Nature Communications | A Phase 1/Randomized Phase 2b Trial of Laser Interstitial Thermal Therapy Combined with Pembrolizumab for Recurrent High-Grade Astrocytoma

This study is the first clinical trial to demonstrate that laser interstitial thermal therapy (LITT) significantly enhances the efficacy of pembrolizumab in patients with recurrent high-grade astrocytoma, substantially prolonging progression-free survival and overall survival. It also reveals the mechanism by which LITT activates innate immunity and promotes T-cell responses.

 

Literature Overview

This article, 'Laser interstitial thermal therapy and adjuvant pembrolizumab in recurrent high-grade astrocytoma: a Phase 1/randomized Phase 2b trial,' published in Nature Communications, reviews and summarizes a Phase 1/randomized Phase 2b clinical trial evaluating laser interstitial thermal therapy (LITT) combined with pembrolizumab for recurrent high-grade astrocytoma (rHGA). Through dose-escalation and randomized controlled designs, the study assessed the safety and efficacy of LITT combined with immune checkpoint inhibitors, integrating single-cell sequencing to deeply analyze systemic immune remodeling mechanisms. Results showed that LITT combined with pembrolizumab significantly improved patient survival, and immune profiling revealed critical roles of non-classical monocyte activation and CD8⁺ T-cell clonal expansion. This study provides a novel strategy to overcome the immunosuppressive microenvironment of brain tumors and holds significant translational value.

Background Knowledge

Recurrent high-grade astrocytomas (rHGA), including glioblastoma (GBM) and IDH-mutant WHO grade 3–4 astrocytomas, are among the most challenging malignancies in neuro-oncology. Despite standard treatments involving maximal safe resection, radiotherapy, and temozolomide chemotherapy, treatment options after recurrence are limited and prognosis remains extremely poor. Immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab have achieved breakthroughs in various solid tumors but show minimal efficacy in high-grade gliomas, primarily due to the blood-brain barrier, low tumor neoantigen burden, and a highly immunosuppressive tumor microenvironment (TME), which restrict CD8⁺ T-cell infiltration and function. Previous attempts to administer ICIs before surgery (neoadjuvant) aimed to 'activate' the TME, but although these briefly enhanced immune infiltration, they failed to translate into sustained survival benefits. Laser interstitial thermal therapy (LITT) is a minimally invasive, MRI-guided thermal ablation technique that enables local tumor cytoreduction while inducing transient blood-brain barrier disruption and tumor antigen release, theoretically initiating antigen presentation and T-cell responses. Thus, LITT may act as an 'in situ vaccine' to enhance ICI efficacy. However, high-quality clinical evidence supporting this combination strategy has been lacking. This study was designed to evaluate the safety and efficacy of LITT combined with pembrolizumab and to explore its immunological mechanisms, offering a new pathway to improve outcomes in rHGA patients.

 

 

Research Methods and Experiments

This was a Phase 1/randomized Phase 2b clinical trial (NCT02311582), enrolling 54 patients. The Phase 1 portion used a 3+3 dose-escalation design with 9 patients to evaluate the safety of pembrolizumab (100 mg, 150 mg, or 200 mg every 3 weeks) administered within one week after LITT, determining the recommended Phase 2 dose (RP2D). The Phase 2 portion initially planned to randomly assign 45 patients in a 1:1 ratio to either LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery followed by pembrolizumab (NLS+PEM; completion rate: 6/6), with the primary endpoint being progression-free survival (PFS) and secondary endpoints including overall survival (OS), safety, and immune profiling. After 21 patients were enrolled, the independent data and safety monitoring board halted randomization based on interim analysis, due to limited efficacy in the NLS+PEM arm; the subsequent 24 patients were all assigned to the LITT+PEM group. Tumor response was assessed using RANO criteria. 5′ single-cell RNA sequencing (scRNA-seq) and TCR sequencing were performed on peripheral blood mononuclear cells (PBMCs) from selected patients to analyze dynamic changes in immune cell subsets, T-cell clonal expansion, and functional states.

Key Conclusions and Perspectives

• Phase 1 results showed no dose-limiting toxicities across all three pembrolizumab doses; 200 mg every 3 weeks was established as the RP2D, with the combination of LITT and pembrolizumab showing favorable safety
• In the per-protocol population (n=39), the LITT+PEM group demonstrated significantly longer median overall survival (11.8 vs 5.2 months, HR=0.17, P=0.0002) and 18-month survival rate (42% vs 0%) compared to the NLS+PEM group, with significantly prolonged median progression-free survival as well (4.5 vs 1.6 months, HR=0.21, P=0.0006)
• Significant survival benefits with LITT+PEM were also observed in the intention-to-treat analysis (n=21) and the wild-type IDH GBM subgroup, and results remained significant in multivariable Cox models
• The treatment was well tolerated, with main adverse events being grade 1–2, including elevated transaminases, diarrhea, and muscle weakness; no grade 5 treatment-related adverse events occurred
• Single-cell sequencing revealed early activation of non-classical monocytes post-LITT, characterized by upregulation of migration, metabolic, and inflammatory pathways, and this activation signal correlated with longer survival
• LITT+PEM induced CD8⁺ T-cell activation, proliferation, and clonal expansion; long-term survivors exhibited coordinated transition from memory to effector T cells, whereas short-term survivors showed signs of T-cell exhaustion
• IDO-1 expression was effectively downregulated in long-term survivors receiving LITT+PEM, suggesting the combination therapy may suppress alternative immune checkpoint pathways

Research Significance and Prospects

This study is the first prospective clinical trial to demonstrate that LITT effectively enhances the antitumor activity of pembrolizumab in recurrent high-grade astrocytoma, significantly extending patient survival. The mechanism may involve LITT inducing immunogenic cell death, disrupting the blood-brain barrier, and releasing tumor antigens, thereby initiating innate immune responses—particularly activation of non-classical monocytes—that promote T-cell activation and clonal expansion, overcoming the immune-desert state of gliomas. This 'in situ vaccine' strategy offers a new paradigm for immunotherapy in cold tumors.

The study also reveals the potential role of alternative immune checkpoints such as IDO-1 in treatment response, suggesting future exploration of combination strategies targeting both PD-1 and IDO-1. Furthermore, the activation signature of non-classical monocytes may serve as a predictive biomarker for patient stratification. Although early termination of randomization limits statistical power, findings were validated in the expanded cohort, supporting further multicenter Phase 3 trials. Future studies could integrate spatial transcriptomics and multi-omics analyses to more comprehensively dissect the spatiotemporal dynamics of LITT-induced tumor microenvironment remodeling.

 

 

Conclusion

This study systematically evaluated the safety and efficacy of laser interstitial thermal therapy combined with pembrolizumab in patients with recurrent high-grade astrocytoma. The results show that the combination regimen is well tolerated and significantly extends both progression-free and overall survival, offering a clear advantage over non-LITT surgery combined with immunotherapy. Mechanistic analyses revealed that LITT early activates peripheral non-classical monocytes, enhancing their migratory and inflammatory functions, thereby promoting CD8⁺ T-cell proliferation, clonal expansion, and effector differentiation induced by pembrolizumab, leading to long-term antitumor immune memory. Additionally, downregulation of IDO-1 expression in long-term survivors suggests the combination therapy may simultaneously suppress multiple immunosuppressive pathways. This study provides clinical evidence and mechanistic insights into overcoming the immunosuppressive microenvironment of high-grade gliomas, supporting the potential of LITT as an immune-priming strategy. Larger studies are needed to validate this combination approach and to explore biomarker-guided personalized therapies based on immune profiles, advancing brain tumor immunotherapy into the era of precision medicine.

 

Jian L Campian, Son B Le, Ashley Ghiaseddin, Eric C Leuthardt, and David D Tran. Laser interstitial thermal therapy and adjuvant pembrolizumab in recurrent high-grade astrocytoma: a Phase 1/randomized Phase 2b trial. Nature Communications.