Efficacy of multimodal thermal therapy combined with immune checkpoint inhibitors and chemotherapy in unresectable pancreatic cancer with liver metastases.

4209 Background: Treatment of pancreatic cancer with liver metastasis (PCLM) remains extremely challenging. Multimodal thermal therapy (MTT) is a novel treatment method consisting of alternated liquid nitrogen cooling and radiofrequency heating, which was proven to effectively remodel the immune environment and trigger systemic antitumor immunity. This study aims to explore the primary application of MTT combined with subsequent ICls-based systemic therapy in PCLM. Methods: Patients aged 18-70 years with primary diagnosed unresectable PCLM were enrolled in this single-center, prospective clinical trial. Participants received MTT at least one of the liver metastases combined with subsequent ICls and chemotherapy (camrelizumab 200 mg IV on Day 1, gemcitabine 1000 mg/m2 IV, and nab-paclitaxel 125 mg/m2 IV on Days 1 and 8, every 3 weeks for 6 cycles), which was started on day 7 post MTT. The primary endpoints were safety and efficacy. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Exploratory endpoints included immune marker changes induced by MTT. Results: Five patients were enrolled in the trial group and four patients in the control group. All patients in the trial group were well tolerated with MTT, and the MTT-treated liver tumors were completely ablated. One patient withdrew due to autoimmune hepatitis after the first ICIs treatment. One patient achieved success conversion and underwent curative resection 6 months after MTT. Median OS per RECIST was 16.0 months (95% CI 15.3–16.7) in the trial group surpassing 6.2 months (95% CI 1.8–9.2) in the control group (HR 0.26 [95% CI 0.04–1.99]). Histological analysis indicated that combination therapy reversed the immunosuppressive tumor microenvironment, accompanied by enhanced immune-cell infiltration and tertiary lymphoid structures formation within both primary and metastatic lesions. Single-cell RNA-seq of peripheral blood immune cells on day 7 after MTT but prior to ICIs and chemotherapy revealed that MTT promoted the maturation of APCs, increased expression of homing-associated chemokine receptors on circulating B cells and monocytes, and induced the expansion of tumor-trafficking monocytes and CD8 + T cells subsets, which were correlated with favorable prognosis. The effector functions of T cells were also enhanced post MTT, accompanied by increased PD-1 level, which provided the basis for subsequent anti-PD-1 therapy. Conclusions: MTT reshaped both primary and metastatic tumor immune environments, sensitized tumors to subsequent immunotherapy and chemotherapy, well correlating to prolonged OS of PCLM patients. Clinical trial information: NCT06307080 .