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      Utility of Serial Donor-derived Cell-free DNA Measurements for Detecting Allograft Rejection in a Kidney Transplant Recipient After PD-1 Checkpoint Inhibitor Administration

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          Abstract

          Background.

          Donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker of rejection that originates from allograft cells undergoing injury. Plasma levels <1% in kidney transplant recipients have a high negative predictive value for active allograft rejection. The utility of this biomarker in kidney transplant recipients receiving immune checkpoint inhibitor therapy is unknown.

          Methods.

          We describe a case in which serial dd-cfDNA monitoring facilitated the use of immune checkpoint inhibitor therapy, which is known to be associated with high rates of rejection, in a kidney transplant recipient with metastatic cancer.

          Results.

          A 72-y-old man with end-stage kidney disease secondary to autosomal dominant polycystic kidney disease underwent living unrelated kidney transplant in December 2010. His immunosuppression regimen included tacrolimus, mycophenolate, and prednisone. In July 2017, he presented with metastatic cutaneous squamous cell carcinoma. After his disease progressed through radiation therapy and cetuximab, he received pembrolizumab (antiprogrammed cell death protein 1). His dd-cfDNA level was undetectable at baseline, then increased during treatment but remained <1%. This trend, despite fluctuations in serum creatinine levels during therapy, allowed for continuation of pembrolizumab and successful treatment of his metastatic cancer without clinically evident allograft rejection. After discontinuation of pembrolizumab, dd-cfDNA levels fell below the level of detection. Genetic analysis of the cutaneous squamous cell carcinoma demonstrated a genetic profile distinct from the dd-cfDNA, indicating that tumor lysis did not impact increases in dd-cfDNA.

          Conclusions.

          Serial dd-cfDNA measurements may provide a useful, noninvasive biomarker for detecting allograft injury that may facilitate the use of immunomodulatory therapies in organ transplant recipients with cancer.

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          New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

          E A Eisenhauer, P Therasse, J. Bogaerts … (2009)
          Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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            Cell-Free DNA and Active Rejection in Kidney Allografts.

            Roy Bloom, Jonathan S Bromberg, Emilio D Poggio … (2017)
            Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P 1% indicate a probability of active rejection.
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              Universal noninvasive detection of solid organ transplant rejection.

              H A Valantine, Shane Snyder, Kiran Khush … (2011)
              It is challenging to monitor the health of transplanted organs, particularly with respect to rejection by the host immune system. Because transplanted organs have genomes that are distinct from the recipient's genome, we used high throughput shotgun sequencing to develop a universal noninvasive approach to monitoring organ health. We analyzed cell-free DNA circulating in the blood of heart transplant recipients and observed significantly increased levels of cell-free DNA from the donor genome at times when an endomyocardial biopsy independently established the presence of acute cellular rejection in these heart transplant recipients. Our results demonstrate that cell-free DNA can be used to detect an organ-specific signature that correlates with rejection, and this measurement can be made on any combination of donor and recipient. This noninvasive test holds promise for replacing the endomyocardial biopsy in heart transplant recipients and may be applicable to other solid organ transplants.
              Article 0 comments Cited 132 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Transplant Direct
                Journal ID (iso-abbrev): Transplant Direct
                Journal ID (publisher-id): TXD
                Title: Transplantation Direct
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Electronic): 2373-8731
                Publication date (Electronic): 15 January 2021
                Publication date Collection: February 2021
                Volume: 7
                Issue: 2
                Electronic Location Identifier: e656
                Affiliations
                [1 ] Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
                [2 ] Johns Hopkins Medical Institute, Baltimore, MD.
                [3 ] James D Eason Transplant Institute, Methodist University Hospital, University of Tennessee Health Science Center, Memphis, TN.
                [4 ] Beth Israel Deaconess Medical Center, Boston, MA.
                [5 ] Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Kimmel Cancer Center, Baltimore, MD.
                [6 ] Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
                Author notes
                Correspondence: Daniel C. Brennan, MD, FACP, Division of Nephrology, Johns Hopkins University School of Medicine, Medical Director The Comprehensive Transplant Center, Carnegie 668A, 600 N. Wolfe St., Baltimore, MD 21287. ( dbrenna4@ 123456jhmi.edu ).
                Article
                Accession ID: 00009
                DOI: 10.1097/TXD.0000000000001113
                PMC ID: 7817285
                PubMed ID: 33490381
                SO-VID: f552c31a-1142-4237-bd09-5d855cef5c26
                Copyright © Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                Date received : 9 October 2020
                Date revision received : 3 November 2020
                Date accepted : 04 November 2020
                Categories
                Subject: 016
                Subject: Kidney Transplantation
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                OPEN-ACCESS TRUE

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