Zai Lab Study in Cell Offers New Insights for HRD-Positive Ovarian Cancer Treatment

Zai Lab Limited has announced new findings published in the journal Cell regarding the effects of neoadjuvant monotherapy with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib. The study reveals that niraparib leads to a high response rate and alters the tumor microenvironment (TME), creating new targets for immunotherapy and combination treatments in patients with homologous recombination deficiency (HRD) positive ovarian cancer. The research indicates that niraparib selectively inhibits specific immune cells that promote the growth of HRD-positive ovarian tumors.

The research, supported by Zai Lab, also found that targeting infiltrating regulatory T cells (eTregs) with Zai Lab’s investigational CCR8 antibody, ZL-1218, significantly enhanced the efficacy of niraparib against HRD tumors in pre-clinical models, leading to a reduced tumor burden.

Professor Qinglei Gao, Chief of Gynecologic Oncology at Tongji Hospital, commented on the study's significance, stating that it addresses a critical knowledge gap about the impact of HRD and related therapies on the TME. By understanding how tumor-reactive T cells in the HRD-positive TME are regulated by eTregs, the findings could have important implications for future oncology research and the development of therapies for HRD-positive ovarian cancer and other related cancers.

To explore the effects of HRD, neoadjuvant therapies, and their interactions on the TME, researchers used tumor tissues from a clinical study (NCT04507841) evaluating niraparib for the neoadjuvant treatment of unresectable ovarian cancer. Additionally, tissue samples from patients undergoing neoadjuvant chemotherapy (NACT) were collected.

The profiling of these samples provided valuable insights into the differences in TME between HRD-positive and homologous recombination-proficient (HRP) tumors, as well as their phenotypic changes following neoadjuvant therapies.

Key findings from the study include:

- Patients treated with neoadjuvant monotherapy with niraparib showed response rates of 62.5% and 73.6% according to RECIST v.1.1 and GCIG CA125, respectively.
- The safety profile of niraparib was manageable, with no new safety concerns observed and hematologic toxicities being the most common treatment-related adverse events.
- The results suggest that niraparib is an effective neoadjuvant treatment option for controlling disease progression in patients with HRD-positive high-grade serous ovarian cancer (HGSOC).
- eTregs were identified as key responders to HRD and neoadjuvant therapies, occurring alongside other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells.
- Combining the CCR8 antibody, ZL-1218, with niraparib significantly inhibited eTregs in pre-clinical models, suppressing tumor growth without observable toxicities, highlighting the potential of eTreg-focused therapies for HGSOC and other HRD-related tumors.

Rafael G. Amado, M.D., President and Head of Global Research and Development at Zai Lab, expressed excitement over supporting this significant translational research. He emphasized that the findings could help identify new immunotherapeutic targets in the TME, potentially improving outcomes for patients with HRD+ tumors.

Zai Lab is a biopharmaceutical company based in China and the United States, focusing on discovering, developing, and commercializing innovative products that address significant unmet medical needs in oncology, autoimmune disorders, infectious diseases, and neuroscience.