Advancing immunotherapy in gestational trophoblastic neoplasia: current progress and future directions

Introduction

Gestational trophoblastic neoplasia (GTN) is a group of malignant tumours caused by the abnormal proliferation of placental trophoblastic cells. It primarily includes invasive mole, choriocarcinoma, placental site trophoblastic tumour and epithelioid trophoblastic tumour.1 While the cure rate for patients with low-risk GTN treated with chemotherapy approaches 100%, approximately 10%–20% of high-risk patients and nearly 40% of ultra-high-risk patients experience chemotherapy resistance or relapse,2 posing significant challenges in clinical management. In recent years, immunotherapy has shown remarkable efficacy across various malignancies. GTN is inherently highly antigenic due to its origin in trophoblastic cells, which possess genomic semi-allogeneic properties. Moreover, GTN is often characterised by abundant immune cell infiltration and high expression of the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint pathway.3 4 These unique features of the immune microenvironment establish a theoretical foundation for the application of immune checkpoint inhibitors (ICIs) in GTN, offering a novel therapeutic option for chemotherapy-resistant patients.

Early exploration and practice

In 2017, Ghorani et al 5 first reported the use of the PD-1 inhibitor pembrolizumab in four patients with high-risk chemotherapy-resistant or recurrent GTN, achieving complete remission (CR) in three cases, demonstrating its potential in GTN treatment. Subsequently, the French TROPHIMMUN study (table 1) explored the efficacy of the PD-L1 inhibitor avelumab. In the 2020 cohort A study,6 15 low-risk chemotherapy-resistant patients were treated with avelumab monotherapy, achieving a CR rate of only 53.3%(n=8/15). Among the remaining seven patients who were resistant to avelumab, 57.1% (n=4/7) still required combination chemotherapy or surgery to achieve remission. The 2023 cohort B study7 targeted seven high-risk, multi-drug-resistant patients, with only one achieving CR, leading to early termination of the trial. These studies suggest that the efficacy of ICIs alone may sometimes be limited for chemotherapy-resistant GTN, underscoring that combination therapies tailored to different risk groups may be a key direction for future research.

Pioneering advances in China

Building on international findings, Peking Union Medical College Hospital (PUMCH) has made significant progress in GTN immunotherapy research. Immunohistochemical analysis of tumour tissues from 112 patients with GTN revealed high expression of immune checkpoint molecules PD-L1, B7-H3 and VISTA in tumour cells3 and elevated levels of PD-1, TIM-3, LAG-3 and GAL-9 in tumour-infiltrating immune cells,8 providing key theoretical and scientific support for immunotherapy. In clinical practice, PUMCH reported in 2020 on eight patients with resistant or recurrent GTN treated with the PD-1 inhibitor pembrolizumab, achieving a CR rate of 50% and no relapse after more than 2 years of follow-up.9 In 2021, PUMCH published the CAP01 study (NCT04047017),10 a phase II trial involving 20 patients with high-risk GTN treated with the PD-1 inhibitor camrelizumab and anti-angiogenic agent apatinib, achieving an objective response rate of 55% and a CR rate of 50% with good tolerance. In 2023, a multicentre retrospective study11 led by PUMCH compared PD-1 inhibitor monotherapy to combination therapy with chemotherapy. The combination therapy group achieved a significantly higher CR rate (87.1%) compared with monotherapy (54.3%), underscoring the enhanced efficacy of combining immunotherapy with chemotherapy.

Expanding treatment horizons

PUMCH is also actively advancing immunotherapy-related research (table 1) through one single-centre (NCT05139095) and two multicentre (NCT0602075, NCT06028672) phase II clinical trials to evaluate the benefits of combining ICIs with chemotherapy or targeted therapy in patients with GTN at varying risk levels. The NCT05139095 trial employs a dual-cohort design, targeting ultra-high-risk patients (cohort A) and high-risk chemotherapy-resistant/recurrent patients (cohort B) with a treatment regimen combining chemotherapy with camrelizumab and apatinib. Preliminary results showed CR rates of 88.2% (cohort A) and 100.0% (cohort B), with recurrence rates of 13.3% and 14.3%, respectively. Both cohorts demonstrated good tolerance, with no grade 4 immune-related adverse events or treatment-related deaths. The NCT06020755 and NCT06028672 trials investigated toripalimab combined with actinomycin D in patients with International Federation of Gynecology and Obstetrics (FIGO) scores of 7 and 5–6, respectively. Initial data revealed 100% CR rates for FIGO 5–6 patients and 66.7% for FIGO 7 patients, significantly higher than historical reports of monotherapy.12 13 Adverse effects were manageable, with lower rates of grade 3 or 4 side effects compared with traditional combination chemotherapy. These findings highlight the clinical efficacy and safety of combination therapies across risk groups. Although current studies primarily support the use of ICIs as a later-line treatment for patients with multi-agent chemotherapy resistance, ongoing clinical trials may further refine their indications and expand their application in GTN management.

Challenges and future directions

Despite the significant efficacy of immunotherapy in GTN, some patients remain unresponsive to treatment. Due to the relatively recent adoption of PD-1 inhibitors, the rarity of GTN and its sensitivity to chemotherapy, research on resistance mechanisms remains limited. McNally et al14 conducted next-generation sequencing analysis on 30 GTN samples and found that 92.8% exhibited low tumour mutational burden (TMB), while 100% were microsatellite stable (MSS). These findings suggest that TMB and MSS may not be reliable biomarkers for predicting resistance to ICIs in GTN. To address this, the research team at PUMCH used extensive tissue samples and applied spatial transcriptomics and proteomics. We identified significant upregulation of HLA-G and immune-suppressive pathways like Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) in resistant patients, highlighting tumour microenvironment heterogeneity linked to immune response. Future research on immunotherapy for GTN will focus on developing tumour–immune interaction models to better understand resistance mechanisms, alongside dynamic monitoring of the tumour microenvironment to detect early resistance signals and guide personalised adjustments. Innovations such as bi-specific antibodies, CAR-T cells or inhibitors targeting other immune checkpoints can be explored to enhance treatment efficacy. Real-world studies and dedicated databases will provide valuable insights for broader applications. Furthermore, immunotherapy shows promise as a viable option for younger patients with reproductive needs; however, careful evaluation of its impact on fertility and pregnancy outcomes is essential to ensure long-term safety and reproductive potential.

Looking ahead, the treatment of GTN requires ongoing optimisation of comprehensive strategies. Exploring the optimal combination of chemotherapy, immunotherapy and targeted therapies is essential to enhance efficacy while minimising treatment-related toxicity. Multi-omics research holds great potential for identifying predictive biomarkers and discovering new therapeutic targets, paving the way for personalised and precision medicine. Long-term follow-up studies on immunotherapy are also crucial for evaluating its long-term efficacy and safety, facilitating its broader real-world application. These efforts aim to provide patients with more effective, durable and personalised treatment options, driving further advancements in the field.