述评：卵巢癌：通向有效治疗之路。

Commentary: Ovarian Cancer: Path to Effective Treatments.

机构信息

Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA.

The Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA; UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; The VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.

出版信息

Crit Rev Immunol. 2025;45(1):93-99. doi: 10.1615/CritRevImmunol.2024053766.

DOI:10.1615/CritRevImmunol.2024053766

PMID:39612280

Abstract

Despite advancements in cancer therapeutics such as checkpoint inhibitors and some targeted therapies, we have not achieved success in effectively treating ovarian cancer, since these therapeutics only benefit a subset of patients, and also provide short-term protection. The use of chemotherapy and radiation therapy can cause depletion and/or lack of immune cells' function. Chimeric antigen receptor T (CAR-T) cell therapy is found to be effective against several blood-based cancers, but limited success was seen against solid tumors. Targeting fewer antigens and significant side effects of therapy decreases the efficacy of CAR-T cells as immunotherapeutic in solid tumors, even though there is a great drive and significant effort to establish these therapies around the world. Bispecific and tri-specific antibodies have recently been advocated as effective cancer therapeutics. However, at present, these also suffer the fate of CAR-Ts since the loss of antigen on tumor cells will render these therapeutics ineffective. At present, we should design therapeutics that may have synergistic effects on killing/treating tumors. The only way we can establish that will be by learning the mechanisms of actions of immune therapeutics. Thus, advancement in the knowledge and effective strategies are required to develop cancer immuno-therapeutics. We have dedicated our efforts to understand the immunobiology of natural killer (NK) cells. One of our most important discoveries was demonstration of targeting of cancer stem-like cells (CSCs)/poorly differentiated tumors exhibiting lower major histocompability complex class I expression by the NK cells. In addition, we showed that supercharged NK (sNK) cells had great ability to target both CSCs/poorly differentiated and well differentiated ovarian tumors, whereas activated primary NK cells only targeted CSCs/poorly differentiated tumors. Therefore, the use of sNK cells in immunotherapy should result in effective elimination of heterogeneous populations of ovarian tumors.

摘要

尽管癌症治疗领域取得了进展，如检查点抑制剂和一些靶向治疗方法，但我们在有效治疗卵巢癌方面尚未取得成功，因为这些治疗方法仅对一部分患者有效，并且提供的保护也是短期的。化疗和放疗的使用会导致免疫细胞的耗竭和/或功能丧失。嵌合抗原受体 T (CAR-T) 细胞疗法已被证明对几种血液癌有效，但对实体瘤的疗效有限。针对较少的抗原和治疗的显著副作用会降低 CAR-T 细胞作为实体瘤免疫疗法的疗效，尽管全球范围内都在大力推动并投入大量努力来建立这些疗法。双特异性和三特异性抗体最近被提倡作为有效的癌症治疗方法。然而，目前这些疗法也遭受了与 CAR-T 相同的命运，因为肿瘤细胞上抗原的丢失会使这些疗法无效。目前，我们应该设计可能对杀伤/治疗肿瘤具有协同作用的疗法。我们唯一能确定这一点的方法是了解免疫治疗的作用机制。因此，需要在知识和有效策略方面取得进展，以开发癌症免疫治疗方法。我们一直致力于了解自然杀伤 (NK) 细胞的免疫生物学。我们最重要的发现之一是证明 NK 细胞能够靶向癌症干细胞样细胞 (CSCs)/低分化肿瘤，这些肿瘤表现出较低的主要组织相容性复合物 I 表达。此外，我们还表明，超充能 NK (sNK) 细胞具有靶向 CSCs/低分化和高分化卵巢肿瘤的巨大能力，而激活的原始 NK 细胞仅靶向 CSCs/低分化肿瘤。因此，在免疫治疗中使用 sNK 细胞应该能够有效消除卵巢肿瘤的异质群体。