On July 15, 2024 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) reported that data published in the journal Cell demonstrate that neoadjuvant monotherapy with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib results in a high response rate and reshapes the tumor microenvironment (TME), providing new targets for immunotherapy and combination regimens in patients with homologous recombination deficiency (HRD) positive ovarian cancer (Press release, Zai Laboratory, JUL 15, 2024, View Source [SID1234644879]). The study revealed niraparib preferentially suppresses certain immune cells that support the growth of HRD-positive ovarian tumors.
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This Zai Lab-supported study also showed that targeted clearance of infiltrating regulatory T cells (eTregs) using Zai Lab’s investigational CCR8 antibody, ZL-1218, significantly sensitized niraparib against HRD tumors, resulting in decreased tumor burden in pre-clinical models.
"Given the prevalence of HRD in cancer and its role in rendering tumors vulnerable to PARP inhibition, this study fills the knowledge gap regarding the impact of HRD and related therapies on the tumor microenvironment," said Professor Qinglei Gao, Chief of Gynecologic Oncology Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. "By decoding the tumor-reactive T cells in the HRD-positive TME that are regulated by eTregs, these findings have profound implications for future oncology research and therapeutic development for HRD-positive ovarian cancer and other HRD-related cancers."
To investigate the effects of HRD, neoadjuvant therapies, and their interactions on the TME, investigators utilized tumor tissues from a clinical study (NCT04507841) evaluating niraparib for the neoadjuvant treatment of unresectable ovarian cancer. In parallel, tissue samples from patients receiving neoadjuvant chemotherapy (NACT) were also collected.
Profiling of these samples yielded valuable data delineating the divergence in TME between HRD-positive vs. homologous recombination-proficient (HRP) tumors, as well as their respective phenotypic evolution following the introduction of neoadjuvant therapies.
Key findings of the study included:
Patients receiving neoadjuvant monotherapy with niraparib achieved 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively.
Overall, the safety profile of NANT was manageable, and no new safety signal was observed, with hematologic toxicities as the most common treatment-related adverse events.
The results indicate that NANT 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, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells.
The addition of the CCR8 antibody, ZL-1218, to niraparib showed a significantly pronounced inhibitory effect on eTregs in pre-clinical models, suppressing tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.
"Zai Lab is pleased to support this important translational research which breaks new ground in our understanding of the tumor microenvironment in HRD-positive ovarian cancer," said Rafael G. Amado, M.D., President, Head of Global Research and Development, Zai Lab. "By identifying new immunotherapeutic targets in the TME, these findings could bolster efforts to improve outcomes for patients with HRD+ tumors."