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Tumor regression concomitant with steroid-refractory GvHD highlights the pitfalls of PD-1 blockade following allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 52, pages 759–761 (2017)Cite this article

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For Hodgkin lymphoma (HL) patients who fail front-line therapy, salvage regimens including autologous and allogeneic hematopoietic stem cell transplant (alloHSCT) may cure select patients, although relapse remains a significant cause of transplant failure. Treatment strategies aimed at bolstering post-transplant immunity to both prevent and treat relapse following alloHSCT are of significant interest, especially immune checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) monoclonal Abs.

Programmed death ligand 1 (PD-L1) binds to its cognate receptor, PD-1, found on activated T cells, resulting in suppression of T-cell activation and proliferation. Classical Hodgkin lymphoma (cHL) is characterized by tumor-infiltrating T cells expressing PD-1 while surrounding malignant Reed-Sternberg (RS) cells.1 RS cells constitutively express PD-L1, although amplification of chromosome 9p24.1 and its induction by JAK2 results in increased expression.2, 3 Blockade of the PD-L1/PD-1 pathway restores antitumor activity of CD4+ HL-infiltrating T cells and IFN-γ production.1 The PD-1 inhibitor, nivolumab, initially showed remarkable efficacy with an overall response rate (ORR) of 87% in a phase 1 study of heavily pretreated relapsed/refractory HL patients, excluding allotransplant patients.4 The ongoing phase 2 study of nivolumab in HL patients who failed to respond to autologous HSCT and brentuximab recently reported an ORR of >66% and recent use of pembrolizumab phase I data in similar patients revealed an ORR of 65%.5, 6 These studies excluded allotransplant recipients based upon evidence that prior murine models demonstrated mice subjected to PD-1/PD-L1 blockade developed rapid, lethal acute GvHD (aGvHD).7

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Acknowledgements

This work was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute of the National Institutes of Health.

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  1. Department of Hematology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    E McDuffee, G Aue, L Cook, C Ramos-Delgado, R Shalabi, T Worthy, P Vo & R W Childs

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Correspondence to R W Childs.

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McDuffee, E., Aue, G., Cook, L. et al. Tumor regression concomitant with steroid-refractory GvHD highlights the pitfalls of PD-1 blockade following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 52, 759–761 (2017). https://doi.org/10.1038/bmt.2016.346

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