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Human Vaccines & Immunotherapeutics Aug 2023Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD...
Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.
Topics: Humans; Kidney Transplantation; Receptors, Chimeric Antigen; Organ Transplantation; Lymphoproliferative Disorders; T-Lymphocytes
PubMed: 37278257
DOI: 10.1080/21645515.2023.2216116 -
Clinical Gastroenterology and... Jun 2021
Topics: Arthritis, Rheumatoid; Humans; Intestine, Small; Lymphoproliferative Disorders; Methotrexate
PubMed: 32205225
DOI: 10.1016/j.cgh.2020.03.037 -
Clinical & Developmental Immunology 2013Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disease that arises in 2%-10% of solid organ and hematopoietic stem cell transplants and is... (Review)
Review
Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disease that arises in 2%-10% of solid organ and hematopoietic stem cell transplants and is most frequently of B-cell origin. This very heterogeneous disorder ranges from benign lymphoproliferations to malignant lymphomas, and despite the clear association with Epstein-Barr Virus (EBV) infection, its etiology is still obscure. Although a number of risk factors have been identified (EBV serostatus, graft type, and immunosuppressive regimen), it is currently not possible to predict which transplant patient will eventually develop PTLD. Genetic studies have linked translocations (involving C-MYC, IGH, BCL-2), various copy number variations, DNA mutations (PIM1, PAX5, C-MYC, RhoH/TTF), and polymorphisms in both the host (IFN-gamma, IL-10, TGF-beta, HLA) and the EBV genome to B-cell PTLD development. Furthermore, the tumor microenvironment seems to play an important role in the course of disease representing a local niche that can allow antitumor immune responses even in an immunocompromised host. Taken together, B-cell PTLD pathogenesis is very complex due to the interplay of many different (patient-dependent) factors and requires thorough molecular analysis for the development of novel tailored therapies. This review aims at giving a global overview of the currently known parameters that contribute to the development of B-cell PTLD.
Topics: B-Lymphocytes; DNA Copy Number Variations; Epstein-Barr Virus Infections; Gene Expression; Genetic Heterogeneity; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Lymphoproliferative Disorders; Mutation; Neoplasm Proteins; Organ Transplantation; Translocation, Genetic; Tumor Microenvironment
PubMed: 23690819
DOI: 10.1155/2013/150835 -
Turk Patoloji Dergisi 2022Human herpes virus-8 (HHV-8) is linked to four lymphoproliferative diseases: primary effusion lymphoma, HHV-8 positive multicentric Castleman disease (MCD), HHV-8...
Human herpes virus-8 (HHV-8) is linked to four lymphoproliferative diseases: primary effusion lymphoma, HHV-8 positive multicentric Castleman disease (MCD), HHV-8 positive diffuse large B cell lymphoma and HHV-8 positive germinotropic lymphoproliferative disorder (GLPD). The diagnosis of HHV-8 associated lymphoproliferative diseases is quite challenging because each entity is rare and has a wide morphological spectrum. Our aim is to emphasize the overlapping histopathological features of MCD and GLPD as well as to underline the importance of clinicopathological correlation in case these two entities cannot be distinguished by pathological examination. We present here a case of an 82-year-old male patient who was examined for weight loss and multiple lymphadenopathy. Histopathological examination of the axillary lymph node revealed lymphoid follicle structures of varying shapes and sizes, including some atrophic germinal centers. Plasmablast-like cells were notable in some of these areas. HHV-8 and Epstein Barr Virus (EBV) positivity were noted in some of these cells and in a small number of cells in the mantle zone. Based on these findings; a diagnosis of "HHV-8 and EBV positive lymphoproliferative disease" was established. Since HHV-8 positive MCD and GLPD have similar histopathological features, it may not be possible to distinguish these two entities by histopathological examination only. At this point, the importance of clinicopathological correlation becomes more evident, especially in the determination of the treatment protocol to be applied to the patient.
Topics: Aged, 80 and over; Castleman Disease; Epstein-Barr Virus Infections; Herpesviridae Infections; Herpesvirus 4, Human; Herpesvirus 8, Human; Humans; Lymphoproliferative Disorders; Male
PubMed: 34514570
DOI: 10.5146/tjpath.2021.01540 -
Transplant International : Official... Mar 2007Post-transplant lymphoproliferative disorder (PTLD) is a serious and still frequently observed complication of solid organ transplantation. Despite the recent... (Review)
Review
Post-transplant lymphoproliferative disorder (PTLD) is a serious and still frequently observed complication of solid organ transplantation. Despite the recent introduction of anti B-cell monoclonal antibody therapy (rituximab) for treatment of PTLD, mortality rates remain high. Because PTLD often presents in a nonspecific way in clinically unsuspected patients, it is a major challenge to diagnose PTLD at an early stage. Epstein-Barr virus (EBV)-DNA load monitoring is a promising tool for the identification of patients at risk for PTLD development. However, there are some limitations of this method, and not all patients at risk for PTLD can be identified by EBV-DNA measurements alone. Therefore, it is of major importance to recognize early clinical signs and symptoms of PTLD. In this review, risk factors for PTLD development, disease presentation, and methods for early detection will be discussed. Special attention is given to allograft and digestive tract localization and the relation with time of onset of PTLD. The value and pitfalls of EBV-DNA load monitoring are discussed. In addition, because fluorodeoxyglucose (FDG)-positron emission tomography (PET) has shown to be a powerful tool for staging and response evaluation of malignant lymphoma, the role of FDG-PET for early diagnosis and staging of PTLD is addressed.
Topics: Cytomegalovirus Infections; DNA, Viral; Epstein-Barr Virus Infections; Fluorodeoxyglucose F18; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Interleukin-10; Lymphoproliferative Disorders; Organ Transplantation; Positron-Emission Tomography; Postoperative Complications; Risk Factors; Time Factors
PubMed: 17291214
DOI: 10.1111/j.1432-2277.2006.00416.x -
Experimental and Clinical... Aug 2012Antigen expression by neoplastic cells is important because of its effects on the behavior and survival of patients. We sought to gather data on renal transplant... (Review)
Review
OBJECTIVES
Antigen expression by neoplastic cells is important because of its effects on the behavior and survival of patients. We sought to gather data on renal transplant recipients who had developed posttransplant lymphoproliferative disorders in their posttransplant era, and had a documented report on CD20 antigen testing.
MATERIALS AND METHODS
A comprehensive search of the literature was done for reports that indicate test results for the CD20 antigen in kidney recipients having lymphoproliferative disorders after transplant. Their demographics, disease characteristics, and prognoses were analyzed.
RESULTS
CD20-positive posttransplant lymphoproliferative disorder patients had a significantly shorter time from transplant to developing posttransplant lymphoproliferative disorder (P < .001). None of patients who had early onset posttransplant lymphoproliferative disorder was CD20 negative. Bone marrow involvement was significantly more prevalent among CD20-negative patients (P < .05) with no CD20-positive patient developing a bone marrow metastasis. Log-rank test showed a relatively worse survival for renal recipients expressing the CD20 antigen (P = .07).
CONCLUSIONS
CD20-positive posttransplant lymphoproliferative disorder lesions in kidney transplant patients are significantly more likely to develop early after transplant and represent an inferior outcome. We suggest that all renal transplant recipients who develop posttransplant lymphoproliferative disorder within their early time after surgery should be given anti-CD20 therapy. Future prospective studies are required to confirm our conclusions.
Topics: Adult; Antigens, CD20; Biomarkers; Bone Marrow Examination; Bone Marrow Neoplasms; Chi-Square Distribution; Female; Humans; Kaplan-Meier Estimate; Kidney Transplantation; Linear Models; Lymphoproliferative Disorders; Male; Middle Aged; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Young Adult
PubMed: 22758374
DOI: 10.6002/ect.2011.0181 -
Frontiers in Immunology 2022Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors include primary Epstein-Barr virus...
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. In our previous studies EBV infection was demonstrated to markedly alter the expression of host B cell microRNA (miR). Specifically, miR-194 expression was uniquely suppressed in EBV+ B cell lines from PTLD patients and the 3'untranslated region of IL-10 was determined to be targeted by miR-194. Although EBV has been shown to regulate host miR expression in B cell lymphoma cell lines, the expression of miRs in the circulation of patients with EBV-associated PTLD has not been studied. The objective of this study was to determine if changes in miR expression are associated with EBV+ PTLD. In this study, we have shown that miR-194 is significantly decreased in EBV+PTLD tumors and that additional miRs, including miRs-17, 19 and 106a are also reduced in EBV+PTLD as compared to EBV-PTLD. We quantitated the levels of miRs-17, 19, 106a, 155, and 194 in the plasma and extracellular vesicles (EV; 50-70 nm as determined by nanoparticle tracking analysis) from pediatric recipients of solid organ transplants with EBV+ PTLD+ that were matched 1:2 with EBV+ PTLD- pediatric transplant recipients as part of the NIH-sponsored Clinical Trials in Organ Transplantation in Children, (CTOTC-06) study. Levels of miRs-17, 19, 106a, and 194 were reduced in the plasma and extracellular vesicles (EV) of EBV+ PTLD+ group compared to matched controls, with miRs-17 (p = 0.034; plasma), miRs-19 (p = 0.029; EV) and miR-106a (p = 0.007; plasma and EV) being significantly reduced. Similar levels of miR-155 were detected in the plasma and EV of all pediatric SOT recipients. Importantly, ~90% of the cell-free miR were contained within the EV supporting that EBV+ PTLD tumor miR are detected in the circulation and suggesting that EVs, containing miRs, may have the potential to target and regulate cells of the immune system. Further development of diagnostic, mechanistic and potential therapeutic uses of the miRs in PTLD is warranted.
Topics: Child; Humans; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Transplant Recipients; Lymphoproliferative Disorders; Organ Transplantation; MicroRNAs
PubMed: 36304469
DOI: 10.3389/fimmu.2022.994552 -
American Journal of Transplantation :... May 2011Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of major, life-threatening lymphoproliferative diseases occurring in the post-transplant setting. The... (Review)
Review
Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of major, life-threatening lymphoproliferative diseases occurring in the post-transplant setting. The majority of PTLD is of B-cell origin and is associated with several risk factors, the most significant being Epstein-Barr virus (EBV) infection. EBV's in vitro transforming abilities, distinctive latency, clonality within the malignant cells and response to targeted therapies implicate a critical role in the biology of PTLD. This minireview focuses on EBV-related PTLD pathogenesis, in particular the interplay between aspects of the EBV life cycle and latency with nonviral factors resulting in the wide spectrum of histology and clinical presentations encountered in PTLD. With the increased prevalence of transplantation a rise in the incidence of PTLD may be expected. Therefore the importance of laboratory and animal models in the understanding of PTLD and the development of novel therapeutic approaches is discussed.
Topics: Biopsy; Child; Child, Preschool; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Immunotherapy; Lymphoma; Lymphoproliferative Disorders; Organ Transplantation; Postoperative Complications; Risk Factors; Time Factors; Transplantation, Homologous; Viral Load
PubMed: 21521464
DOI: 10.1111/j.1600-6143.2011.03499.x -
European Journal of Nuclear Medicine... Mar 2020Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, requiring a timely and...
PURPOSE
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, requiring a timely and accurate diagnosis. In this study, we evaluated the diagnostic performance of FDG-PET/CT in patients with suspected PTLD and examined if lactate dehydrogenase (LDH) levels, Epstein-Barr virus (EBV) load, or timing of FDG-PET/CT relate to detection performance of FDG-PET/CT.
METHODS
This retrospective study included 91 consecutive patients with clinical suspicion of PTLD and a total of 97 FDG-PET/CT scans within an 8-year period. Pathology reports and a 2-year follow-up were used as the reference standard. Diagnostic performance of FDG-PET/CT for detection of PTLD as well as logistic regression analysis for factors expected to affect diagnostic yield were assessed.
RESULTS
The diagnosis of PTLD was established in 34 patients (35%). Fifty-seven FDG-PET/CT scans (59%) were true negative, 29 (30%) were true positive, 6 (6%) false positive, and 5 (5%) false negative. Sensitivity of FDG-PET/CT for the detection of PTLD was 85%, specificity 90%, positive predictive value 83%, and negative predictive value 92%, with good inter-observer variability (k = 0.78). Of the parameters hypothesized to be associated with a true positive FDG-PET/CT result for the diagnosis of PTLD, only LDH was statistically significant (OR 1.03, p = 0.04).
CONCLUSION
FDG-PET/CT has a good diagnostic performance in patients suspected of PTLD, with a good inter-observer agreement. Only LDH levels seemed to influence the detection performance of FDG-PET/CT. EBV-DNA load and timing of FDG-PET/CT after transplantation did not affect FDG-PET/CT diagnostic yield.
Topics: Epstein-Barr Virus Infections; Fluorodeoxyglucose F18; Herpesvirus 4, Human; Humans; Lymphoproliferative Disorders; Positron Emission Tomography Computed Tomography; Retrospective Studies
PubMed: 31444510
DOI: 10.1007/s00259-019-04481-7 -
Balkan Medical Journal May 2021
Topics: Female; Humans; Lymphoproliferative Disorders; Melanoma; Middle Aged; Myeloproliferative Disorders
PubMed: 34142965
DOI: 10.5152/balkanmedj.2021.21010