Chauchet Xavier, Cons Laura, Chatel Laurence, Daubeuf Bruno, Didelot Gérard, Moine Valéry, Chollet Didier, Malinge Pauline, Pontini Guillemette, Masternak Krzysztof, Ferlin Walter, Buatois Vanessa, Shang Limin
Light Chain Bioscience/Novimmune S.A, 15 Chemin du Pré-Fleuri, 1228, Plan-les-Ouates, Switzerland.
iGE3 Genomics Platform, CMU-University of Geneva, Geneva, Switzerland.
Exp Hematol Oncol. 2022 May 10;11(1):26. doi: 10.1186/s40164-022-00279-w.
CD47/SIRPα axis is recognized as an innate immune checkpoint and emerging clinical data validate the interest of interrupting this pathway in cancer, particularly in hematological malignancies. In preclinical models, CD47/SIRPα blocking agents have been shown to mobilize phagocytic cells and trigger adaptive immune responses to eliminate tumors. Here, we describe the mechanisms afforded by a CD47xCD19 bispecific antibody (NI-1701) at controlling tumor growth in a mouse xenograft B-cell lymphoma model.
The contribution of immune effector cell subsets behind the antitumor activity of NI-1701 was investigated using flow cytometry, transcriptomic analysis, and in vivo immune-cell depletion experiments.
We showed that NI-1701 treatment transformed the tumor microenvironment (TME) into a more anti-tumorigenic state with increased NK cells, monocytes, dendritic cells (DC) and MHCII tumor-associated macrophages (TAMs) and decreased granulocytic myeloid-derived suppressor cells. Notably, molecular analysis of isolated tumor-infiltrating leukocytes following NI-1701 administration revealed an upregulation of genes linked to immune activation, including IFNγ and IL-12b. Moreover, TAM-mediated phagocytosis of lymphoma tumor cells was enhanced in the TME in the presence of NI-1701, highlighting the role of macrophages in tumor control. In vivo cell depletion experiments demonstrated that both macrophages and NK cells contribute to the antitumor activity. In addition, NI-1701 enhanced dendritic cell-mediated phagocytosis of tumor cells in vitro, resulting in an increased cross-priming of tumor-specific CD8 T cells.
The study described the mechanisms afforded by the CD47xCD19 bispecific antibody, NI-1701, at controlling tumor growth in lymphoma mouse model. NI-1701 is currently being evaluated in a Phase I clinical trial for the treatment of refractory or relapsed B-cell lymphoma (NCT04806035).
CD47/SIRPα轴被认为是一种先天性免疫检查点，新出现的临床数据证实了在癌症中，尤其是血液系统恶性肿瘤中阻断该信号通路的价值。在临床前模型中，CD47/SIRPα阻断剂已被证明可动员吞噬细胞并触发适应性免疫反应以消除肿瘤。在此，我们描述了一种CD47xCD19双特异性抗体（NI-1701）在小鼠异种移植B细胞淋巴瘤模型中控制肿瘤生长的机制。
使用流式细胞术、转录组分析和体内免疫细胞清除实验，研究了NI-1701抗肿瘤活性背后免疫效应细胞亚群的作用。
我们发现，NI-1701治疗可将肿瘤微环境（TME）转变为更具抗肿瘤性的状态，自然杀伤细胞、单核细胞、树突状细胞（DC）和MHCII肿瘤相关巨噬细胞（TAM）增多，粒细胞性骨髓来源的抑制细胞减少。值得注意的是，对NI-1701给药后分离出的肿瘤浸润白细胞进行分子分析发现与免疫激活相关的基因上调，包括IFNγ和IL-12b。此外，在存在NI-1701的情况下，TME中TAM介导的淋巴瘤肿瘤细胞吞噬作用增强，突出了巨噬细胞在肿瘤控制中的作用。体内细胞清除实验表明巨噬细胞和自然杀伤细胞均有助于抗肿瘤活性。此外，NI-1701在体外增强了树突状细胞介导的肿瘤细胞吞噬作用，导致肿瘤特异性CD8 T细胞的交叉启动增加。
该研究描述了CD47xCD19双特异性抗体NI-1701在淋巴瘤小鼠模型中控制肿瘤生长的机制。NI-1701目前正在进行治疗难治性或复发性B细胞淋巴瘤的I期临床试验（NCT04806035）。
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