Shu Runzhe, Evtimov Vera J, Hammett Maree V, Nguyen Nhu-Y N, Zhuang Junli, Hudson Peter J, Howard Maureen C, Pupovac Aleta, Trounson Alan O, Boyd Richard L
Cartherics Pty, Ltd., Clayton, VIC 3168, Australia.
Avipep Pty, Ltd., Parkville, VIC 3052, Australia.
Mol Ther Oncolytics. 2021 Jan 16;20:325-341. doi: 10.1016/j.omto.2021.01.002. eCollection 2021 Mar 26.
Chimeric antigen receptor (CAR) T cells have revolutionized blood cancer immunotherapy; however, their efficacy against solid tumors has been limited. A common mechanism of tumor escape from single target therapies is downregulation or mutational loss of the nominal epitope. Targeting multiple antigens may thus improve the effectiveness of CAR immunotherapies. We generated dual CAR-T cells targeting two tumor antigens: TAG-72 (tumor-associated glycoprotein 72) and CD47. TAG-72 is a pan-adenocarcinoma oncofetal antigen, highly expressed in ovarian cancers, with increased expression linked to disease progression. CD47 is ubiquitously overexpressed in multiple tumor types, including ovarian cancer; it is a macrophage "don't eat me" signal. However, CD47 is also expressed on many normal cells. To avoid this component of the dual CAR-T cells killing healthy tissue, we designed a truncated CD47 CAR devoid of intracellular signaling domains. The CD47 CAR facilitates binding to CD47 cells, increasing the prospect of TAG-72 cell elimination via the TAG-72 CAR. Furthermore, we could reduce the damage to normal tissue by monomerizing the CD47 CAR. Our results indicate that the co-expression of the TAG-72 CAR and the CD47-truncated monomer CAR on T cells could be an effective, dual CAR-T cell strategy for ovarian cancer, also applicable to other adenocarcinomas.
嵌合抗原受体(CAR)T细胞彻底改变了血癌免疫疗法;然而,它们对实体瘤的疗效一直有限。肿瘤从单一靶点疗法中逃逸的常见机制是名义表位的下调或突变缺失。因此,靶向多种抗原可能会提高CAR免疫疗法的有效性。我们生成了靶向两种肿瘤抗原的双特异性CAR-T细胞:TAG-72(肿瘤相关糖蛋白72)和CD47。TAG-72是一种泛腺癌癌胚抗原,在卵巢癌中高度表达,其表达增加与疾病进展相关。CD47在包括卵巢癌在内的多种肿瘤类型中普遍过度表达;它是一种巨噬细胞“别吃我”信号。然而,CD47也在许多正常细胞上表达。为避免双特异性CAR-T细胞的这一组成部分杀死健康组织,我们设计了一种不含细胞内信号结构域的截短型CD47 CAR。CD47 CAR有助于与CD47细胞结合,增加通过TAG-72 CAR消除TAG-72细胞的可能性。此外,我们可以通过将CD47 CAR单体化来减少对正常组织的损伤。我们的结果表明,在T细胞上共表达TAG-72 CAR和截短型单体CD47 CAR可能是一种有效的卵巢癌双特异性CAR-T细胞策略,也适用于其他腺癌。
Mol Ther Oncolytics. 2021-1-16
Cancers (Basel). 2017-10-21
J Transl Med. 2023-9-22
J Immunother Cancer. 2023-3
Cancers (Basel). 2020-1-28
Curr Trends Immunol. 2016
Gynecol Oncol. 2016-11
Mol Cancer. 2025-7-26
Front Endocrinol (Lausanne). 2025-2-11
J Hematol Oncol. 2024-11-5
Semin Immunopathol. 2024-10-21
Front Oncol. 2024-9-13
Heliyon. 2024-8-22
Front Immunol. 2020
N Engl J Med. 2020-4-2
Mol Ther Oncolytics. 2019-8-28
Biomed Pharmacother. 2019-9-4
Am J Cancer Res. 2019-2-1