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Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

ABSTRACT: 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.

SUBMITTER: Kline K

PROVIDER: S-EPMC10305491 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

Kline Kathryn K Chen Wengen W Kallen Michael E ME Koka Rima R Omili Destiny D Fan Xiaoxuan X Iraguha Thierry T Gebru Etse E Dishanthan Nishanthini N Baker Jillian M JM Dietze Kenneth A KA Yared Jean A JA Hankey Kim K Dahiya Saurabh S Niederhaus Silke V SV Dunleavy Kieron K Hardy Nancy M NM Luetkens Tim T Rapoport Aaron P AP Atanackovic Djordje D

Human vaccines & immunotherapeutics 20230606 2

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 e ...[more]

PMID: 37278257

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Project description:Post-transplant lymphoproliferative disorders (PTLD) are among the most serious complications after solid organ transplantation (SOT). Monomorphic diffuse large B-cell lymphoma (DLBCL) is the most common subtype of PTLD. Historically, outcomes of PTLD have been poor with high mortality rates and allograft loss, although this has improved in the last 10 years. Most of our understanding about PTLD DLBCL is extrapolated from studies in non-PTLD DLBCL, and while several clinical factors have been identified and validated for predicting non-PTLD DLBCL outcomes, the molecular profile of PTLD DLBCL has not yet been characterized. Compartment-specific metabolic reprograming has been described in non-PTLD DLBCL with a lactate uptake metabolic phenotype with high monocarboxylate transporter 1 (MCT1) expression associated with worse outcomes. The aim of our study was to compare the outcomes of PTLD in our transplant center to historic cohorts, as well as study a subgroup of our PTLD DLBCL tumors and compare metabolic profiles with non-PTLD DLBCL. We performed a retrospective single institution study of all adult patients who underwent a SOT between the years 1992-2018, who were later diagnosed with PTLD. All available clinical information was extracted from the patients' medical records. Tumor metabolic markers were studied in a subgroup of PTLD DLBCL and compared to a group of non-PTLD DLBCL. Thirty patients were diagnosed with PTLD following SOT in our center. Median time from SOT to PTLD diagnosis was 62.8 months (IQR 7.6; 134.4), with 37% of patients diagnosed with early PTLD, and 63% with late PTLD. The most common PTLD subtype was DLBCL. Most patients were treated with reduction of their immunosuppression (RIS) including a group who were switched from calcineurin inhibitor (CNI) to mTOR inhibitor based IS, in conjunction with standard anti-lymphoma chemoimmunotherapy. Progression free survival of the PTLD DLBCL cohort was calculated at 86% at 1 year, and 77% at 3 and 5-years, with overall survival of 86% at 1 and 3-years, and 75% at 5 years. Death censored allograft survival in the kidney cohort was 100% at 1 year, and 93% at 3, 5 and 10 years. MCT1 H scores were significantly higher in a subset of the non-PTLD DLBCL patients than in a PTLD DLBCL cohort. Our data is concordant with improved PTLD outcomes in the last 10 years. mTOR inhibitors could be an alternative to CNI as a RIS strategy. Finally, PTLD DLBCL may have a distinct metabolic profile with reduced MCT1 expression compared to non-PTLD DLBCL, but further studies are needed to corroborate our limited cohort findings and to determine if a specific metabolic profile is associated with outcomes.

Dataset Information

Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

Publications

Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

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