Posttransplant cyclophosphamide after allogeneic hematopoietic cell transplantation mitigates the immune activation induced by previous nivolumab therapy

• Published in: Leukemia 2020-12, Vol.34 (12), p.3420-3425
• Main Authors: Nieto, Juan C., Roldán, Elisa, Jiménez, Isabel, Fox, Laura, Carabia, Júlia, Ortí, Guillermo, Puigdefàbregas, Lluís, Gallur, Laura, Iacoboni, Gloria, Raheja, Priyanka, Pérez, Ana, Bobillo, Sabela, Salamero, Olga, Palacio, Carlos, Valcárcel, David, Crespo, Marta, Bosch, Francesc, Barba, Pere
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 631/250/1904; 692/699/1541/1990/291; Cancer Research; Care and treatment; Cell activation; Cells, Cultured; Critical Care Medicine; Cyclophosphamide; Cyclophosphamide - therapeutic use; Exposure; Female; Graft versus host reaction; Graft vs Host Disease - drug therapy; Graft vs Host Disease - prevention & control; Hematology; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Humans; Immunosuppressive Agents - therapeutic use; Immunotherapy; Intensive; Internal Medicine; Letter; Leukemia; Leukocytes, Mononuclear - drug effects; Lymphocytes; Lymphocytes T; Male; Medicine; Medicine & Public Health; Monoclonal antibodies; Nivolumab - therapeutic use; Oncology; PD-1 protein; Prevention; Prophylaxis; Rapamycin; Risk; Sirolimus - therapeutic use; Stem cell transplantation; T-Lymphocytes - drug effects; Tacrolimus; Targeted cancer therapy; Transplantation; Transplantation, Homologous - methods
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-0851-8

Patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT) after the use of PD-1 inhibitors seem to be at a higher risk of developing acute graft-versus-host disease (aGHVD) through etiopathogenetic mechanisms not fully elucidated. Herein, we investigated the effect of nivolumab administered prior to allo-HCT on the following early T-cell reconstitution and its modulation by the GVHD prophylaxis (tacrolimus/sirolimus vs. posttransplant cyclophosphamide [PTCY]). In all nivolumab-exposed patients we detected circulating nivolumab in plasma for up to 56 days after allo-HCT. This residual nivolumab was able to bind and block PD-1 on T-cells at day 21 after allo-HCT, inducing a T cell activation that was differentially modulated depending on the GVHD prophylactic regimen. Among patients receiving tacrolimus/sirolimus, nivolumab-exposed patients had a higher incidence of severe aGVHD and a more effector T-cell profile compared with anti-PD-1-naïve patients. Conversely, patients receiving PTCY-based prophylaxis showed a similar risk of aGVHD and T-cell profile irrespective of the previous nivolumab exposure. In conclusion, nivolumab persists in plasma after transplantation, binds to allogeneic T cells and generates an increased T-cell activation. This T-cell activation status can be mitigated with the use of PTCY, thus reducing the risk of aGVHD.