Single dose of CD137-Antibody Drug Conjugate protects non-human primate allogeneic HCT recipients against acute GVHD

Rapid CD137 upregulation on alloreactive T-cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody-drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and non-human primate (NHP) activated T-cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human hematopoietic stem cell grafts, as well as in NHP undergoing MHC-haploidentical HCT. Flow cytometry analysis of NHP T-cells indicated specific depletion of activated PD-1+ CD4 and CD8 T-cells, while sparing naïve and PD-1-OX40+ memory T-cell subsets. CD137-ADC-treated NHP recipients demonstrated robust hematopoietic and immune reconstitution. Hallmarks of T-cell recovery after CD137-ADC, which were associated with long-term aGVHD-free survival, included reconstitution of CD4 memory T-cells expressing TRAIL, terminally-differentiated CD8 T-cells expressing CX3CR1, and CD4 FoxP3+ Tregs – cell types not expected to be involved in aGVHD pathogenesis. CD137-ADC-treated recipients demonstrated a higher risk of reactivation of rhLCV (the rhesus macaque EBV analogue), which was associated with reconstitution of follicular helper T-cells, interferon signaling-associated memory, and gamma-delta T-cell subsets. This reactivation was controllable with rituximab administration. These results document effective depletion of alloreactive T-cells and prevention of aGVHD following a single dose of CD137-ADC, suggesting that clinical translation should be carefully explored. This series extends the dataset in GSE157280 by adding 68 CD4+ samples and two CD8+ samples

同种异体刺激后，同种反应性T细胞上的CD137（CD137）会快速上调，这提示选择性清除这类细胞可预防同种异体造血干细胞移植（allogeneic hematopoietic stem cell transplantation, HCT）后的急性移植物抗宿主病（acute graft-versus-host disease, aGVHD）。本研究中，我们开发了一种新型aGVHD预防性治疗方案：在移植当日单次给予抗CD137抗体药物偶联物（anti-CD137 antibody-drug conjugate, CD137-ADC），无需额外免疫抑制治疗。CD137-ADC可同时清除人类与非人灵长类（non-human primate, NHP）的活化T细胞，并在接受人造血干细胞移植物的小鼠中以及接受MHC单倍体相合HCT的非人灵长类中，均展现出优异的异种aGVHD预防效果。对非人灵长类T细胞的流式细胞术分析显示，CD137-ADC可特异性清除活化的PD-1+ CD4及CD8 T细胞，同时保留初始T细胞以及PD-1-OX40+记忆T细胞亚群。接受CD137-ADC治疗的非人灵长类移植受体展现出良好的造血与免疫重建能力。CD137-ADC治疗后的T细胞恢复特征与长期无aGVHD存活相关，其包括表达TRAIL的CD4记忆T细胞、表达CX3CR1的终末分化CD8 T细胞，以及CD4 FoxP3+调节性T细胞（FoxP3+ Tregs）——这类细胞原本不被认为参与aGVHD的发病过程。接受CD137-ADC治疗的受体出现rhLCV（恒河猴EB病毒类似物，rhesus macaque EBV analogue）再激活的风险更高，该现象与滤泡辅助性T细胞、干扰素信号通路相关记忆细胞以及γδ T细胞亚群的重建相关。该再激活可通过利妥昔单抗给药得到控制。上述结果证实，单次给予CD137-ADC可有效清除同种反应性T细胞并预防aGVHD，提示应当审慎探索其临床转化价值。本数据集在GSE157280的基础上新增了68份CD4+样本与2份CD8+样本。