CAR T-cell Infusion Following Checkpoint Inhibition Can Induce Remission in Chemorefractory Post-transplant Lymphoproliferative Disorder of the CNS.
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ABSTRACT:
SUBMITTER: Rosler W
PROVIDER: S-EPMC9208876 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
Publications
CAR T-cell Infusion Following Checkpoint Inhibition Can Induce Remission in Chemorefractory Post-transplant Lymphoproliferative Disorder of the CNS.
Rösler Wiebke W Bink Andrea A Bissig Marina M Imbach Lukas L Marques Maggio Ewerton E Manz Markus G MG Müller Thomas T Roth Patrick P Rushing Elisabeth E Widmer Corinne C Zenz Thorsten T von Moos Seraina S Müller Antonia M S AMS
HemaSphere 20220617 7
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Project description: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.
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Project description:Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein-Barr virus (EBV) infection or reactivation in the post-transplant period, rare cases of T cell and natural killer (NK) cell-originated PTLDs have also been described. A general assumption is that PTLDs result from the impairment of anti-viral and anti-tumoral immunosurveillance due to the long-term use of immunosuppressants in transplant recipients. T cell impairment is known to play a critical role in the immune-pathogenesis of post-transplant EBV-linked complications, while the role of NK cells has been less investigated, and is probably different between EBV-positive and EBV-negative PTLDs. As a part of the innate immune response, NK cells are critical for protecting hosts during the early response to virus-induced tumors. The complexity of their function is modulated by a myriad of activating and inhibitory receptors expressed on cell surfaces. This review outlines our current understanding of NK cells in the pathogenesis of PTLD, and discusses their potential implications for current PTLD therapies and novel NK cell-based therapies for the containment of these disorders.
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Project description:PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a strong association with Epstein-Barr virus (EBV) infection and the iatrogenic, immunosuppression-related decrease in T-cell immune surveillance. Without appropriate T-cell response, EBV-infected B cells persist and proliferate, resulting in malignant transformation. Classification is based on the histologic subtype and ranges from nondestructive hyperplasias to monoclonal aggressive lymphomas, with the most common subtype being diffuse large B-cell lymphoma-like PTLD. Management focuses on prevention of PTLD development, as well as therapy for active disease. Treatment is largely based on the histologic subtype. However, given lack of clinical trials providing evidence-based data on PLTD therapy-related outcomes, there are no specific management guidelines. In this review, we discuss the pathogenesis, histologic classification, and risk factors of PTLD. We further focus on common preventive and frontline treatment modalities, as well as describe the application of novel therapies for PLTD and elaborate on potential challenges in therapy.
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Project description:BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a devastating complication of immunosuppressive treatment in both solid organ transplantations (SOT) and hematopoietic stem cell transplantations (HSCT). Epstein-Barr virus (EBV) infection precedes PTLD in 90% of patients. Rituximab, a monoclonal anti-CD20 antibody, depletes B-lymphocytes, which are the ultimate reservoir for EBV. Although rituximab therapy is commonly used as a preventive measure for PTLD in high-risk HSCT, it is not established in SOT.MethodsPediatric kidney transplant recipients (PKTR) underwent routine EBV-PCR surveillance. Patients with increasing viral loads, despite immunosuppressive dose reduction, were managed with preventive rituximab therapy.ResultsBetween 2012 and 2023, we identified eight episodes of asymptomatic EBV-PCR-positive blood tests in seven out of 65 PKTR (11%) under our care. EBV DNAemia emerged 120-720 days post-transplantation. Five of seven patients with EBV DNAemia (71%) were EBV-seronegative prior to transplantation. All five patients did not respond to MMF dose reduction and were therefore treated with preventive rituximab therapy. Following this treatment, EBV PCR clearance was observed in all patients with only minimal complications.ConclusionsPKTR who are EBV-naïve prior to transplantation are expected to have a higher prevalence of EBV DNAemia. We found that PKTR who were EBV seronegative prior to transplantation were less likely to achieve EBV clearance in response to immunosuppression dose reduction. We suggest that rituximab therapy in PKTR may be safe and effective in EBV clearance and PTLD prevention.
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Project description:Post-transplant lymphoproliferative disorder (PTLD) is a rare complication. It represents a spectrum of lymphoid proliferations which occur in the setting of immunosuppression and organ transplantation. There are no reported cases or recommendations for the treatment of residual masses post rituximab of PTLD.A patient with a long standing history of immunosuppression due to multiple kidney transplants starting in 1979, presented with a very large palpable hard abdominal mass (2004) after a fourth renal transplant. There was a past history of heavy immune suppression. CT scans revealed a conglomerate mass involving the right native kidney and two prior right sided renal allografts that crossed the midline. Biopsy of the large right retroperitoneal mass revealed large B cell lymphoma (CD 20 positive); consistent with post-transplant lymphoproliferative disorder (PTLD).Management of bulky PTLD, in a highly sensitized, heavily immune suppressed patient is not well described in the literature. The mainstay of therapy is IR and Ritixumab (R) monotherapy and combination R-CHOP. CHOP chemotherapy has an associated mortality rate of up to 38%. Radiotherapy is often considered over surgery and surgery has been most frequently used when associated with bowel complications. In this case report we describe upfront Ritiximab followed by consolidation resection and cytotoxic chemotherapy as a management strategy to reduce toxicity.The approach taken by our surgical team illustrates the benefits of disease debulking in certain cases of PTLD, by guiding further therapy and spacing and reducing chemotherapy in immune suppressed patients.
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Project description:In this study we focussed on malignant post-transplant lymphomas. Post-transplant lymphoma is strongly associated with Epstein-Barr Virus (EBV) infection in contrast to lymphoma arising in an immunocompetent population. Nevertheless, about 1 in 3 PTLD cases are negative for EBV. We used a microarray to define the gene expression profile of different PTLDs to elucidate the pathogenesis of EBV(+) and EBV(-) PTLD and to define whether EBV(-) PTLD is biologically different from EBV(-) lymphoma arising in an immunocompetent host. PTLD patient samples were randomly selected for RNA extraction and hybridization on an Affymetrix platform. The post-transplant tumors consisted of homogenous sheets of neoplastic cells ensuring reliability of the gene expression data.
2012-06-22 | E-GEOD-38885 | biostudies-arrayexpress
Project description:In this study we focussed on malignant post-transplant lymphomas. Post-transplant lymphoma is strongly associated with Epstein-Barr Virus (EBV) infection in contrast to lymphoma arising in an immunocompetent population. Nevertheless, about 1 in 3 PTLD cases are negative for EBV. We used a microarray to define the gene expression profile of different PTLDs to elucidate the pathogenesis of EBV(+) and EBV(-) PTLD and to define whether EBV(-) PTLD is biologically different from EBV(-) lymphoma arising in an immunocompetent host.
2012-06-23 | GSE38885 | GEO