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來自胚胎干細(xì)胞的CAR-NK細(xì)胞抑制異種移植動(dòng)物中人類b細(xì)胞惡性腫瘤的進(jìn)展

更新時(shí)間:2025-01-27  |  點(diǎn)擊率:92

202410月,中國科學(xué)院動(dòng)物研究所干細(xì)胞與生殖生物學(xué)國家重點(diǎn)實(shí)驗(yàn)室;北京干細(xì)胞與再生醫(yī)學(xué)研究所;暨南大學(xué)第一附屬醫(yī)院血液科(State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China;Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China;Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, China) Qi Zhang老師研究團(tuán)隊(duì)在《Cancer Immunity and Immunotherapy》上發(fā)表論文:

Hypoimmunogenic CD19 CAR-NK cells derived from embryonic stem cells suppress the progression of human B-cell malignancies in xenograft animals"

 

“來自胚胎干細(xì)胞的低免疫原性CD19 CAR-NK細(xì)胞抑制異種移植動(dòng)物中人類b細(xì)胞惡性腫瘤的進(jìn)展"

 

Abstract

Background: Chimeric antigen receptor (CAR) engineered natural killer (NK) cells exhibit advantages such as MHC-independent recognition and strong anti-tumor functions. However, allogeneic CAR-NK cells derived from human tissues are heterogeneous and susceptible to clearance by hosts.

Methods: We generated a B2M knockout, HLA-E and CD19 CAR ectopic expressing embryonic stem cell (ESC) line, which differentiated normally and gave rise to homogeneous CD19 CAR-NK (CD19 CAR-UiNK) cells using an organoid aggregate induction method. The CD19 CAR-UiNK were co-cultured with T cells or NK cells derived from peripheral blood mononuclear cells (PBMC) with the mismatched HLA to evaluate the immunogenicity of CD19 CAR-UiNK cells. We further assessed the therapeutic effects of CD19 CAR-UiNK cells on CD19+ tumor cells through in vitro cytotoxicity assays and in vivo animal models.

Results: The CD19 CAR-UiNK cells exhibited typical expression patterns of activating and inhibitory receptors, and crucial effector molecules of NK cells, similar to those of unmodified NK cells. In co-culture assays, the CD19 CAR-UiNK cells evaded allogeneic T cell response and suppressed allogeneic NK cell response. Functionally, the CD19 CAR-UiNK cells robustly secreted IFN-γ and TNF-α, and upregulated CD107a upon stimulation with Nalm-6 tumor cells. The CD19 CAR-UiNK cells effectively eliminated CD19+ tumor cells in vitro, including B-cell cancer cell lines and primary tumor cells from human B-cell leukemia and lymphoma. Further, the CD19 CAR-UiNK cells exhibited strong anti-tumor activity in xenograft animals.

Conclusion: We offer a strategy for deriving homogeneous and hypoimmunogenic CD19 CAR-iNK cells with robust anti-tumor effects from ESCs. Our study has significant implications for developing hypoimmunogenic CD19 CAR-NK cell therapy using human ESC as an unlimited cell source.


摘要:

背景:嵌合抗原受體(CAR)修飾的自然殺傷細(xì)胞(NK)具有不依賴mhc識(shí)別和強(qiáng)大的抗腫瘤功能等優(yōu)勢(shì)。然而,來源于人體組織的同種異體CAR-NK細(xì)胞是異質(zhì)的,容易被宿主清除。

 

方法:利用類器官聚集誘導(dǎo)法,制備B2M敲除、HLA-ECD19 CAR異位表達(dá)的胚胎干細(xì)胞(ESC)系,使其正常分化并產(chǎn)生同質(zhì)的CD19 CAR- nk CD19 CAR- uink)細(xì)胞。將CD19 CAR-UiNK細(xì)胞與HLA錯(cuò)配的外周血單個(gè)核細(xì)胞(PBMC)的T細(xì)胞或NK細(xì)胞共培養(yǎng),評(píng)估CD19 CAR-UiNK細(xì)胞的免疫原性。該研究通過體外細(xì)胞毒性實(shí)驗(yàn)和體內(nèi)動(dòng)物模型進(jìn)一步評(píng)估了CD19 CAR-UiNK細(xì)胞對(duì)CD19+腫瘤細(xì)胞的治療作用。

 

結(jié)果:CD19 CAR-UiNK細(xì)胞表現(xiàn)出與未修飾NK細(xì)胞相似的活化和抑制受體以及NK細(xì)胞關(guān)鍵效應(yīng)分子的典型表達(dá)模式。在共培養(yǎng)實(shí)驗(yàn)中,CD19 CAR-UiNK細(xì)胞避開了同種異體T細(xì)胞的反應(yīng),抑制了同種異體NK細(xì)胞的反應(yīng)。在功能上,CD19 CAR-UiNK細(xì)胞強(qiáng)烈分泌IFN-γ和TNF-α,并在Nalm-6腫瘤細(xì)胞刺激下上調(diào)CD107aCD19 CAR-UiNK細(xì)胞在體外有效地清除了CD19+腫瘤細(xì)胞,包括b細(xì)胞癌細(xì)胞系和來自人b細(xì)胞白血病和淋巴瘤的原代腫瘤細(xì)胞。此外,CD19 CAR-UiNK細(xì)胞在異種移植動(dòng)物中表現(xiàn)出很強(qiáng)的抗腫瘤活性。

 

結(jié)論:該研究提供了一種從ESCs中獲得具有強(qiáng)大抗腫瘤作用的均勻性和低免疫原性CD19 CAR-iNK細(xì)胞的策略。該研究的研究對(duì)開發(fā)低免疫原性CD19 CAR-NK細(xì)胞療法具有重要意義,該療法使用人類ESC作為無限細(xì)胞來源。

 

該論文中,ESC、OP9細(xì)胞、表達(dá)熒光素酶的Nalm-6細(xì)胞、從三名患者的骨髓中分離出原發(fā)性人類白血病和淋巴瘤細(xì)胞的體外培養(yǎng)是使用Ausbian特級(jí)胎牛血清完成的。


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