Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg.
Affimed GmbH, Im Neuenheimer Feld, Heidelberg, Germany.
J Immunother. 2019 Jun;42(5):180-188. doi: 10.1097/CJI.0000000000000267.
Immunotherapy of B-cell malignancies with bispecific antibodies is an emerging treatment option. However, not all patients benefit from these therapies, presumably due to pretreatment regimens. Therefore, we determined the effect of different treatment lines on the activity of T cells and their responsiveness to AFM11. AFM11 is a tetravalent, bispecific CD19/CD3 immunoengager based on Affimed's ROCK platform, currently being investigated in phase I clinical trials for non-Hodgkin lymphoma and acute lymphoblastic leukemia. T cells from B-cell lymphoma patients treated with either rituximab+bendamustine (R-Benda), rituximab+CHOP (R-CHOP), or with high-dose BEAM chemotherapy (HD-BEAM) and autologous HSCT were compared with T cells from healthy donors. Overall, in these patients, T-cell numbers were significantly reduced. To determine whether distinct chemotherapy affects AFM11 efficacy, functional T-cell assays were performed. It is interesting to note that, only in assays that combine target cell lysis, cytokine production and proliferation over 4 days at an effector to target ratio of up to 1:25 significant differences could be detected between the different treatment groups: T cells after R-CHOP showed only modest decrease in their functionality when compared with healthy controls, whereas R-Benda and HD-BEAM had a profound effect on AFM11-induced T-cell cytotoxicity. In conclusion, T cells from lymphoma patients are reduced in number and have functional defects following treatment with certain chemotherapy regimens, also reducing AFM11 efficacy. Importantly, AFM11 was still able to trigger B-cell-directed T-cell immunity in all treatment groups.
双特异性抗体的 B 细胞恶性肿瘤免疫疗法是一种新兴的治疗选择。然而，并非所有患者都从这些治疗中获益，推测是由于预处理方案。因此，我们确定了不同治疗方案对 T 细胞活性及其对 AFM11 的反应性的影响。AFM11 是一种基于 Affimed 的 ROCK 平台的四价双特异性 CD19/CD3 免疫结合物，目前正在 I 期临床试验中用于非霍奇金淋巴瘤和急性淋巴细胞白血病的研究。比较了接受利妥昔单抗+苯达莫司汀（R-Benda）、利妥昔单抗+CHOP（R-CHOP）或高剂量 BEAM 化疗（HD-BEAM）和自体 HSCT 治疗的 B 细胞淋巴瘤患者的 T 细胞与健康供体的 T 细胞。总体而言，这些患者的 T 细胞数量明显减少。为了确定不同的化疗是否会影响 AFM11 的疗效，进行了功能性 T 细胞测定。有趣的是，仅在结合靶细胞裂解、细胞因子产生和增殖的测定中，在效应物与靶物比例高达 1:25 的情况下，才能在不同治疗组之间检测到显著差异：与健康对照组相比，R-CHOP 后的 T 细胞功能仅略有下降，而 R-Benda 和 HD-BEAM 对 AFM11 诱导的 T 细胞细胞毒性有深远影响。总之，淋巴瘤患者的 T 细胞数量减少，并且在接受某些化疗方案治疗后功能缺陷，从而降低了 AFM11 的疗效。重要的是，在所有治疗组中，AFM11 仍能引发针对 B 细胞的 T 细胞免疫。
