Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant
Siegel, S. J.; DeWolf, S.; Schmalz, J.; Saber, W.; Dong, J.; Martens, M. J.; Logan, B.; Albanese, A.; Iovino, L.; Chen, E.; Kaminski, J.; Neuberg, D.; Hebert, K.; Keskula, P.; Zavistaski, J.; Steinberg, L.; Schichter, I.; Cagnin, L.; Hernandez, V.; Warren, M.; Applegate, K.; Bar, M.; Chhabra, S.; Choi, S. W.; Clark, W.; Das, S.; Jenq, R.; Jones, R. J.; Levine, J. E.; Murthy, H.; Rashidi, A.; Riches, M.; Sandhu, K.; Sung, A. D.; Larkin, K.; Al Malki, M. M.; Gooptu, M.; Elmariah, H.; Alousi, A.; Runaas, L.; Shaffer, B.; Rezvani, A.; El Jurdi, N.; Loren, A. W.; Scheffey, D.; Sanders, C.; Hamadani
Show abstract
Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T-cell-mediated post-transplant complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for post-transplant cyclophosphamide (PT-Cy)-based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but did not improve overall survival. To compare T-cell biology between GVHD prophylaxis regimens, 324 patients were co-enrolled onto BMT CTN 1801 (NCT03959241). We quantified T-cell immune reconstitution using multi-modal analysis, including T-cell receptor (TCR) sequencing of 2,359 longitudinal samples (180,432,350 T-cells). Compared to Tac/MTX, PT-Cy was associated with an early, substantial reduction in TCR diversity that was sustained for 2 years. PT-Cy led to a T-cell reconstitution bottleneck, including reduced thymic output and virus-associated TCRs. Decreased D+14 TCR diversity predicted prevention of chronic GVHD, but also correlated with increased moderate-to-severe infections. This study reveals how distinct immunosuppression strategies have significant effects on the global immune repertoire, underpinning post-transplant clinical outcomes.
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