumors in SOTRs necessitate tailored pathways for screening and treatment, distinct from those designed for immunocompetent patients. Despite the proven efficacy of immune checkpoint inhibitors (ICIs) in several cancers, SOTRs have often been systematically excluded from clinical trials due to concerns about potential allograft rejection and loss. Consequently, most data on the safety and efficacy of ICIs in SOTRs are derived from case series and reports. Given the significant risks involved, alternative therapeutic options should be thoroughly discussed with patients before considering ICI therapy. This literature review aims to provide an overview of CSCC in SOTRs, with a specific emphasis on therapeutic and screening strategies, particularly highlighting immunotherapy.
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Affiliation(s)
- Ann-Kristin Struckmeier
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
| | - Martin Gosau
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Ralf Smeets
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; Department of Oral and Maxillofacial Surgery, Division of Regenerative Orofacial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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4
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Khaddour K, Murakami N, Ruiz ES, Silk AW. Cutaneous Squamous Cell Carcinoma in Patients with Solid-Organ-Transplant-Associated Immunosuppression. Cancers (Basel) 2024; 16:3083. [PMID: 39272941 PMCID: PMC11394667 DOI: 10.3390/cancers16173083] [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: 07/23/2024] [Revised: 08/26/2024] [Accepted: 09/03/2024] [Indexed: 09/15/2024] Open
Abstract
The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.
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Affiliation(s)
- Karam Khaddour
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
| | - Naoka Murakami
- Harvard Medical School, Boston, MA 02115, USA
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Emily S Ruiz
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Ann W Silk
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
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5
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Ge Y, Saad M, Nemani S, Shi Y, Lineaweaver WC, Yang Y. Diagnosis and Treatment of Skin Lesions in Renal Transplant Recipients: A Retrospective Review. Ann Plast Surg 2024; 93:S51-S54. [PMID: 39101849 DOI: 10.1097/sap.0000000000003930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2024]
Abstract
BACKGROUND Immunosuppressive therapy is essential for to prevent graft rejection in renal transplant patients; however, it is associated with elevating the risk of several pathologies in these patients particularly infectious and neoplastic conditions. In this study, we explore the diagnosis and treatment of skin lesions in renal transplant patients. METHODS A retrospective chart review of 12 renal transplant recipients referred to plastic and reconstructive surgery with skin lesions from 2000 to 2020 was performed. RESULTS The mean age of the 12 patients was 49.6 years. Time to plastic surgery after renal transplantation ranged between 1 and 16 years. Nine cases of basal cell carcinoma, 2 cases of squamous cell carcinoma, and 1 case of skin and soft tissue infection of the lower extremity and cutaneous extranodal NK/T-cell lymphoma, nasal type was observed. Flaps, skin grafts, and artificial dermis grafts constitute the main reconstructive methods. There were no postoperative infections or wound dehiscence. CONCLUSIONS Cutaneous infections and skin malignancy account for most of the skin lesions developing after renal transplantation. Posttransplant lymphoproliferative disorder warrants equal attention and should not be disregarded. Early diagnosis and treatment significantly improve prognosis as patients with longer duration of transplant were found to have more aggressive tumors. Plastic and reconstructive surgery offers a safe therapeutic method of treatment in these cases.
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Affiliation(s)
- Yining Ge
- From the Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mariam Saad
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sriya Nemani
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yuedong Shi
- From the Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - William C Lineaweaver
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yanwen Yang
- From the Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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6
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Fernández Madrigal L, García Samblás V, Sánchez Escudero L. Experience with pembrolizumab in a renal transplant patient with advanced lung cancer: a case report and review. Anticancer Drugs 2024; 35:563-568. [PMID: 38453157 DOI: 10.1097/cad.0000000000001596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2024]
Abstract
The treatment of non-small cell lung cancer (NSCLC) has undergone a change because of the advancement of new therapies, like immune checkpoint inhibitors (ICIs), including pembrolizumab. A 64-year-old woman received a kidney transplant in 2012 because of chronic kidney disease secondary to glomerulosclerosis, diagnosed in 2020 with stage IV NSCLC because of metastasis in the contralateral lung, with programmed death ligand 1programmed death ligand 1 expression of 98%, starting treatment with ICIs, despite presenting a graft rejection risk around 40%. After three ICIs cycles, the patient presented a partial response, with good tolerance to treatment and no signs of graft failure. ICIs were maintained for 19 cycles, until disease progression was observed on a reassessment computed tomography, with a progression-free interval of 18 months, with no evidence of treatment rejection. In transplant patients diagnosed with some type of tumor, antineoplastic therapies may be less effective than in the general population. The current evidence derives from observational studies and case series, since this patient population was excluded from clinical trials, suggesting that the use of ICIs in patients with kidney transplants can lead to acute graft rejection. This is still a controversial issue, it is necessary to improve the quality of the data, with the implementation of clinical trials or prospective studies.
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Affiliation(s)
- Laura Fernández Madrigal
- Medical oncology service, Hospital Juan Ramón Jiménez, Hospital Universitario Juan Ramón Jiménez, Huelva, Spain
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Ben Nasr M, Usuelli V, Dellepiane S, Seelam AJ, Fiorentino TV, D'Addio F, Fiorina E, Xu C, Xie Y, Balasubramanian HB, Castillo-Leon E, Loreggian L, Maestroni A, Assi E, Loretelli C, Abdelsalam A, El Essawy B, Uccella S, Pastore I, Lunati ME, Sabiu G, Petrazzuolo A, Ducci G, Sacco E, Centofanti L, Venturini M, Mazzucchelli S, Mattinzoli D, Ikehata M, Castellano G, Visner G, Kaifeng L, Lee KM, Wang Z, Corradi D, La Rosa S, Danese S, Yang J, Markmann JF, Zuccotti GV, Abdi R, Folli F, Fiorina P. Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule. Cell Metab 2024; 36:1302-1319.e12. [PMID: 38838642 DOI: 10.1016/j.cmet.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 12/06/2023] [Accepted: 05/02/2024] [Indexed: 06/07/2024]
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1Rpos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1Rpos and GLP-1Rneg CD3+ T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1Rpos are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer.
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Affiliation(s)
- Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Sergio Dellepiane
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Andy Joe Seelam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Emma Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Cong Xu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
| | - Yanan Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
| | - Hari Baskar Balasubramanian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Eduardo Castillo-Leon
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lara Loreggian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Anna Maestroni
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Ahmed Abdelsalam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Basset El Essawy
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Medicine, Al-Azhar University, Cairo, Egypt
| | - Silvia Uccella
- Humanitas University and IRCCS Humanitas Research Hospital, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli Sacco, Milan, Italy
| | | | - Gianmarco Sabiu
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Adriana Petrazzuolo
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Giacomo Ducci
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy; Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy
| | - Elena Sacco
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy; Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy
| | - Lucia Centofanti
- Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy
| | | | | | - Deborah Mattinzoli
- Nephrology, dialysis and renal transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Masami Ikehata
- Nephrology, dialysis and renal transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Castellano
- Nephrology, dialysis and renal transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Gary Visner
- Pulmonary Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Liu Kaifeng
- Pulmonary Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Kang Mi Lee
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zhimin Wang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Domenico Corradi
- Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Technological innovation, University of Insubria, Varese, Italy; Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele, Milan, Italy
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
| | - James F Markmann
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Gian Vincenzo Zuccotti
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Department of Pediatrics, Children's Hospital Buzzi, University of Milan, Milan, Italy
| | - Reza Abdi
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Franco Folli
- Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy.
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Endocrinology, ASST Fatebenefratelli Sacco, Milan, Italy.
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8
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Cillo U, Carraro A, Avolio AW, Cescon M, Di Benedetto F, Giannelli V, Magistri P, Nicolini D, Vivarelli M, Lanari J. Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT). Updates Surg 2024; 76:725-741. [PMID: 38713396 DOI: 10.1007/s13304-024-01845-z] [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: 07/13/2023] [Accepted: 07/31/2023] [Indexed: 05/08/2024]
Abstract
Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.
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Affiliation(s)
- Umberto Cillo
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy.
| | - Amedeo Carraro
- Liver Transplant Unit, Department of Surgery and Oncology, University Hospital Trust of Verona, Verona, Italy
| | - Alfonso W Avolio
- Department of General Surgery and Liver Transplantation, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Matteo Cescon
- General Surgery and Transplantation Unit, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria-Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Fabrizio Di Benedetto
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Valerio Giannelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Paolo Magistri
- Hepatopancreatobiliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Daniele Nicolini
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Marco Vivarelli
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Riuniti Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Jacopo Lanari
- Department of Surgical, Oncological and Gastroenterological Sciences, General Surgery 2 Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Padua University Hospital, Via Giustiniani 2, 34128, Padua, PD, Italy
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Fernández Madrigal L, García Samblásand V, Sánchez Escudero L. Experience with pembrolizumab in a renal transplant patient with advanced lung cancer: a case report and review. Anticancer Drugs 2024; 35:377-382. [PMID: 38271682 DOI: 10.1097/cad.0000000000001570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
The treatment of non-small cell lung cancer (NSCLC) has undergone a change due to the advancement of new therapies, like immune checkpoint inhibitors (ICIs), including pembrolizumab. A 64-year-old woman received a kidney transplant in 2012 due to chronic kidney disease secondary to glomerulosclerosis, diagnosed in 2020 with stage IV NSCLC due to metastasis in the contralateral lung, with PD-L1 expression of 98%, starting treatment with ICIs, despite presenting a graft rejection risk around 40%. After 3 ICI cycles, the patient presented a partial response, with good tolerance to treatment and no signs of graft failure. ICIs were maintained for 19 cycles, until disease progression was observed on a reassessment computed tomography, with a progression-free interval of 18 months, with no evidence of treatment rejection. In transplant patients diagnosed with some type of tumor, antineoplastic therapies may be less effective than in the general population. The current evidence derives from observational studies and case series, since this patient population was excluded from clinical trials, suggesting that the use of ICIs in patients with kidney transplants can lead to acute graft rejection. This is still a controversial issue, it is necessary to improve the quality of the data, with the implementation of clinical trials or prospective studies.
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Zheng S, He A, Chen C, Gu J, Wei C, Chen Z, Liu J. Predicting immunotherapy response in melanoma using a novel tumor immunological phenotype-related gene index. Front Immunol 2024; 15:1343425. [PMID: 38571962 PMCID: PMC10987686 DOI: 10.3389/fimmu.2024.1343425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/29/2024] [Indexed: 04/05/2024] Open
Abstract
Introduction Melanoma is a highly aggressive and recurrent form of skin cancer, posing challenges in prognosis and therapy prediction. Methods In this study, we developed a novel TIPRGPI consisting of 20 genes using Univariate Cox regression and the LASSO algorithm. The high and low-risk groups based on TIPRGPI exhibited distinct mutation profiles, hallmark pathways, and immune cell infiltration in the tumor microenvironment. Results Notably, significant differences in tumor immunogenicity and TIDE were observed between the risk groups, suggesting a better response to immune checkpoint blockade therapy in the low-TIPRGPI group. Additionally, molecular docking predicted 10 potential drugs that bind to the core target, PTPRC, of the TIPRGPI signature. Discussion Our findings highlight the reliability of TIPRGPI as a prognostic signature and its potential application in risk classification, immunotherapy response prediction, and drug candidate identification for melanoma treatment. The "TIP genes" guided strategy presented in this study may have implications beyond melanoma and could be applied to other cancer types.
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Affiliation(s)
- Shaoluan Zheng
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Anqi He
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Chenxi Chen
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China
| | - Jianying Gu
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Artificial Intelligence Center for Plastic Surgery and Cutaneous Soft Tissue Cancers, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chuanyuan Wei
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhiwei Chen
- Big Data and Artificial Intelligence Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiaqi Liu
- Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Artificial Intelligence Center for Plastic Surgery and Cutaneous Soft Tissue Cancers, Zhongshan Hospital, Fudan University, Shanghai, China
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Schenk KM, Deutsch JS, Chandra S, Davar D, Eroglu Z, Khushalani NI, Luke JJ, Ott PA, Sosman JA, Aggarwal V, Schollenberger MD, Sharfman WH, Bibee KP, Scott JF, Loss MJ, Wang H, Qi H, Sharon E, Streicher H, Chen HX, Woodward RN, Bagnasco SM, Taube JM, Topalian SL, Brennan DC, Lipson EJ. Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers. J Clin Oncol 2024; 42:1011-1020. [PMID: 38252910 PMCID: PMC11677297 DOI: 10.1200/jco.23.01497] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/31/2023] [Accepted: 12/08/2023] [Indexed: 01/24/2024] Open
Abstract
PURPOSE Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.
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Affiliation(s)
- Kara M. Schenk
- Department of Oncology, Bozeman Health Deaconess Cancer Center, Bozeman, MT, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD, USA
| | - Julie Stein Deutsch
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sunandana Chandra
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Diwakar Davar
- Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Zeynep Eroglu
- Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Nikhil I. Khushalani
- Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jason J. Luke
- Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick A. Ott
- Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA, USA
| | - Jeffrey A. Sosman
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Vikram Aggarwal
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - William H. Sharfman
- Department of Oncology, Johns Hopkins University, Baltimore, MD, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kristin P. Bibee
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jeffrey F. Scott
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Clinical Skin Center of Northern Virginia, Fairfax, VA, USA
| | - Manisha J. Loss
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hao Wang
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Quantitative Sciences, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Hanfei Qi
- Division of Quantitative Sciences, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Elad Sharon
- National Cancer Institute, Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD, USA
| | - Howard Streicher
- National Cancer Institute, Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD, USA
| | - Helen X. Chen
- National Cancer Institute, Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD, USA
| | | | - Serena M. Bagnasco
- Department of Pathology, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD, USA
| | - Janis M. Taube
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Suzanne L. Topalian
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel C. Brennan
- Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Evan J. Lipson
- Department of Oncology, Johns Hopkins University, Baltimore, MD, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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12
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Lewis KD, Peris K, Sekulic A, Stratigos AJ, Dunn L, Eroglu Z, Chang ALS, Migden MR, Yoo SY, Mohan K, Coates E, Okoye E, Bowler T, Baurain JF, Bechter O, Hauschild A, Butler MO, Hernandez-Aya L, Licitra L, Neves RI, Ruiz ES, Seebach F, Lowy I, Goncalves P, Fury MG. Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors. Ann Oncol 2024; 35:221-228. [PMID: 38072158 DOI: 10.1016/j.annonc.2023.10.123] [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: 04/03/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 01/19/2024] Open
Abstract
BACKGROUND Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.
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Affiliation(s)
- K D Lewis
- Department of Medicine-Medical Oncology, University of Colorado School of Medicine, Aurora, USA.
| | - K Peris
- Department of Medicine and Translational Surgery, Dermatology, Università Cattolica del Sacro Cuore, Rome; Department of Medical and Surgical Sciences, Dermatology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
| | - A Sekulic
- Department of Dermatology, Mayo Clinic, Scottsdale, USA
| | - A J Stratigos
- First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros Hospital, Athens, Greece
| | - L Dunn
- Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York
| | - Z Eroglu
- Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa
| | - A L S Chang
- Dermatology Department, Stanford University School of Medicine, Redwood City
| | - M R Migden
- Department of Dermatology and Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston; Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston
| | - S-Y Yoo
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - K Mohan
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - E Coates
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - E Okoye
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - T Bowler
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - J-F Baurain
- Department of Medical Oncology, Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels
| | - O Bechter
- Department of General Medical Oncology, University Hospitals, Leuven, Belgium
| | - A Hauschild
- Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Kiel, Germany
| | - M O Butler
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - L Hernandez-Aya
- Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St Louis, USA
| | - L Licitra
- Department of Medical Oncology Head and Neck Cancer, Istituto Nazionale dei Tumori, Milan; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - R I Neves
- Division of Plastic Surgery, Penn State Milton S. Hershey Medical Center, Hershey
| | - E S Ruiz
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
| | - F Seebach
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - I Lowy
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - P Goncalves
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
| | - M G Fury
- Regeneron Pharmaceuticals, Inc., Tarrytown, USA
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13
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Li S, Zou D. Harnessing mixed chimerism and programmed cell death protein 1/programmed death ligand 1 signaling for transplant tolerance. Am J Transplant 2024; 24:147-148. [PMID: 37757911 DOI: 10.1016/j.ajt.2023.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023]
Affiliation(s)
- Shuang Li
- Department of Cardiovascular Science, Houston Methodist Research Institute, Houston, Texas, USA
| | - Dawei Zou
- Immunobiology and Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
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Stratigos AJ, Garbe C, Dessinioti C, Lebbe C, van Akkooi A, Bataille V, Bastholt L, Dreno B, Dummer R, Fargnoli MC, Forsea AM, Harwood CA, Hauschild A, Hoeller C, Kandolf-Sekulovic L, Kaufmann R, Kelleners-Smeets NW, Lallas A, Leiter U, Malvehy J, Del Marmol V, Moreno-Ramirez D, Pellacani G, Peris K, Saiag P, Tagliaferri L, Trakatelli M, Ioannides D, Vieira R, Zalaudek I, Arenberger P, Eggermont AMM, Röcken M, Grob JJ, Lorigan P. European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma: Part 2. Treatment-Update 2023. Eur J Cancer 2023; 193:113252. [PMID: 37708630 DOI: 10.1016/j.ejca.2023.113252] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 07/18/2023] [Indexed: 09/16/2023]
Abstract
In order to update recommendations on treatment, supportive care, education, and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV), and the European Organisation of Research and Treatment of Cancer (EORTC) was formed. Recommendations were based on an evidence-based literature review, guidelines, and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable), and distant metastatic cSCC. For common primary cSCC, the first-line treatment is surgical excision with postoperative margin assessment or micrographically controlled surgery. Achieving clear surgical margins is the most important treatment consideration for patients with cSCCs amenable to surgery. Regarding adjuvant radiotherapy for patients with high-risk localised cSCC with clear surgical margins, current evidence has not shown significant benefit for those with at least one high-risk factor. Radiotherapy should be considered as the primary treatment for non-surgical candidates/tumours. For cSCC with cytologically or histologically confirmed regional nodal metastasis, lymph node dissection is recommended. For patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiotherapy, anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drugs Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC, include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiotherapy. Multidisciplinary board decisions are mandatory for all patients with advanced cSCC, considering the risks of toxicity, the age and frailty of patients, and co-morbidities, including immunosuppression. Patients should be engaged in informed, shared decision-making on management and be provided with the best supportive care to improve symptom management and quality of life. The frequency of follow-up visits and investigations for subsequent new cSCC depends on underlying risk characteristics.
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Affiliation(s)
- Alexander J Stratigos
- First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros Hospital, Athens, Greece.
| | - Claus Garbe
- Centre for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
| | - Clio Dessinioti
- First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros Hospital, Athens, Greece
| | - Celeste Lebbe
- Université Paris Cite, Dermato-Oncology AP-HP Hôpital Saint Louis, Cancer Institute APHP. Nord-Université Paris Cite, INSERM U976, Paris, France
| | - Alexander van Akkooi
- Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; Melanoma Institute Australia, Sydney, New South Wales, Australia
| | | | - Lars Bastholt
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | - Brigitte Dreno
- Nantes Université, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes, France
| | - Reinhard Dummer
- Skin Cancer Centre at University Hospital, Zurich, Switzerland
| | - Maria Concetta Fargnoli
- Dermatology Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Ana Maria Forsea
- Carol Davila University of Medicine and Pharmacy Bucharest, Department of Oncologic Dermatology, Elias University Hospital Bucharest, Bucharest, Romania
| | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Axel Hauschild
- Department of Dermatology, University Hospital (UKSH), Kiel, Germany
| | - Christoph Hoeller
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | | | - Roland Kaufmann
- Department of Dermatology, Venereology and Allergology, Frankfurt University Hospital, Frankfurt, Germany
| | - Nicole Wj Kelleners-Smeets
- GROW-School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands; Department of Dermatology, Maastricht University Medical Centre+, Maastricht University, Maastricht, the Netherlands
| | - Aimilios Lallas
- First Department of Dermatology, Aristotle University, Thessaloniki, Greece
| | - Ulrike Leiter
- Centre for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
| | - Josep Malvehy
- Dermatology Department of Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBER de enfermedades raras, Instituto Carlos III, Barcelona, Spain
| | - Veronique Del Marmol
- Department of Dermatology, University Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - David Moreno-Ramirez
- Department of Medical and Surgical Dermatology Service, Hospital Universitario Virgen Macarena, Sevilla, Spain
| | | | - Ketty Peris
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy; Dermatologia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Philippe Saiag
- Department of General and Oncologic Dermatology, Ambroise-Paré hospital, APHP, and EA 4340 'Biomarkers in Cancerology and Hemato-oncology', UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
| | - Luca Tagliaferri
- UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
| | - Myrto Trakatelli
- Department of Dermatology, Papageorgiou Hospital, Aristotle University Department of Medicine, Thessaloniki, Greece
| | | | - Ricardo Vieira
- Department of Dermatology, Coimbra Hospital and University Centre, Coimbra, Portugal
| | - Iris Zalaudek
- Department of Dermatology, University of Trieste, Trieste, Italy
| | - Petr Arenberger
- Department of Dermatovenereology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alexander M M Eggermont
- University Medical Center Utrecht and Princess Máxima Center, Utrecht, the Netherlands; Comprehensive Cancer Center Munich, Technical University Munich and Ludwig Maximilian University, Munich, Germany
| | - Martin Röcken
- Centre for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
| | | | - Paul Lorigan
- Division of Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, UK
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15
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Ji S, Liu H, Pachella L, Stephenson RD, Groisberg R, Weiss SA. Use of immune checkpoint inhibitors in solid organ transplant recipients with advanced cutaneous malignancies. FRONTIERS IN TRANSPLANTATION 2023; 2:1284740. [PMID: 38993910 PMCID: PMC11235332 DOI: 10.3389/frtra.2023.1284740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/13/2023] [Indexed: 07/13/2024]
Abstract
Background Immune checkpoint inhibitors (ICI) are standard of care therapy for patients with cutaneous malignancies, the most frequently diagnosed cancers in solid organ transplant (SOT) recipients. The activity and rate of allograft rejection in SOT recipients with advanced skin cancers treated with ICI is understudied. Methods We conducted a retrospective analysis of SOT recipients with advanced melanoma, cutaneous squamous cell carcinoma (cSCC), and merkel cell carcinoma (MCC) who were treated with ICI. Unpublished cases from our institution and published cases from the literature were aggregated. Demographics, type of immunosuppressive therapy, type of ICI(s) administered, prior systemic therapies, tumor response to ICI, and evidence of organ rejection and/or failure were recorded. Objective response rates (ORR) and rates of graft rejection and failure are reported. Results Ninety patients were identified; four patients from our institution and 86 unique patients from a literature review. ORR to first-line ICI for the entire cohort was 41.1% (37/90). ORR by tumor type was 31% (18/58), 64.3% (18/28), and 25.0% (1/4) for melanoma, cSCC, and MCC, respectively. The rate of graft rejection was 37.8% (34/90) with 61.8% (21/34) of these cases progressing to graft failure. Number of immunosuppressive agents (0, 1, 2, or 3) was inversely associated with rate of graft failure. Conclusions In this retrospective analysis, ICIs demonstrate clinical activity in SOT recipients with cutaneous malignancies; however, the rate of graft rejection is high. Treatment plans should be individualized through thorough interdisciplinary discussion. Immunosuppressive modifications may be considered prior to starting treatment, but when feasible, enrollment on clinical trials is preferred.
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Affiliation(s)
- Stephanie Ji
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
| | - Hao Liu
- Department of Biostatistics and Epidemiology, Rutgers School of Public Health, New Brunswick, NJ, United States
| | - Laura Pachella
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| | - Ryan D Stephenson
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| | - Roman Groisberg
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| | - Sarah A Weiss
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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16
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Dessinioti C, Stratigos AJ. Immunotherapy and Its Timing in Advanced Basal Cell Carcinoma Treatment. Dermatol Pract Concept 2023; 13:dpc.1304a252. [PMID: 37992360 PMCID: PMC10656142 DOI: 10.5826/dpc.1304a252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2023] [Indexed: 11/24/2023] Open
Abstract
For patients with advanced basal cell carcinoma (BCC), including locally advanced or metastatic BCC not amenable to curative surgery or radiotherapy, hedgehog pathway inhibitors (HHI) vismodegib and sonidegib are approved as first-line systemic treatment. Results from clinical trials highlight that the overall discontinuation rate of HHI treatment varies from 88% to 92% with vismodegib and is approximately 92% with sonidegib, and half of patients will discontinue HHI after approximately 8 to 12 months. The main factors weighing in on the decision to discontinue HHI include efficacy (tumor response), adverse events and patient decision. In clinical practice, some of the patients that stop HHI may be re-evaluated if the tumor becomes amenable to surgery, or restart HHI at a later time, while others will need to switch to immunotherapy, depending on the reasons for HHI discontinuation. In this review, we revisit the therapeutic decisions considering a switch from HHI to immunotherapy with anti-PD-1 agent cemiplimab and we highlight the place of cemiplimab in the therapeutic ladder for patients with advanced BCC. We discuss the evidence on the efficacy and safety of anti-PD-1 agents as second-line systemic monotherapy, or in combination with other treatments, and the emergence of checkpoint immunotherapy as a neoadjuvant treatment.
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Affiliation(s)
- Clio Dessinioti
- Skin Cancer and Melanoma Unit, 1st Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros Hospital, Athens, Greece
| | - Alexander J Stratigos
- Skin Cancer and Melanoma Unit, 1st Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros Hospital, Athens, Greece
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Alonso F, Martín de Francisco ÁLM, Auñón P, García-Carro C, García P, Gutiérrez E, Mcía M, Quintana LF, Quiroga B, Soler MJ, Torregrosa I. Adverse renal effects of check-point inhibitors (ICI) in cancer patients: Recommendations of the Onco-nephrology Working Group of the Spanish Society of Nephrology. Nefrologia 2023; 43:622-635. [PMID: 38000944 DOI: 10.1016/j.nefroe.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/10/2022] [Indexed: 11/26/2023] Open
Abstract
The most widely used approach in the immunotherapy treatment of cancer is the administration of monoclonal antibodies directed against regulatory molecules of immune control that inhibit the activation of T cells, the so-called check point inhibitors (ICI). ICI nephrotoxicity epidemiology and pathology; its diagnosis with or without kidney biopsy; the type and duration of treatment; the possibility of rechallenging after kidney damage; and its indication in patients with cancer and renal transplantation are certainly controversial. In the absence of definitive studies, this document is intended to specify some recommendations agreed by the group of Onconephrology experts of the Spanish Society of Nephrology in those areas related to ICI nephrotoxicity, in order to help decision-making in daily clinical practice in Onconephrology consultations.
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Affiliation(s)
| | | | - Pilar Auñón
- Hospital Universitario Doce de Octubre, Madrid, Spain
| | | | - Patricia García
- Hospital Universitario Candelaria, Santa Cruz de Tenerife, Spain
| | | | - Manuel Mcía
- Hospital Universitario Candelaria, Santa Cruz de Tenerife, Spain
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18
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Szymanska S, Markiewicz-Kijewska M, Pyzlak M, Karkucinska-Wienckowska A, Ciopinski M, Czubkowski P, Kaliciński P. Tissue Expression of Programmed Cell Death 1 Ligand1 (PD-L1) in Biopsies of Transplant Livers of Pediatric Patients as a Possible Marker of Acute Cellular Rejection. J Clin Med 2023; 12:4269. [PMID: 37445304 DOI: 10.3390/jcm12134269] [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: 06/02/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
INTRODUCTION Preclinical models have demonstrated that PD-1 and its ligand programmed death ligand1 (PD-L1) play significant roles in both graft induction and the maintenance of immune tolerance. It has also been suggested that PD-L1 tissue expression may predict graft rejection; however, the available data are sparse and inconclusive. Some studies were conducted on patients with cancer; most of them do not concern the liver, especially within the context of the use of immunohistochemical tests. Therefore, the aim of our study was to assess the relationship between tissue expression of PD-L1 in a unique material, i.e., in the liver biopsies of pediatric patients after transplantation with the presence of acute cellular rejection (ACR). MATERIAL AND METHODS This retrospective study enrolled 55 biopsies from 55 patients who underwent protocol liver biopsies. The control group consisted of 19 biopsies from 13 patients diagnosed with acute cellular rejection (rejection activity index/RAI/ from 2 to 8). An immunohistochemical (IHC) staining for PD-L1 was performed in all of the liver specimens; its expression was analyzed in different regions of liver tissue (in inflammatory infiltrates and within the endothelium and hepatocytes). The following changes were re-evaluated in each specimen: features of any kind of rejection (acute cellular, antibody-mediated, chronic); the presence and severity of fibrosis (Ishak scale); and the presence of cholestasis and steatosis. Clinical parameters were also evaluated, including tests of liver function (AST, ALT, GGT, bilirubin). RESULTS The age of patients in the study group ranged from 2.37 to 18.9 years (median 13.87 years), with the time after transplantation being 1-17 years (median 8.36 years). The age of patients in the control group ranged from 1.48 to 17.51 years (median 7.93 years), with their biopsies being taken 0.62-14.39 years (median 1.33 years) after transplantation. We found a statistically significant relationship between PD-L1 expression on inflammatory infiltrates and ACR; however, there was no statistically significant relationship between PD-L1 endothelial expression and ACR. PD-L1 was not positive in the hepatocytes regardless of if it was the study or control group that was under observation. CONCLUSION PD-L1 appears to be a promising marker to predict graft rejection.
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Affiliation(s)
- Sylwia Szymanska
- Department of Pathology, The Children's Memorial Health Institute, 04-736 Warsaw, Poland
| | - Malgorzata Markiewicz-Kijewska
- Department of Pediatric Surgery and Organ's Transplantation, The Children's Memorial Health Institute, 04-736 Warsaw, Poland
| | - Michal Pyzlak
- Warsaw Department of Pathology, The Institute of Mather and Child, 01-211 Warsaw, Poland
| | | | - Mateusz Ciopinski
- Department of Pediatric Surgery and Organ's Transplantation, The Children's Memorial Health Institute, 04-736 Warsaw, Poland
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutrition Disorder and Pediatric, The Children's Memorial Health Institute, 04-736 Warsaw, Poland
| | - Piotr Kaliciński
- Department of Pediatric Surgery and Organ's Transplantation, The Children's Memorial Health Institute, 04-736 Warsaw, Poland
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19
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Shaw R, Haque AR, Luu T, O’Connor TE, Hamidi A, Fitzsimons J, Varda B, Kwon D, Whitcomb C, Gregorowicz A, Roloff GW, Bemiss BC, Kallwitz ER, Hagen PA, Berg S. Multicenter analysis of immunosuppressive medications on the risk of malignancy following adult solid organ transplantation. Front Oncol 2023; 13:1146002. [PMID: 37397376 PMCID: PMC10313202 DOI: 10.3389/fonc.2023.1146002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/09/2023] [Indexed: 07/04/2023] Open
Abstract
Objective This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types. Methods This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy. Results A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 - 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 - 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 - 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 - 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 - 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 - 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia. Conclusion Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.
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Affiliation(s)
- Reid Shaw
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Ali R. Haque
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Tyler Luu
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Timothy E. O’Connor
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Adam Hamidi
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Jack Fitzsimons
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Bianca Varda
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Danny Kwon
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Cody Whitcomb
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Alex Gregorowicz
- Department of Pharmacy, Hines Veterans Affairs Hospital, Hines, United States
| | - Gregory W. Roloff
- Section of Hematology and Oncology, The University of Chicago, Chicago, United States
| | - Bradford C. Bemiss
- Division of Pulmonary and Critical Care Medicine, Loyola University Medical Center, Maywood, United States
| | - Eric R. Kallwitz
- Division of Hepatology, Loyola University Medical Center, Maywood, United States
| | - Patrick A. Hagen
- Division of Hematology and Oncology, Loyola University Medical Center, Maywood, United States
| | - Stephanie Berg
- Department of Medical Oncology, Lank Center for Genitourinary (GU) Dana-Farber Cancer Institute (DFCI), Harvard Medical School, Boston, MA, United States
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20
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Rao Ullur A, Côté G, Pelletier K, Kitchlu A. Immunotherapy in oncology and the kidneys: a clinical review of the evaluation and management of kidney immune-related adverse events. Clin Kidney J 2023; 16:939-951. [PMID: 37261008 PMCID: PMC10229281 DOI: 10.1093/ckj/sfad014] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Indexed: 11/07/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) are now widely used in the treatment of many cancers, and currently represent the standard of care for multiple malignancies. These agents enhance the T cell immune response to target cancer tissues, and have demonstrated considerable benefits for cancer outcomes. However, despite these improved outcomes, there are important kidney immune-related adverse events (iRAEs) associated with ICI. Acute tubulo-interstitial nephritis remains the most frequent kidney iRAE, however glomerular lesions and electrolytes disturbances are increasingly being recognized and reported. In this review, we summarize clinical features and identify risk factors for kidney iRAEs, and discuss the current understanding of pathophysiologic mechanisms. We highlight the evidence basis for guideline-recommended management of ICI-related kidney injury as well as gaps in current knowledge. We advocate for judicious use of kidney biopsy to identify ICI-associated kidney injury, and early use of corticosteroid treatment where appropriate. Selected patients may also be candidates for re-challenge with ICI therapy after a kidney iRAE, in view of current data on recurrent rates of kidney injury. Risk of benefits of re-challenge must be considered on an individual considering patient preferences and prognosis. Lastly, we review current knowledge of ICI use in the setting of patients with end-stage kidney disease, including kidney transplant recipients and those receiving dialysis, which suggest that these patients should not be summarily excluded from the potential benefits of these cancer therapies.
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Affiliation(s)
- Avinash Rao Ullur
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada
| | - Gabrielle Côté
- Division of Nephrology, Department of Medicine, CHU de Québec, Université Laval, Quebec City, Canada
| | - Karyne Pelletier
- Department of Medicine, Hôpital du Sacré-Coeur de Montréal, Faculty of Medicine, Université de Montréal, Montréal, Canada
| | - Abhijat Kitchlu
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada
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21
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Madill-Thomsen KS, Böhmig GA, Bromberg J, Einecke G, Eskandary F, Gupta G, Myslak M, Viklicky O, Perkowska-Ptasinska A, Solez K, Halloran PF. Relating Molecular T Cell-mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis. Transplantation 2023; 107:1102-1114. [PMID: 36575574 PMCID: PMC10125115 DOI: 10.1097/tp.0000000000004396] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/29/2022] [Accepted: 09/12/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND We studied the variation in molecular T cell-mediated rejection (TCMR) activity in kidney transplant indication biopsies and its relationship with histologic lesions (particularly tubulitis and atrophy-fibrosis) and time posttransplant. METHODS We examined 175 kidney transplant biopsies with molecular TCMR as defined by archetypal analysis in the INTERCOMEX study ( ClinicalTrials.gov #NCT01299168). TCMR activity was defined by a molecular classifier. RESULTS Archetypal analysis identified 2 TCMR classes, TCMR1 and TCMR2: TCMR1 had higher TCMR activity and more antibody-mediated rejection ("mixed") activity and arteritis but little hyalinosis, whereas TCMR2 had less TCMR activity but more atrophy-fibrosis. TCMR1 and TCMR2 had similar levels of molecular injury and tubulitis. Both TCMR1 and TCMR2 biopsies were uncommon after 2 y posttransplant and were rare after 10 y, particularly TCMR1. Within late TCMR biopsies, TCMR classifier activity and activity molecules such as IFNG fell progressively with time, but tubulitis and molecular injury were sustained. Atrophy-fibrosis was increased in TCMR biopsies, even in the first year posttransplant, and rose with time posttransplant. TCMR1 and TCMR2 both reduced graft survival, but in random forests, the strongest determinant of survival after biopsies with TCMR was molecular injury, not TCMR activity. CONCLUSIONS TCMR varies in intensity but is always strongly related to molecular injury and atrophy-fibrosis, which ultimately explains its effect on survival. We hypothesize, based on the reciprocal relationship with hyalinosis, that the TCMR1-TCMR2 gradient reflects calcineurin inhibitor drug underexposure, whereas the time-dependent decline in TCMR activity and frequency after the first year reflects T-cell exhaustion.
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Affiliation(s)
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Gunilla Einecke
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Farsad Eskandary
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Marek Myslak
- Department of Clinical Interventions, Department of Nephrology and Kidney Transplantation SPWSZ Hospital, Pomeranian Medical University, Szczecin, Poland
| | - Ondrej Viklicky
- Department of Nephrology and Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | | | - Kim Solez
- Department of Laboratory Medicine and Pathology, Division of Anatomical Pathology, University of Alberta, Edmonton, Canada
| | - Philip F. Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
- Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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22
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Russomanno K, Abdel Azim S, Patel VA. Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives. Clin Cosmet Investig Dermatol 2023; 16:1025-1045. [PMID: 37095898 PMCID: PMC10122480 DOI: 10.2147/ccid.s362171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/20/2023] [Indexed: 04/26/2023]
Abstract
Non-melanoma skin cancers (NMSCs) are the most common cancers worldwide and may be associated with significant morbidity and mortality, especially in immunosuppressed populations. Successful management of NMSC must take primary, secondary and tertiary prevention strategies into consideration. In response to an improved understanding of the pathophysiology of NMSC and associated risk factors, multiple systemic and topical immunomodulatory drugs have been developed and integrated into clinical practice. Many of these drugs are efficacious in the prevention and treatment of precursor lesions (actinic keratoses; AKs), low-risk NMSC, and advanced disease. The identification of patients at high risk for the development of NMSC is critical in reducing disease morbidity. Understanding the various treatment options available and their comparative effectiveness is paramount for developing a personalized treatment regimen for such patients. This review article provides an updated overview of the various topical and systemic immunomodulatory drugs available for the prevention and treatment of NMSC, and the published data supporting their use in clinical practice.
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Affiliation(s)
- Kristen Russomanno
- Department of Dermatology, Medstar Georgetown University Hospital/Medstar Medical Group, Washington, DC, USA
| | - Sara Abdel Azim
- School of Medicine, Georgetown University, Washington, DC, USA
| | - Vishal A Patel
- Department of Dermatology, George Washington University, Washington, DC, USA
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23
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Cui X, Yan C, Xu Y, Li D, Guo M, Sun L, Zhu Z. Allograft rejection following immune checkpoint inhibitors in solid organ transplant recipients: A safety analysis from a literature review and a pharmacovigilance system. Cancer Med 2023; 12:5181-5194. [PMID: 36504294 PMCID: PMC10028127 DOI: 10.1002/cam4.5394] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/13/2022] [Accepted: 10/21/2022] [Indexed: 12/14/2022] Open
Abstract
AIM This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). METHODS Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. RESULTS A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025 : 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. CONCLUSION Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs.
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Affiliation(s)
- Xiangli Cui
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Cilin Yan
- School of Automation Science and Electrical Engineering, Beihang University, Beijing, China
| | - Ye Xu
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dandan Li
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mingxing Guo
- Pharmacy Department of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Liying Sun
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhijun Zhu
- Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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24
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Jiang J, Huang H, Chen R, Lin Y, Ling Q. Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors? Front Immunol 2023; 14:1092401. [PMID: 36875077 PMCID: PMC9978931 DOI: 10.3389/fimmu.2023.1092401] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally and liver transplantation (LT) can serve as the best curative treatment option. However, HCC recurrence after LT remains the major obstacle to the long-term survival of recipients. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers and provided a new treatment strategy for post-LT HCC recurrence. Evidence has been accumulated with the real-world application of ICIs in patients with post-LT HCC recurrence. Notably, the use of these agents as immunity boosters in recipients treated with immunosuppressors is still controversial. In this review, we summarized the immunotherapy for post-LT HCC recurrence and conducted an efficacy and safety evaluation based on the current experience of ICIs for post-LT HCC recurrence. In addition, we further discussed the potential mechanism of ICIs and immunosuppressive agents in regulating the balance between immune immunosuppression and lasting anti-tumor immunity.
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Affiliation(s)
- Jingyu Jiang
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Haitao Huang
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ruihan Chen
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yimou Lin
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Ling
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Abstract
PURPOSE OF REVIEW The development of immune checkpoint inhibitor (ICI) immunotherapy has revolutionized the treatment of several cancers. Malignancies are one of the leading causes of death in solid organ transplant recipients (SOTRs). Although ICI treatment may be an effective option in treating malignancies in SOTRs, concerns about triggering allograft rejection have been raised in this population. Herein, we will review currently available data regarding patients, allograft and malignancy outcomes in SOTRs who received ICI therapy. RECENT FINDINGS Cancer incidence is three to five-fold higher among SOTRs, compared with the general population. Skin cancer is the most prevalent cancer after transplant, followed by kidney cancer, lymphoma and Kaposi sarcoma. There are no large prospective studies evaluating ICI therapy's use for treating cancers in SOTRs. However, retrospective studies have shown that ICI treatment may be associated with improved malignancy outcomes and overall survival (OS). However, the risk of allograft rejection is high (around 40%) of whom about half lose their allograft. Maintaining higher levels of immunosuppression may be associated with a lower risk of allograft rejection, but potentially worse malignancy outcomes. SUMMARY Although ICI treatment may be associated with improved patient and malignancy outcomes, the risk of allograft rejection and loss are high. Prospective studies are needed to confirm the benefits of ICI therapy in SOTRs and to evaluate the optimal immunosuppression regimen modifications, if any, to improve patient, malignancy and allograft outcomes in transplant recipients.
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Affiliation(s)
- Nora Alzahrani
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ayman Al Jurdi
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Leonardo V. Riella
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
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26
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Li J, Yang F, Li J, Huang ZY, Cheng Q, Zhang EL. Postoperative adjuvant therapy for hepatocellular carcinoma with microvascular invasion. World J Gastrointest Surg 2023; 15:19-31. [PMID: 36741072 PMCID: PMC9896490 DOI: 10.4240/wjgs.v15.i1.19] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/29/2022] [Accepted: 12/21/2022] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal tumors in the world. Liver resection (LR) and liver transplantation (LT) are widely considered as radical treatments for early HCC. However, the recurrence rates after curative treatment are still high and overall survival is unsatisfactory. Microvascular invasion (MVI) is considered to be one of the important prognostic factors affecting postoperative recurrence and long-term survival. Unfortunately, whether HCC patients with MVI should receive postoperative adjuvant therapy remains unknown. In this review, we summarize the therapeutic effects of transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, tyrosine protein kinase inhibitor-based targeted therapy, and immune checkpoint inhibitors in patients with MVI after LR or LT, aiming to provide a reference for the best adjuvant treatment strategy for HCC patients with MVI after LT or LR.
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Affiliation(s)
- Jiang Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Shihezi University, Shihezi 832000, Xinjiang Uygur Autonomous Regions, China
| | - Fan Yang
- Department of General Surgery, Affiliated Hospital of Hubei Minzu University, Enshi 445000, Hubei Province, China
| | - Jian Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhi-Yong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Qi Cheng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Er-Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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27
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Christenson ES, Lee V, Wang H, Yarchoan M, De Jesus-Acosta A, Azad N, Gurakar A, Lin MT, Le DT, Brennan DC, Jaffee EM, Bever K. Solid Organ Transplantation Is Associated with an Increased Rate of Mismatch Repair Deficiency and PIK3CA Mutations in Colorectal Cancer. Curr Oncol 2022; 30:75-84. [PMID: 36661655 PMCID: PMC9858144 DOI: 10.3390/curroncol30010006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/17/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Solid organ transplants are associated with a modestly increased risk of colorectal cancers (CRC). However, the molecular profile of these cancers has not been described. We hypothesized that transplant-related immunosuppression may promote development of more immunogenic tumors as suggested by a high tumor mutation burden or mismatch repair deficiency. We performed an electronic medical record search for patients seen in the Johns Hopkins University Health System (JHHS) between 2017 and 2022 who developed CRC following solid organ transplantation. A comparator cohort of patients treated for CRC at JHHS with molecular profiling data was also identified. In this case, 29 patients were identified that developed post-transplant CRC (renal transplant, n = 18; liver transplant, n = 8; kidney-liver transplantation, n = 3). Compared to the JHHS general population CRC cohort, patients who developed post-transplant CRC had a higher rate of mismatch repair deficiency (41% versus 12%, p-value = 0.0038), and elevated tumor mutation burden (median of 22 mut/Mb versus 3.5 mut/Mb, p-value = 0.033) (range 3.52-53.65). Post-transplant tumors were enriched for PIK3CA mutations (43% versus 24%, p-value = 0.042). Post-Transplant CRCs are associated with clinical and molecular features of immune sensitivity, supporting a potential role for impaired immune surveillance in shaping the landscape of CRCs. These results may help inform the management of patients with post-transplant CRC.
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Affiliation(s)
- Eric S. Christenson
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Valerie Lee
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Hao Wang
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ana De Jesus-Acosta
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Nilo Azad
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ahmet Gurakar
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ming-Tseh Lin
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Dung T. Le
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Daniel C. Brennan
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Elizabeth M. Jaffee
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Katherine Bever
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
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Catalano M, Roviello G, Galli IC, Santi R, Nesi G. Immune checkpoint inhibitor induced nephrotoxicity: An ongoing challenge. Front Med (Lausanne) 2022; 9:1014257. [PMID: 36606052 PMCID: PMC9807763 DOI: 10.3389/fmed.2022.1014257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Although immune checkpoint inhibitors (ICIs) have dramatically revolutionized the field of oncology over the last decade, severe immune-related adverse events (irAEs) are potentially life-threatening. In comparison with toxicities involving the skin, gastrointestinal tract and endocrine system, nephrotoxicity is less common but often underestimated due to difficult diagnosis. Management usually consists of treatment discontinuation and/or corticosteroid use. In this review, we summarize current knowledge of ICI-induced nephrotoxicity, evaluating drawbacks and future perspectives.
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Affiliation(s)
- Martina Catalano
- School of Human Health Sciences, University of Florence, Florence, Italy
| | | | - Ilaria Camilla Galli
- Histopathology and Molecular Diagnostics, Careggi Teaching Hospital, Florence, Italy
| | - Raffaella Santi
- Department of Health Sciences, University of Florence, Florence, Italy
| | - Gabriella Nesi
- Histopathology and Molecular Diagnostics, Careggi Teaching Hospital, Florence, Italy
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29
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Joseph A, Lafarge A, Azoulay E, Zafrani L. Acute Kidney Injury in Cancer Immunotherapy Recipients. Cells 2022; 11:cells11243991. [PMID: 36552755 PMCID: PMC9776910 DOI: 10.3390/cells11243991] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/02/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer immunotherapy has now entered clinical practice and has reshaped the standard of care for many cancer patients. With these new strategies, specific toxicities have emerged, and renal side effects have been described. In this review, we will describe the causes of acute kidney injury in CAR T cell, immune checkpoint inhibitors and other cancer immuno-therapy recipients. CAR T cell therapy and bispecific T cell engaging antibodies can lead to acute kidney injury as a consequence of cytokine release syndrome, tumor lysis syndrome, sepsis or specific CAR T cell infiltration. Immune checkpoint blockade most often results in acute tubular interstitial nephritis, but glomerular diseases have also been described. Although the pathophysiology remains mostly elusive, we will describe the mechanisms of renal damage in these contexts, its prognosis and treatment. As the place of immunotherapy in the anti-cancer armamentarium is exponentially increasing, close collaboration between nephrologists and oncologists is of utmost importance to provide the best standard of care for these patients.
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30
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Murianni V, Cerbone L, Rescigno P, Catalano F, Damassi A, Cremante M, Gandini A, Puglisi S, Pesola G, Banna GL, Buti S, Signori A, Fornarini G, Rebuzzi SE. Combined response of advanced cutaneous squamous cell carcinoma and renal cell carcinoma to immunotherapy: a case report. Immunotherapy 2022; 14:1419-1427. [PMID: 36597723 DOI: 10.2217/imt-2022-0150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Immune checkpoint inhibitors have significantly improved the therapeutic scenario of many different advanced malignancies and could be an effective treatment strategy in synchronous or metachronous tumors. The authors describe the clinical case of a patient who experienced a long-lasting response of his metastatic renal cell carcinoma and an optimal response of his locally advanced cutaneous squamous cell carcinoma to immunotherapy. The systemic treatment was chosen based on a literature review of several clinical reports, since there was no prospective study on anti-PD-1 blockade activity in cutaneous squamous cell carcinoma when the patient started the treatment. This clinical case supports the growing evidence for immunotherapy as a valid treatment option across different types of advanced tumors.
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Affiliation(s)
- Veronica Murianni
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Luigi Cerbone
- Mesothelioma & Rare Cancer Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, 15121, Alessandria, Italy
| | | | - Fabio Catalano
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Alessandra Damassi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Malvina Cremante
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Annalice Gandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Silvia Puglisi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Guido Pesola
- Clinic of Medical Oncology, Oncology Institute of Southern Switzerland, 6500, Bellinzona, Switzerland
| | - Giuseppe Luigi Banna
- Department of Oncology, Portsmouth Hospitals University NHS Trust, SO16 6YD, Portsmouth, UK
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, 43126, Parma, Italy.,Department of Medicine & Surgery, University of Parma, 43126, Parma, Italy
| | - Alessio Signori
- Department of Health Sciences (DISSAL), University of Genova, 16132, Genova, Italy
| | - Giuseppe Fornarini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genova, Italy
| | - Sara Elena Rebuzzi
- Medical Oncology Unit, Ospedale San Paolo, 17100, Savona, Italy.,Department of Internal Medicine & Medical Specialties (Di.M.I.), University of Genova, 16132, Genova, Italy
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31
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Immune checkpoint blockade for organ-transplant recipients with cancer: A review. Eur J Cancer 2022; 175:326-335. [DOI: 10.1016/j.ejca.2022.08.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/24/2022]
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32
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Fronek L, Giansiracusa D, Nourmohammadi N, Johnson C, Yelich A, Hogan D. A Review of Cutaneous Diseases Observed in Solid Organ Transplant Recipients. THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY 2022; 15:21-31. [PMID: 36312823 PMCID: PMC9586525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Solid organ transplant recipients are at increased risk for numerous cutaneous conditions that fall within four categories: pre-neoplastic, neoplastic, infectious, or idiopathic. Many of these diseases can be attributed to immunosuppressive medications, including mycophenolate mofetil, cyclosporine, azathioprine, tacrolimus, or glucocorticoids. Iatrogenic lessening of the immune system places the patient at risk of malignancies, opportunistic infections, immune-mediated dermatoses, and adverse effects of medications. As the life expectancy of patients with solid organ transplants continues to increase, dermatologists and transplant physicians must stay abreast of this spectrum of dermatologic conditions, their respective prognoses, prevention, mitigation, and treatment.
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Affiliation(s)
- Lisa Fronek
- Dr. Fronek is with Bighorn Mohs Surgery and Dermatology Center, Scripps Clinic, La Jolla, California
| | - Derrek Giansiracusa
- Mr. Giansiracusa and Ms. Nourmohammadi are with Lake Erie College of Osteopathic Medicine in Bradenton, Florida
| | - Niki Nourmohammadi
- Mr. Giansiracusa and Ms. Nourmohammadi are with Lake Erie College of Osteopathic Medicine in Bradenton, Florida
| | - Cassandra Johnson
- Drs. Johnson, Yelich, and Hogan are with HCA Healthcare and USF Morsani College of Medicine at Largo Medical Center in Largo, Florida
| | - Allyson Yelich
- Drs. Johnson, Yelich, and Hogan are with HCA Healthcare and USF Morsani College of Medicine at Largo Medical Center in Largo, Florida
| | - Daniel Hogan
- Drs. Johnson, Yelich, and Hogan are with HCA Healthcare and USF Morsani College of Medicine at Largo Medical Center in Largo, Florida
- Dr. Hogan is additionally with the Department of Dermatology at Bay Pines Veterans Affairs Healthcare System in Bay Pines, Florida
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33
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Shaikh A. Immunotherapies and Renal Injury. CURRENT OPINION IN TOXICOLOGY 2022; 31:100362. [PMID: 39086475 PMCID: PMC11290437 DOI: 10.1016/j.cotox.2022.100362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Cancer immunotherapy represents a giant leap forward in the management of malignant diseases. An optimal anti-tumor immune response requires cancer antigen recognition by T-cells followed by an effector immune response. Suppression of T-cell activation prevents cancer cell clearance resulting in tumor proliferation. Recent clinical successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies has transformed the landscape of cancer immunotherapy. The goal of immunotherapy is to boost host-protective anti-tumor immunity without concomitantly causing immune-related adverse events. However, immunotherapies can cause multiorgan dysfunction including acute kidney injury. Prompt recognition and management of immunotherapy-associated kidney injury is critical in preserving kidney function and improving patient outcomes.
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Affiliation(s)
- Aisha Shaikh
- Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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34
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Hanania HL, Lewis DJ. Systematic Review of Programmed Cell Death-1 Inhibitor Therapy for Advanced-Stage Cutaneous Squamous Cell Carcinoma in Solid-organ Transplant Recipients. J DERMATOL TREAT 2022; 33:3119-3126. [PMID: 36018250 DOI: 10.1080/09546634.2022.2118516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
BACKGROUND Programmed cell death-1 (PD-1) inhibitors represent an effective treatment option for advanced cutaneous squamous cell carcinoma (cSCC). However, solid organ transplant (SOT) recipients with cSCC have traditionally been excluded from clinical trials. OBJECTIVE To assess the safety and efficacy of PD-1 inhibitors for stage III-IV cSCC in SOT recipients. MATERIALS & METHODS A systematic review was performed using the PubMed, EMBASE, and Scopus databases. RESULTS We identified 21 articles describing 33 SOT recipients (26 kidney, four liver, two lung, and one heart) with stage III-IV cSCC treated with PD-1 inhibitors. Eleven patients (33.3%) experienced allograft rejection. Of the 25 cases with iRECIST scores, twelve patients (48.0%) had a complete response (CR), eight (32.0%) showed a partial response (PR), three (12.0%) progressive disease, and two (8.0%) stable disease (SD). Including patients without available iRECIST scores, 21 patients (63.6%) showed tumor response. Eleven patients died, with six (50.0%) due to tumor progression and one (11.1%) due to allograft rejection after foregoing dialysis. CONCLUSION PD-1 inhibitors demonstrate efficacy for advanced cSCC and confer a risk of allograft rejection in SOT recipients, requiring careful assessment of risks and benefits. If anti-PD-1 therapy is pursued, use of mTOR inhibitors, prophylactic steroids, and donor-derived cell-free DNA monitoring may mitigate the risk of rejection.
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Affiliation(s)
- Hannah L Hanania
- Baylor College of Medicine, School of Medicine, Houston, TX, USA
| | - Daniel J Lewis
- Perelman School of Medicine at the University of Pennsylvania, Department of Dermatology, Philadelphia, PA, USA
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35
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Zelin E, Maronese CA, Dri A, Toffoli L, Di Meo N, Nazzaro G, Zalaudek I. Identifying Candidates for Immunotherapy among Patients with Non-Melanoma Skin Cancer: A Review of the Potential Predictors of Response. J Clin Med 2022; 11:3364. [PMID: 35743435 PMCID: PMC9225110 DOI: 10.3390/jcm11123364] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/02/2022] [Accepted: 06/09/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Non-melanoma skin cancer (NMSC) stands as an umbrella term for common cutaneous malignancies, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), together with rarer cutaneous cancers, such as Merkel cell carcinoma (MCC) and other forms of adnexal cancers. The majority of NMSCs can be successfully treated with surgery or radiotherapy, but advanced and metastatic stages may require systemic approaches such as immunotherapy with immune checkpoint inhibitors (ICIs). SUMMARY Since immunotherapy is not effective in all patients and can potentially lead to severe adverse effects, an important clinical question is how to properly identify those who could be suitable candidates for this therapeutic choice. In this paper, we review the potential features and biomarkers used to predict the outcome of ICIs therapy for NMSCs. Moreover, we analyze the role of immunotherapy in special populations, such as the elderly, immunocompromised patients, organ transplant recipients, and subjects suffering from autoimmune conditions. KEY MESSAGES Many clinical, serum, histopathological, and genetic features have been investigated as potential predictors of response in NMSCs treated with ICIs. Although this field of research is very promising, definitive, cost-effective, and reproducible biomarkers are still lacking and further efforts are needed to validate the suggested predictors in larger cohorts.
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Affiliation(s)
- Enrico Zelin
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (E.Z.); (L.T.); (N.D.M.); (I.Z.)
| | - Carlo Alberto Maronese
- Dermatology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Arianna Dri
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy;
- Department of Medical Oncology, Azienda Sanitaria Friuli Centrale (ASUFC), 33100 Udine, Italy
| | - Ludovica Toffoli
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (E.Z.); (L.T.); (N.D.M.); (I.Z.)
| | - Nicola Di Meo
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (E.Z.); (L.T.); (N.D.M.); (I.Z.)
| | - Gianluca Nazzaro
- Dermatology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Iris Zalaudek
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (E.Z.); (L.T.); (N.D.M.); (I.Z.)
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36
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Kawashima S, Joachim K, Abdelrahim M, Abudayyeh A, Jhaveri KD, Murakami N. Immune checkpoint inhibitors for solid organ transplant recipients: clinical updates. KOREAN JOURNAL OF TRANSPLANTATION 2022; 36:82-98. [PMID: 35919193 PMCID: PMC9296977 DOI: 10.4285/kjt.22.0013] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 11/22/2022] Open
Abstract
Transplant care continues to advance with increasing clinical experience and improvements in immunosuppressive therapy. As the population ages and long-term survival improves, transplant patient care has become more complex due to comorbidities, frailty, and the increased prevalence of cancer posttransplantation. Immune checkpoint inhibitors (ICIs) have become a standard treatment option for many cancers in non-transplant patients, but the use of ICIs in transplant patients is challenging due to the possibility of disrupting immune tolerance. However, over the past few years, ICIs have gradually started to be used in transplant patients as well. In this study, we review the current use of ICIs after all solid organ transplantation procedures (kidney, liver, heart, and lung). Increasing data suggest that the type and number of immunosuppressants may affect the risk of rejection after immunotherapy. Immunotherapy for cancer in transplant patients may be a feasible option for selected patients; however, prospective trials in specific organ transplant recipients are needed.
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Affiliation(s)
- Shun Kawashima
- Transplantation Research Center, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Kole Joachim
- Transplantation Research Center, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, USA
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kenar D. Jhaveri
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, Great Neck, NY, USA
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Naoka Murakami
- Transplantation Research Center, Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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37
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Xie M, Dang ZP, Sun XG, Zhang B, Zhang Q, Tian QJ, Cai JZ, Rao W. An analysis report on the application of immune checkpoint inhibitors after liver transplantation. Ther Adv Chronic Dis 2022; 13:20406223221099334. [PMID: 35620187 PMCID: PMC9127875 DOI: 10.1177/20406223221099334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 04/21/2022] [Indexed: 01/05/2023] Open
Abstract
Up to now, a variety of immune checkpoint inhibitors (ICIs) have been proved to have good therapeutic effects in the treatment of hepatocellular carcinoma (HCC). However, the effects of their applications in liver transplant (LT) recipients are still unclear. In this analysis report, the clinical applications and therapeutic effects of ICIs on LT recipients with hepatic tumor recurrence or de novo carcinoma based on eight databases, including PubMed, EMBASE, Web of Science, Google Scholar, China National Knowledge Infrastructure, Wanfang Data, and CQVIP, were investigated. And the prior treatment, disease response, adverse reactions, and prognosis of patients with malignant tumors after LT and receiving ICI treatments were analyzed. After screening, a total of 28 articles with 47 recipients on the application of ICIs after LT were included. In these patients, their median age was 57 (14–71) years and the main type of tumor after LT was HCC (59.6%). The overall remission rate following ICI treatment was 29.8% (14/47) and the disease progression rate was 68.1% (32/47). Among all these patients, 31.9% (15/47) of patients had immune rejection; the median survival time was 6.5 (0.3–48) months, and the fatality rate was 61.7% (29/47). Considering that the therapeutic effect of ICIs in LT recipients with HCC recurrence or de novo carcinoma is not ideal, ICI treatment should be carefully considered for LT patients, and further research is needed.
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Affiliation(s)
- Man Xie
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhi-ping Dang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xue-guo Sun
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bei Zhang
- Department of Immunology, Medical College of Qingdao University, Qingdao, China
| | - Qun Zhang
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiu-ju Tian
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jin-zhen Cai
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Rao
- Division of Hepatology, Liver Disease Center, Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, No. 59 Hai’er Road, Laoshan District, Qingdao City 266600, Shandong Province, China
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Datta RR, Schran S, Persa OD, Aguilar C, Thelen M, Lehmann J, Garcia-Marquez MA, Wennhold K, Preugszat E, Zentis P, von Bergwelt-Baildon MS, Quaas A, Bruns CJ, Kurschat C, Mauch C, Löser H, Stippel DL, Schlößer HA. Post-transplant Malignancies Show Reduced T-cell Abundance and Tertiary Lymphoid Structures as Correlates of Impaired Cancer Immunosurveillance. Clin Cancer Res 2022; 28:1712-1723. [PMID: 35191474 DOI: 10.1158/1078-0432.ccr-21-3746] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/11/2021] [Accepted: 02/03/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE An increased risk to develop cancer is one of the most challenging negative side effects of long-term immunosuppression in organ transplant recipients and impaired cancer immunosurveillance is assumed as underlying mechanism. This study aims to elucidate transplant-related changes in the tumor immune microenvironment (TME) of cancer. EXPERIMENTAL DESIGN Data from 123 organ transplant recipients (kidney, heart, lung, and liver) were compared with historic data from non-immunosuppressed patients. Digital image analysis of whole-section slides was used to assess abundance and spatial distribution of T cells and tertiary lymphoid structures (TLS) in the TME of 117 tumor samples. Expression of programmed cell death 1 ligand 1 (PD-L1) and human-leucocyte-antigen class I (HLA-I) was assessed on tissue microarrays. RESULTS We found a remarkably reduced immune infiltrate in the center tumor (CT) regions as well as the invasive margins (IM) of post-transplant cancers. These differences were more pronounced in the IM than in the CT and larger for CD8+ T cells than for CD3+ T cells. The Immune-score integrating results from CT and IM was also lower in transplant recipients. Density of TLS was lower in cancer samples of transplant recipients. The fraction of samples with PD-L1 expression was higher in controls whereas decreased expression of HLA-I was more common in transplant recipients. CONCLUSIONS Our study demonstrates the impact of immunosuppression on the TME and supports impaired cancer immunosurveillance as important cause of post-transplant cancer. Modern immunosuppressive protocols and cancer therapies should consider the distinct immune microenvironment of post-transplant malignancies.
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Affiliation(s)
- Rabi R Datta
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Simon Schran
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Oana-Diana Persa
- Department of Dermatology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
| | - Claire Aguilar
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Martin Thelen
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jonas Lehmann
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Maria A Garcia-Marquez
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Kerstin Wennhold
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Ella Preugszat
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Peter Zentis
- Cluster of Excellence for Aging-Associated Diseases, CECAD Imaging Facility Cologne, University of Cologne, Cologne, Germany
| | | | - Alexander Quaas
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Christiane J Bruns
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
| | - Christine Kurschat
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
- Department of Internal Medicine II, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Cornelia Mauch
- Department of Dermatology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
| | - Heike Löser
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Dirk L Stippel
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
| | - Hans A Schlößer
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Department of General, Visceral, Cancer and Transplantation Surgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology, CIO ABCD Aachen, Bonn, Cologne, Düsseldorf
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Portuguese AJ, Tykodi SS, Blosser CD, Gooley TA, Thompson JA, Hall ET. Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review. J Natl Compr Canc Netw 2022; 20:406-416.e11. [PMID: 35390767 DOI: 10.6004/jnccn.2022.7009] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/10/2022] [Indexed: 11/17/2022]
Abstract
Chronic immunosuppression in solid organ transplant recipients (SOTRs) leads to an increased risk of a wide variety of cancers. Immune checkpoint inhibitor (ICI) therapy is indicated for many of these; however, the risks and benefits of ICI use in the SOTR population have not been well characterized. We performed a systematic literature review identifying 119 reported cases of ICI use among SOTRs. Treatments used included PD-1 inhibition (75.6%), CTLA-4 inhibition (12.6%), PD-L1 inhibition (1.7%), and combination and/or sequential ICI therapy (10.1%). The most common cancers included cutaneous melanoma (35.3%), hepatocellular carcinoma (22.7%), and cutaneous squamous cell carcinoma (18.5%). The overall objective response rate (ORR) was 34.5%, with a median duration of response of 8.0 months. Ongoing response was seen in 21.0%. Cutaneous squamous cell carcinoma had significantly better ORR compared with other cancer types (68.2% vs 26.8%; odds ratio [OR], 5.85; P =.0006). Factors associated with improved ORR included increasing time from transplant to ICI (OR, 1.09; P =.008) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (50.0% vs 18.5%; OR, 4.40; P =.0088). Rejection occurred in 41.2%, graft failure in 23.5%, and immune-related adverse events in 18.5%. Factors significantly associated with allograft rejection included allograft PD-L1 positivity (100% vs 0%; P<.0001) and absence of tacrolimus in the immunosuppressive regimen (48.7% vs 25.6%; OR, 0.36; P =.019). The most common cause of death was progressive malignancy (64.0%), followed by graft failure (24.0%). Our analysis provides current benchmark data to help inform management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppression management may help refine decision-making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.
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Affiliation(s)
| | - Scott S Tykodi
- University of Washington.,Fred Hutchinson Cancer Research Center, and
| | | | | | - John A Thompson
- University of Washington.,Fred Hutchinson Cancer Research Center, and
| | - Evan T Hall
- University of Washington.,Fred Hutchinson Cancer Research Center, and
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40
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Zhang K, Kong X, Li Y, Wang Z, Zhang L, Xuan L. PD-1/PD-L1 Inhibitors in Patients With Preexisting Autoimmune Diseases. Front Pharmacol 2022; 13:854967. [PMID: 35370736 PMCID: PMC8971753 DOI: 10.3389/fphar.2022.854967] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/17/2022] [Indexed: 02/04/2023] Open
Abstract
Autoimmune diseases and malignant tumors are the two hotspots and difficulties that are currently being studied and concerned by the medical field. The use of PD-1/PD-L1 inhibitors improves the prognosis of advanced tumors, but excessive immune responses can also induce immune-related adverse events (irAEs). Due to this concern, many clinical trials exclude cancer patients with preexisting autoimmune disease (AID). This review outlines the possible mechanisms of irAE, discusses the safety and efficacy of PD-1/PD-L1 inhibitors in cancer patients with preexisting AID, and emphasizes the importance of early recognition, continuous monitoring, and multidisciplinary cooperation in the prevention and management of cancer patients with preexisting AID.
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Affiliation(s)
- Ke Zhang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Li
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Zhongzhao Wang, ; Lin Zhang, ; Lixue Xuan,
| | - Lin Zhang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Melbourne School of Population and Global Health, the University of Melbourne, Melbourne, VIC, Australia
- Centre of Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
- *Correspondence: Zhongzhao Wang, ; Lin Zhang, ; Lixue Xuan,
| | - Lixue Xuan
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Zhongzhao Wang, ; Lin Zhang, ; Lixue Xuan,
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Abstract
Exhaustion of T cells occurs in response to long-term exposure to self and foreign antigens. It limits T cell capacity to proliferate and produce cytokines, leading to an impaired ability to clear chronic infections or eradicate tumors. T-cell exhaustion is associated with a specific transcriptional, epigenetic, and metabolic program and characteristic cell surface markers' expression. Recent studies have begun to elucidate the role of T-cell exhaustion in transplant. Higher levels of exhausted T cells have been associated with better graft function in kidney transplant recipients. In contrast, reinvigorating exhausted T cells by immune checkpoint blockade therapies, while promoting tumor clearance, increases the risk of acute rejection. Lymphocyte depletion and high alloantigen load have been identified as major drivers of T-cell exhaustion. This could account, at least in part, for the reduced rates of acute rejection in organ transplant recipients induced with thymoglobulin and for the pro-tolerogenic effects of a large organ such as the liver. Among the drugs that are widely used for maintenance immunosuppression, calcineurin inhibitors have a contrasting inhibitory effect on exhaustion of T cells, while the influence of mTOR inhibitors is still unclear. Harnessing or encouraging the natural processes of exhaustion may provide a novel strategy to promote graft survival and transplantation tolerance.
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Murakami N, Webber AB, Nair V. Transplant Onconephrology in Patients With Kidney Transplants. Adv Chronic Kidney Dis 2022; 29:188-200.e1. [PMID: 35817526 PMCID: PMC9326185 DOI: 10.1053/j.ackd.2021.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/10/2021] [Accepted: 09/01/2021] [Indexed: 11/11/2022]
Abstract
Cancer is a leading cause of death in patients with kidney transplantation. Patients with kidney transplants are 10- to 200-times more likely to develop cancers after transplant than the general population, depending on the cancer type. Recent advances in cancer therapies have dramatically improved survival outcomes; however, patients with kidney transplants face unique challenges of immunosuppression management, cancer screening, and recurrence of cancer after transplant. Patients with a history of cancer tend to be excluded from transplant candidacy or are required to have long cancer-free wait time before wait-listing. The strategy of pretransplant wait time management may need to be revisited as cancer therapies improve, which is most applicable to patients with a history of multiple myeloma. In this review, we discuss several important topics in transplant onconephrology: the current recommendations for pretransplant wait times for transplant candidates with cancer histories, cancer screening post-transplant, post-transplant lymphoproliferative disorder, strategies for transplant patients with a history of multiple myeloma, and novel therapies for patients with post-transplant malignancies. With emerging novel cancer treatments, it is critical to have multidisciplinary discussions involving patients, caregivers, transplant nephrologists, and oncologists to achieve patient-oriented goals.
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Affiliation(s)
- Naoka Murakami
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
| | - Allison B. Webber
- Divisino of Nephrology, Kidney Transplant Service, University of California San Francisco, San Francisco, CA
| | - Vinay Nair
- Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
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43
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Toner K, Bollard CM. EBV+ lymphoproliferative diseases: opportunities for leveraging EBV as a therapeutic target. Blood 2022; 139:983-994. [PMID: 34437680 PMCID: PMC8854679 DOI: 10.1182/blood.2020005466] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/24/2021] [Indexed: 11/20/2022] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human tumor virus, which contributes to the development of lymphoproliferative disease, most notably in patients with impaired immunity. EBV-associated lymphoproliferation is characterized by expression of latent EBV proteins and ranges in severity from a relatively benign proliferative response to aggressive malignant lymphomas. The presence of EBV can also serve as a unique target for directed therapies for the treatment of EBV lymphoproliferative diseases, including T cell-based immune therapies. In this review, we describe the EBV-associated lymphoproliferative diseases and particularly focus on the therapies that target EBV.
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Affiliation(s)
- Keri Toner
- Center for Cancer and Immunology Research
- Division of Oncology, and
- Division of Blood and Marrow Transplantation, Children's National Hospital, Washington, DC; and
- GW Cancer Center, George Washington University, Washington, DC
| | - Catherine M Bollard
- Center for Cancer and Immunology Research
- Division of Blood and Marrow Transplantation, Children's National Hospital, Washington, DC; and
- GW Cancer Center, George Washington University, Washington, DC
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44
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Bastos S, Masmoudi W, Pinard C, Duval-Modeste AB, Joly P, Hébert V. Efficacy of nivolumab in the treatment of metastatic cutaneous squamous cell carcinoma in a kidney-transplant patient with a history of allograft rejection. Ann Dermatol Venereol 2022; 149:198-199. [PMID: 35181155 DOI: 10.1016/j.annder.2022.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/11/2021] [Accepted: 01/04/2022] [Indexed: 12/20/2022]
Affiliation(s)
- S Bastos
- Department of Dermatology, Rouen University Hospital, 76000 Rouen, France.
| | - W Masmoudi
- Department of Dermatology, Rouen University Hospital, 76000 Rouen, France
| | - C Pinard
- Department of Dermatology, Rouen University Hospital, 76000 Rouen, France
| | - A-B Duval-Modeste
- Department of Dermatology, Rouen University Hospital, 76000 Rouen, France
| | - P Joly
- Department of Dermatology, Rouen University Hospital, 76000 Rouen, France
| | - V Hébert
- Department of Dermatology, Rouen University Hospital, 76000 Rouen, France
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45
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Shalhout SZ, Kaufman HL, Emerick KS, Miller DM. Immunotherapy for Nonmelanoma skin cancer: Facts and Hopes. Clin Cancer Res 2022; 28:2211-2220. [PMID: 35121622 DOI: 10.1158/1078-0432.ccr-21-2971] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 12/24/2021] [Accepted: 01/26/2022] [Indexed: 11/16/2022]
Abstract
Non-melanoma skin cancer (NMSC) is the most frequently diagnosed malignancy in humans, representing a broad range of cutaneous tumors. Keratinocyte carcinomas, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC), are the most common NMSCs. The incidence of BCC and CSCC are steadily increasing due to a progressively aging population, chronic exposure to ultraviolet radiation, and increased awareness with earlier diagnosis. Rarer NMSCs such as Merkel cell carcinoma (MCC) and cutaneous adnexal carcinomas (CACs) are also on the rise. Although the majority of NMSC tumors are localized at diagnosis and managed effectively with curative surgery and radiation, in rare cases with nodal and distant metastases, systemic therapy is often required. As our understanding of the immunologic characteristics of NMSCs has improved, effective treatment options have expanded with the development of immunotherapy. The U.S. Food and Drug Administration (FDA) recently approved several immune checkpoint inhibitors for the treatment of locally advanced and metastatic MCC, CSCC, and BCC. We review the emerging role of immunotherapy as the standard of care for several advanced NMSCs not amenable to surgery and/or radiation and underscore the need for considering clinical trials of novel strategies in patients when immunotherapy does not provide durable benefit. Finally, we explore the potential of neoadjuvant and adjuvant immunotherapy.
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Affiliation(s)
- Sophia Z Shalhout
- Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Howard L Kaufman
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kevin S Emerick
- Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - David M Miller
- Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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46
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Luo Y, Teng F, Fu H, Ding GS. Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons. World J Gastrointest Oncol 2022; 14:163-180. [PMID: 35116109 PMCID: PMC8790424 DOI: 10.4251/wjgo.v14.i1.163] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/30/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) has emerged as a curative strategy for hepatocellular carcinoma (HCC), but contributes to a higher predisposition to HCC recurrence in the immunosuppression context, especially for tumors beyond the Milan criteria. Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors, including HCC, it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection. Nevertheless, accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC, from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting. Generally, immunotherapy mainly includes immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and vaccine therapy. ICIs, followed by ACT, have been most investigated in LT, with some promising results. Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy, it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients. In addition, the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT. In this review, we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC. Moreover, we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.
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Affiliation(s)
- Yi Luo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Guo-Shan Ding
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
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47
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Nativi-Nicolau J, Stehlik J, Kelkhoff AJ, Khong B, Truax CM, Revelo MP, Gilbert EM, Drakos S, Wever-Pinzon O, Fang J, Catino A, Khong HT. Fatal Allograft Rejection and Cardiac Allograft Vasculopathy After Treatment With Pembrolizumab for Metastatic Melanoma in a Heart Transplant Recipient: A Case Report. Transplant Proc 2022; 54:193-196. [PMID: 35012763 DOI: 10.1016/j.transproceed.2021.09.069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 09/14/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022]
Abstract
Checkpoint inhibitors decrease the progression of many cancers. However, the experience in immunosuppressed patients is limited, with reports of possible serious adverse events. We present a heart transplant recipient treated with pembrolizumab for metastatic melanoma who developed fatal rejection. The patient was a 29 year-old man who underwent heart transplantation at the age of 10 years for congenital heart disease. Seventeen years after transplant, he was diagnosed with scalp melanoma pT3a, N2a, M0, Stage IIIA, positive for BRAF V600E mutation treated with excision, which metastasized to his lungs and brain a year later. Dabrafenib and trametinib were started with transient response. Additional options and their risks were discussed, and pembrolizumab was started 4 months later due to the incomplete response to previous therapy. Five days after initiation the patient presented with moderate cellular rejection and possible antibody mediated rejection (ISHLT Grade 2R, pAMR 1H). Pembrolizumab was discontinued, and he was treated with steroids. Seven months later he presented in cardiogenic shock and severe coronary allograft vasculopathy. Biopsy was negative for cellular rejection, but suspicious for antibody mediated rejection (ISHLT Grade 0R, pAMR 1H), and he had a new serum alloantibody. Despite steroids and plasmapheresis he remained in refractory cardiogenic shock and died of cardiac arrest.
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Affiliation(s)
| | | | | | - Brian Khong
- Adventist Health White Memorial, Los Angeles, California
| | | | | | | | | | | | - James Fang
- University of Utah Health, Salt Lake City, Utah
| | - Anna Catino
- University of Utah Health, Salt Lake City, Utah
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48
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Abdelrahim M, Abudayyeh A. Renal Toxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:389-397. [PMID: 34972976 DOI: 10.1007/978-3-030-79308-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
With the increasing use of immunotherapy, there has been an associated increased survival in many cancers but has also resulted in unregulated organ-specific toxicities. In this review, we will discuss the renal toxicities associated with a checkpoint inhibitor (CPI) from the typical acute tubulointerstitial nephritis to glomerulonephritis and their proposed mechanisms and treatments. We also discuss the use of CPI and reactivation of preexisting autoimmune disease with a focus on renal cell cancer in setting of chronic kidney disease (CKD). Transplant rejection in setting of CPI use has been further evaluated with single-center and multicenter retrospective studies, and available data will be presented in this chapter.
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Affiliation(s)
- Maen Abdelrahim
- Institute of Academic Medicine and Weill Cornell Medical College, Houston Methodist Cancer Center, Houston Methodist Cancer Center, Houston, TX, USA
| | - Ala Abudayyeh
- Division of Internal Medicine, Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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49
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Halloran PF, Einecke G, Sikosana MLN, Madill-Thomsen K. The Biology and Molecular Basis of Organ Transplant Rejection. Handb Exp Pharmacol 2022; 272:1-26. [PMID: 35091823 DOI: 10.1007/164_2021_557] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Allograft rejection is defined as tissue injury in a transplanted allogeneic organ produced by the effector mechanisms of the adaptive alloimmune response. Effector T lymphocytes and IgG alloantibodies cause two different types of rejection that can occur either individually or simultaneously: T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). In TCMR, cognate effector T cells infiltrate the graft and orchestrate an interstitial inflammatory response in the kidney interstitium in which effector T cells engage antigen-presenting myeloid cells, activating the T cells, antigen-presenting cells, and macrophages. The result is intense expression of IFNG and IFNG-induced molecules, expression of effector T cell molecules and macrophage molecules and checkpoints, and deterioration of parenchymal function. The diagnostic lesions of TCMR follow, i.e. interstitial inflammation, parenchymal deterioration, and intimal arteritis. In ABMR, HLA IgG alloantibodies produced by plasma cells bind to the donor antigens on graft microcirculation, leading to complement activation, margination, and activation of NK cells and neutrophils and monocytes, and endothelial injury, sometimes with intimal arteritis. TCMR becomes infrequent after 5-10 years post-transplant, probably reflecting adaptive mechanisms such as checkpoints, but ABMR can present even decades post-transplant. Some rejection is triggered by inadequate immunosuppression and non-adherence, challenging the clinician to target effective immunosuppression even decades post-transplant.
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Affiliation(s)
- Philip F Halloran
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
| | - Gunilla Einecke
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Majid L N Sikosana
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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50
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Vitale G, Gitto S, Campani C, Turco L, Baldan A, Marra F, Morelli MC. Biological therapies in patients with liver disease: are they really lifesavers? Expert Opin Biol Ther 2021; 22:473-490. [PMID: 34860629 DOI: 10.1080/14712598.2022.2013799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION The liver plays a key role in the setting of immune tolerance. Targeting antigens for presentation by antigen-presenting cells in the liver can induce immune tolerance to either autoantigens from the liver itself or organs outside of the liver. Despite its non-conventional capacity for tolerance induction, the liver remains a target organ for autoimmune diseases. Whereas chronic inflammation and intra-hepatic immuno-suppressive microenvironment occurring during liver fibrosis lead to hepatocellular carcinoma. Monoclonal antibodies have revolutionized the therapeutic strategies of many autoimmune diseases and some cancers. AREAS COVERED We review data from literature regarding the safety and efficacy of biologics in treating hepatobiliary autoimmune diseases and primary liver cancers. Furthermore, we describe their potential use in the setting of liver transplants and their main immune-related liver adverse events. EXPERT OPINION Biological therapies have changed the natural history of main autoimmune diseases and solid cancers. Compared to other organs and disease settings, the liver lags behind in biologics and their applications. The development of novel diagnostic and therapeutic strategies based on the immunological and antigenic characteristics of the hepatobiliary system could reduce mortality and transplant rates linked to chronic liver diseases.
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Affiliation(s)
- Giovanni Vitale
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Laura Turco
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Anna Baldan
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria Cristina Morelli
- Division of Internal Medicine for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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