The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers

Journal of Hematology & Oncology

Jiang Chen¹  Lingling Zhu²  Qinghua Zhou²  Jiewei Liu² 

[1] Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, 310016, Hangzhou, Zhejiang Province, China;Lung Cancer Center, West China Hospital of Sichuan University, 610041, Chengdu, Sichuan Province, China;

关键词: Immune checkpoint blockade;    Breast cancer;    Ovarian cancer;    DNA damage repair inhibitor;   

DOI  :  10.1186/s13045-021-01218-8

来源: Springer

【 摘 要 】

The use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.

【 授权许可】

CC BY