Combining CD19 redirection and alloanergization to generate tumor-specific human T cells for allogeneic cell therapy of B-cell malignancies.
Combining CD19 redirection and alloanergization to generate tumor-specific human T cells for allogeneic cell therapy of B-cell malignancies.
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DOI：
10.1158/0008-5472.can-09-3845
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Cooper LJ
中科院分区：
文献类型：
--
作者：
Davies JK;Singh H;Huls H;Yuk D;Lee DA;Kebriaei P;Champlin RE;Nadler LM;Guinan EC;Cooper LJ
异基因造血干细胞移植可以治愈一些高危B细胞恶性肿瘤患者，但移植后疾病复发仍然是一个重大问题。可用于增强供体T细胞介导的抗肿瘤作用的一种方法是输注表达对B细胞抗原CD 19特异性的嵌合抗体受体（CAR）的同种异体供体来源的T细胞。然而，使用此类细胞可能导致毒性，其形式为具有同种异体反应性内源性T细胞受体的CD 19特异性（CD 19-CAR）T细胞介导的移植物抗宿主病。因此，我们研究了通过CAR表达的CD 19重定向和随后的同种异体刺激和伴随的CD 28介导的共刺激的阻断的同种异体无能化的组合，是否可以从健康供体的外周血单核细胞产生非同种异体反应性肿瘤特异性人T细胞。CD 19-CAR T细胞的同种异体作用导致CD 4+和CD 8 + T细胞中同种异体反应的有效和选择性降低，包括同种异体特异性增殖和细胞因子分泌。重要的是，T细胞效应子功能，包括CAR依赖性增殖和特异性靶细胞溶解和细胞因子产生，在同种异体化后得以保留。我们的数据支持应用CD 19-重定向和随后的同种异体化来产生用于临床使用的同种异体供体T细胞，其具有增加的抗肿瘤活性，但介导移植物抗宿主病的能力有限。用这样的细胞治疗可以潜在地减少同种异体移植后的疾病复发而不增加毒性，从而改善接受同种异体移植治疗高风险B细胞恶性肿瘤的患者的结果。
Allogeneic hematopoietic stem-cell transplantation can cure some patients with high-risk B-cell malignancies, but disease relapse following transplantation remains a significant problem. One approach that could be used to augment the donor T cell-mediated anti-tumor effect is the infusion of allogeneic donor-derived T cells expressing a chimeric antibody receptor (CAR) specific to the B-cell antigen CD19. However, the use of such cells might result in toxicity in the form of graft-versus-host disease mediated by CD19-specific (CD19-CAR) T cells possessing alloreactive endogenous T cell receptors. We therefore investigated whether non-alloreactive tumor-specific human T cells could be generated from peripheral blood mononuclear cells of healthy donors by the combination of CD19-redirection via CAR expression and subsequent alloanergization by allostimulation and concomitant blockade of CD28-mediated costimulation. Alloanergization of CD19-CAR T cells resulted in efficient and selective reduction of alloresponses in both CD4+ and CD8+ T cells including allospecific proliferation and cytokine secretion. Importantly, T-cell effector functions including CAR-dependent proliferation and specific target cytolysis and cytokine production were retained after alloanergization. Our data supports the application of CD19-redirection and subsequent alloanergization to generate allogeneic donor T cells for clinical use possessing increased anti-tumor activity, but limited capacity to mediate graft-versus-host disease. Therapy with such cells could potentially reduce disease relapse after allogeneic transplantation without increasing toxicity, thereby improving the outcome of patients undergoing allogeneic transplantation for high-risk B-cell malignancies.