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E. Wagner-Drouet et al.
tion (median 82 days). Moreover, most (31/44 [70.4%]) of the day-100 measurements took place 14 days or later rel- ative to the end of a first antiviral treatment, while most (36/76 [47.4%]) of the measurements at the end of a first CMV reactivation were from the day of discontinuation of antiviral treatment (day 0). This raises the possibility that measuring CMV-CMI 14 days after the end of a treatment-requiring CMV reactivation – rather than on the day of antiviral treatment discontinuation – might improve the predictive value for protection against recur- rent reactivation. This might be explained by the ongoing immune reconstitution that takes place after HSCT. Indeed, a paired comparison of existing day 0, day 7 and day 14 measurements revealed a statistically significant increase in SFC counts between day 7 (or day 0) and day 14 in patients with no future recurrent CMV reactivation (data not shown). A future study should determine whether measuring CMV-CMI 14 days after the end of antiviral treatment and/or whether monitoring the dynamics of response might improve prediction of recur- rent CMV reactivation.
While the current focus on high-risk (D-/R+) HSCT patients for the prediction of recurrent CMV reactivation is of major clinical relevance, it constitutes the main limi- tation of this study. A recent study in intermediate-risk (D+/R+) HSCT patients partly addressed this question by measuring the dynamic changes in CMV-CMI using T- Track® CMV,52 underscoring the usefulness of multiple measurements for risk stratification of HSCT recipients. It should also be emphasized that despite the use of non- standardized conditioning regimens, viral load testing and treatment protocols in this multicenter study, the IFN-γ ELISpot assay performed very well at predicting recurrent CMV reactivation. This further highlights the applicability of using a sensitive and standardized CMV-CMI monitor- ing assay in a real-world setting, as well as its ease of implementation in clinical routine, for the risk stratifica- tion of HSCT patients.
In conclusion, our results suggest that using a standard- ized CMV-CMI monitoring assay can support clinicians in the identification and management of patients with increased risk of recurrent CMV reactivation following HSCT. Beside its applicability in the preemptive setting, the door is also open to its implementation in novel clini- cal settings with unmet medical needs, such as steering the duration of antiviral prophylaxis (e.g., using leter- movir)53 and monitoring immune reconstitution following adoptive T-cell transfer.54
Disclosures
The participating clinical and measurement centers (D.W., EW, DT, CW, DJ, KS-E, JG, SM, MS, GK, MK, IH, ML-T, SK, DH, SK, MV, SG, MD, TG, MK, TH, ML) received research funding from Lophius Biosciences for this study. LD is
an employee, co-founder, Chief Scientific Officer and sharehold- er of Lophius Biosciences. SB is an employee and shareholder of Lophius Biosciences. TS, H.G. and A.R. are employees of Lophius Biosciences. RW is Chairman of the Board and a share- holder of Lophius Biosciences. Issued patents relevant to the T- Track® CMV assay used in this study: WO/2010/115984 “METHOD FOR POLYPEPTIDE TRANSFER INTO CELLS”. WO/2003/080792 “USE OF UREA-ADJUVATED POLYPEPTIDES FOR DIAGNOSIS, PROPHYLAXIS AND TREATMENT”. WO/2003/046212 “METHOD FOR IDENTIFYING TARGET EPITOPES OF THE T CELL MEDIATED IMMUNE RESPONSE AND FOR ASSAYING EPITOPE-SPECIFIC T CELLS"
Contributions
LD, DW, SB and RW contributed to the study conception and design; TS, LD, SB and RW organized, coordinated and super- vised the study and its logistics; DW, EW, DT, CW, DJ, KS-E, JG, SM, MS, GK, MK, IH, ML-T, SK, DH, SK, MV, SG, MD and TG acquired patient samples and contributed to data collection; EW, TH, M.K., M.L. and S.B. performed the ELISpot assays; SB and HG analyzed the ELISpot results; AR, TS, LD and RW conducted and supervised the interpretation of results; AR drafted the manuscript and figures; All authors con- tributed to, reviewed and approved the manuscript.
Acknowledgments
This study was supported in part by the German Federal Ministry of Education and Research (BMBF grant number 031A215) to Lophius Biosciences and by research funding from Lophius Biosciences to DW, EW, DT, CW, DJ, KS-E, JG, SM, MS, GK, MK, IH, ML-T, SK, DH, SK, MV, SG, MD, TG, MK, TH, and ML. DW was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, grant number 324392634 - TRR 221). We are grateful to all study participants for their contribution. The authors acknowl- edge the members of the respective participating centers, as well as Anja Svenson, Julia Batzilla, Hanna Bendfeldt, Astrid Starke and Alcedis GmbH (Giessen, Germany) for their expertise and assistance in data collection, data management, and study plan- ning and coordination. We thank Thomas Keller and Stephan Weber (ACOMED Statistik, Leipzig, Germany) for their statis- tical evaluation. T-Track® CMV tests were provided by Lophius Biosciences GmbH, Regensburg, Germany.
Funding
This study was supported in part by the German Federal Ministry of Education and Research (BMBF grant number 031A215) to Lophius Biosciences and by research funding from Lophius Biosciences to DW, EW, DT, CW, DJ, KS-E, JG, SM, MS, GK, MK, IH, ML-T, SK, DH, SK, MV, SG, MD, TG, MK, TH, and ML. DW was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, grant number 324392634 - TRR 221).
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