PDF(Pubmed)
Abstract：
The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.
摘要：
靶向HLA-A2限制性癌症睾丸表位NY-ESO-1157-165(A2/NY)的T细胞受体工程化(TCR工程化)T细胞(ACT)的过继转移已经产生了针对几种癌症的有利的临床应答。改善ACT的两种方法是TCR亲和力优化和T细胞共工程以表达可以利用内源性免疫的免疫调节分子。通过计算设计，我们先前开发了一组结合增强的A2/NY-TCR，包括A97L，与WT相比，这增强了基因修饰的T细胞的体外功能。这里,我们证明A97L-T细胞具有更高的持久性和改善的肿瘤控制。为了控制肿瘤中的巨噬细胞，我们进一步共同改造A97L-T细胞以分泌高亲和力信号调节蛋白α（SiRPα）诱饵（CV1），阻断CD47。虽然CV1-Fc-共工程改造的A97L-T细胞在Winn测定中显著更好地控制肿瘤生长和存活，在皮下异种移植模型中，T细胞，用CV1-Fc包被，耗尽了。重要的是,人类巨噬细胞对CV1单体共工程T细胞没有吞噬作用。此外，在CV1存在下,阿维鲁单抗和西妥昔单抗在体外增强了巨噬细胞介导的肿瘤细胞吞噬作用,并在与A97L-T细胞共同给药时改善了肿瘤控制.一起来看,我们的研究表明,通过将CV1-协同工程改造的TCR-T细胞与靶向抗体结合以直接吞噬肿瘤细胞,可以利用巨噬细胞发挥重要的临床作用.
