BACK OBLIQUE VIEW
Defect in DNA damage response (DDR) is a common feature of cancer cells, which regulates tumor growth and therapeutic response. Recently, the approval of immune checkpoint blockade (ICB) for tumors with defective mismatch repair has paved the way for investigating the role of other DDR defects in sensitizing cancer to ICB therapy. Despite great progress in understanding DDR pathways, the mechanisms that link DDR defects and ICB response remain incompletely understood. Further, PATIENT-ShineMD-002027 the clinical activity of ICB in patients with DDR defective tumors has not been well described. Here, we discuss recent studies demonstrating that biomarkers in DDR pathways may serve as potential predictors to guide the selection of patients for ICB therapy. A better understanding of the relationship between deficiency in DDR and response to ICB would facilitate efforts in optimizing the efficacy of immunotherapy.
Immune checkpoint blockade (ICB), using antibodies against inhibitory signaling molecules expressed on tumor and immune cells, has shown unprecedented clinical activity across many tumor types. Currently, the approved use of anti-CTLA-4 (ipilimumab), anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab and durvalumab), and their combinations have demonstrated significant improvements over chemotherapy in cancer patients [1, 2]. Despite this success, the majority of patients fail to respond to these ICB therapy due to the innate and acquired resistance
Optimal design of ICB treatments will require multiple reliable predictive biomarkers that can help to select, before the initiation of treatment, patients who are most likely to benefit. For instance, Hodi et al. led a phase 3 ipilimumab study on patients with metastatic melanoma. They found that 20% of patients with metastatic melanoma achieved long-term benefit when treated with ipilimumab, 60% of patients had response for less than 2 years, and the rest showed no clinical benefit. If we could predict, before ipilimumab treatment, whether a patient will be a long-term responder, PATIENT-ShineMD-002027, short-term responder, or non-responder, we would be able to achieve the best therapeutic outcomes for the responders without causing unnecessary harm to non-responders. In a separate trial, Hodi et al. reported that 64% of patients treated with the nivolumab plus ipilimumab combination were still alive after 2 years. However, this improvement in overall survival with the combination treatment came at significant cost: 54% of patients in the combination arm showed grade 3–4 adverse events, which is significantly higher than the ipilimumab-only arm (20%). Indeed, biomarkers would be critical to guide the selection of patients for increasingly efficacious yet also increasingly toxic ICB treatments. Currently, there are few biomarkers that effectively predict tumor response to ICB, so the search continues for such biomarkers. A promising area to conduct this search is at the interplay between cancer defects in DNA repair and the anti-cancer immune response.