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

Abstract

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.

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

“…At present, expanding the use of immune checkpoint inhibitors is a matter of great urgency. DDR displays great potential in this regard [ 249 ], as the alteration of the DDR pathway in tumors as a predictive marker of ICB presents many advantages [ 20 , 249 , 250 ]. More importantly, the benefits of DDR inhibitors have been extended to other immunotherapies beyond ICB [ 130 ].…”

Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors

“…Poor tumor immunogenicity, hampered DC maturation, suboptimal T cell priming/activation, impaired T cell infiltration, and stroma-dependent exclusion participate in immune escape and contribute to immune checkpoint resistance in non-inflamed tumors [ 46 , 47 ]. Hence, for non-inflamed tumors, a combination regimen targeting different immune escape mechanisms might be required [ 46 , 48 , 49 ]. Although our previous work had shown the BsAb YM101 reversed CAF-mediated exclusion and relieved α-PD-L1 resistance, it exhibited modest antitumor activity in immune-desert models.…”

Identification of glycogene signature as a tool to predict the clinical outcome and immunotherapy response in breast cancer

“…Besides PD-L1, CTLA4, LAG3, TIGIT and other checkpoint genes, were all showing high expression in the low-risk group. These checkpoint genes were well explored and were potential targets in the ICB therapy of several solid tumors ( 46 ). Low risk based on this glycogene signature may help guide clinical practice.…”