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CTLA4Ig-based T-cell costimulation blockade is associated with reduction of adenovirus viremia following post-transplantation cyclophosphamide-based haploidentical transplantation

Bone Marrow Transplantation volume 55, pages 649–652 (2020)Cite this article

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The last two decades have seen an improved appreciation of the immunopathology of adenovirus (AdV) infection, but it remains a fatal infection once viremia persists or progresses post transplantation [1,2,3,4,5]. Haploidentical hematopoietic cell transplantation (HCT), on the other hand, has moved from graft manipulation to the use of post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis [6]. However, the impact of this approach on the incidence and outcome of adenovirus infections in children or adults undergoing haploidentical HCT is not known. We had introduced a novel approach of combining pre- and post-transplantation T-cell costimulation blockade (TCOSBL) with CTLA4Ig in combination with PTCy, to reduce early alloreactivity, the impact of which on AdV is unknown [7,8,9].

In a prospective study, we analysed the incidence, risk factors and outcome of adenovirus viremia in 102 patients who underwent PTCy-based haploidentical HCT with CTLA4Ig (n = 60) or PTCy alone (n = 42). Approval was obtained from Institute Review Board in accordance with the Declaration of Helsinki, and written informed consents were obtained from all patients and donors. PTCy-based conditioning regimens for malignant and non-malignant diseases have been described in detail in our previous publications [10]. In the modified protocol, patients received CTLA4Ig (Abatacept, BMS, Mumbai, India) at 10 mg/kg on days −1, +5, +20 and +35 [9]. Those with malignant diseases received cyclosporine (CSA) from D +5 at 1.5 mg/kg 12 h apart to maintain a trough level of 75–150 ng/ml8. In those with non-malignant disorders, abatacept was administered every 4 weeks after day +35 until day +180 and sirolimus was given from day −8, as previously described [9].

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References

  1. Chakrabarti S, Mautner V, Osman H, Collingham KE, Fegan CD, Klapper PE, et al. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood. 2002;100:1619–27. https://doi.org/10.1182/blood-2002-02-0377.

    Article  CAS  PubMed  Google Scholar 

  2. Robin M, Marque-Juillet S, Scieux C, Peffault de Latour R, Ferry C, Rocha V, et al. Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome. Haematologica. 2007;92:1254–7.

    Article  Google Scholar 

  3. van Tol MJ, Kroes AC, Schinkel J, Dinkelaar W, Claas EC, Jol-van der Zijde CM, et al. Adenovirus infection in paediatric stem cell transplant recipients: increased risk in young children with a delayed immune recovery. Bone Marrow Transpl. 2005;36:39–50. https://doi.org/10.1038/sj.bmt.1705003.

    Article  Google Scholar 

  4. Omar H, Yun Z, Lewensohn-Fuchs I, Perez-Bercoff L, Orvell C, Engstrom L, et al. Poor outcome of adenovirus infections in adult hematopoietic stem cell transplant patients with sustained adenovirus viremia. Transpl Infect Dis. 2010;12:465–9. https://doi.org/10.1111/j.1399-3062.2010.00528.x.

    Article  CAS  PubMed  Google Scholar 

  5. Zecca M, Wynn R, Dalle J-H, Feuchtinger T, Vainorius E, Brundage TM, et al. Association between adenovirus viral load and mortality in pediatric allo-HCT recipients: the multinational AdVance study. Bone Marrow Transpl. 2019; https://doi.org/10.1038/s41409-019-0483-7.

    Article  Google Scholar 

  6. Luznik L, O’Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol. 2012;39:683–93. S0093-7754(12)00187-X, [pii];10.1053/j.seminoncol.2012.09.005 [doi]

    Article  CAS  Google Scholar 

  7. Jaiswal SR, Bhakuni P, Joy A, Kaushal S, Chakrabarti A, Chakrabarti S. CTLA4Ig primed donor lymphocyte infusion: a novel approach to immunotherapy following haploidentical transplantation for advanced leukemia. Biol Blood Marrow Transpl. 2019. https://doi.org/10.1016/j.bbmt.2018.12.836.

    Article  Google Scholar 

  8. Jaiswal SR, Bhakuni P, Joy A, Murli N, Rajoreya A, Chakrabarti A, et al. Higher CD45RA(+) regulatory T cells in the graft improves outcome in younger patients undergoing t cell-replete haploidentical transplantation: where donor age matters. Biol Blood Marrow Transpl. 2018;24:2025–33. https://doi.org/10.1016/j.bbmt.2018.06.003.

    Article  CAS  Google Scholar 

  9. Jaiswal SR, Bhakuni P, Zaman S, Bansal S, Bharadwaj P, Bhargava S, et al. T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transpl Immunol. 2017;43-44:54–9. https://doi.org/10.1016/j.trim.2017.07.004.

    Article  CAS  PubMed  Google Scholar 

  10. Jaiswal SR, Zaman S, Chakrabarti A, Sen S, Mukherjee S, Bhargava S, et al. Improved outcome of refractory/relapsed acute myeloid leukemia after post-transplantation cyclophosphamide-based haploidentical transplantation with myeloablative conditioning and early prophylactic granulocyte colony-stimulating factor-mobilized donor lymphocyte infusions. Biol Blood Marrow Transpl. 2016;22:1867–73. https://doi.org/10.1016/j.bbmt.2016.07.016.

    Article  CAS  Google Scholar 

  11. Suparno C, Milligan DW, Moss PA, Mautner V. Adenovirus infections in stem cell transplant recipients: recent developments in understanding of pathogenesis, diagnosis and management. Leuk Lymphoma. 2004;45:873–85. https://doi.org/10.1080/10428190310001628176.

    Article  CAS  PubMed  Google Scholar 

  12. Zaia J, Baden L, Boeckh MJ, Chakrabarti S, Einsele H, Ljungman P, et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transpl. 2009;44:471–82. https://doi.org/10.1038/bmt.2009.258.

    Article  CAS  Google Scholar 

  13. Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch HH, Cordonnier C, et al. European guidelines for diagnosis and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 (2011). Transpl Infect Dis. 2012;14:555–63. https://doi.org/10.1111/tid.12022.

    Article  CAS  PubMed  Google Scholar 

  14. Comoli P, Locatelli F, Moretta A, Montagna D, Calcaterra V, Cometa A, et al. Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses. Bone Marrow Transpl. 2001;27:1263–73.

    Article  CAS  Google Scholar 

  15. Jaiswal SR, Bhakuni P, Joy A, Kaushal S, Sudhish D, Aiyer HM, et al. Early expansion of CD56dimNKG2Alow with late surge and persistence of CD56dimNKG2AnegNKG2Cbright NK cells attenuate cytomegalovirus (CMV) replication and recurrence as well as leukemia relapse following haploidentical HSCT with T cell co-stimulation blockade and PTCy. Biol Blood Marrow Transplant. 2019;25:S328. https://doi.org/10.1016/j.bbmt.2018.12.529.

    Article  Google Scholar 

  16. Lugthart G, Oomen MA, Jol-van der Zijde CM, Ball LM, Bresters D, Kollen WJ, et al. The effect of cidofovir on adenovirus plasma DNA levels in stem cell transplantation recipients without T cell reconstitution. Biol Blood Marrow Transpl. 2015;21:293–9. https://doi.org/10.1016/j.bbmt.2014.10.012.

    Article  CAS  Google Scholar 

  17. Pinelli DF, Wakeman BS, Wagener ME, Speck SH, Ford ML. Rapamycin ameliorates the CTLA4-Ig-mediated defect in CD8(+) T cell immunity during gammaherpesvirus infection. Am J Transpl. 2015;15:2576–87. https://doi.org/10.1111/ajt.13326.

    Article  CAS  Google Scholar 

  18. Davies J, Yuk D, Nadler L, Guinan E, Donor-Derived T. Cells can be rendered hyporesponsive to alloantigen without loss of pathogen or tumor immune responses. Blood. 2015;110:771.

    Article  Google Scholar 

  19. Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo X, et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+natural killer cells with potent function. Blood. 2012;119:2665–74. https://doi.org/10.1182/blood-2011-10-386995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Cellular Therapy and Immunology, Manashi Chakrabarti Foundation, Kolkata, West Bengal, India

    Sarita Rani Jaiswal, Prakash Bhakuni, Aditi Chakrabarti & Suparno Chakrabarti

  2. Department of Blood and Marrow Transplantation, Dharamshila Narayana Superspeciality Hospital and Research Centre, New Delhi, India

    Sarita Rani Jaiswal, Prakash Bhakuni, Gitali Bhagawati & Suparno Chakrabarti

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Contributions

SRJ and SC designed and performed the study; SRJ and PB performed the experiments; GB and PB collected the data and SRJ and SC analysed the data; SRJ, AC and SC wrote the paper. All the co-authors reviewed and approved the paper.

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Correspondence to Suparno Chakrabarti.

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Jaiswal, S.R., Bhakuni, P., Bhagawati, G. et al. CTLA4Ig-based T-cell costimulation blockade is associated with reduction of adenovirus viremia following post-transplantation cyclophosphamide-based haploidentical transplantation. Bone Marrow Transplant 55, 649–652 (2020). https://doi.org/10.1038/s41409-019-0549-6

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