Tran, Nguyen H.

Abstract Introduction: Liver cancer remains a leading cause of cancer mortality globally with limited treatment options for patients (pts) with unresectable hepatocellular carcinoma [HCC] and intrahepatic cholangiocarcinoma [iCCA][1,2,3,4]. We hypothesize that combining the intratumoral dendritic cell (DC) vaccination after external beam radiotherapy (EBRT) without (phase I) and with (phase II) systemic atezolizumab and bevacizumab (atezo/bev for HCC) would enhance tumor-specific immunity and improve clinical outcomes, and present preliminary results from our phase I/II trial (NCT03942328). Methods: Peripheral blood mononuclear cells (PBMCs) were collected at baseline (PRE), after radiation (EBRT), and after completion of DC without or with atezo/bev (POST). Single-cell RNA sequencing with TCR sequencing were analyzed using CellRanger v7.0.1, Immunopipe, Seurat v5.3.0, & Gene-set enrichment analysis (GSEA). Long EFS (EFS-L) is defined as >=12 months (mo) for phase I and >=18mo for phase II, and short EFS (EFS-S) below that. Results: Seventeen patients have been analyzed to date (Phase I: n=8 [4 HCC, 4 iCCA]; Phase II: n=9 HCC). 674,106 cells were sequenced (146,843 PRE; 168,838 EBRT; 114,437 POST). GSEA for EFS-L vs EFS-S were comparable at PRE, EBRT and POST between phase I and phase II. EFS-S was associated with enrichment of interferon alpha (IFNα; B naïve, monocytes, pDC, cDC2, NK, Treg, CD8 Tcm and Tem at PRE and POST; B intermediate, CD4 Tem and NK at EBRT) and reactive oxygen species (ROS; PRE: pDC, CD8 Tcm, Tem. EBRT: CD4 Tem. POST: CD8 T naïve Tem, CD4 Tcm & Tem, cDC2) pathways. In contrast, EFS-L was associated with enrichment of WNT-β-catenin (WNT; CD14 mono at EBRT & POST, B intermediate at EBRT), TGFb (PRE: NK; EBRT: B intermed, CD4 Tem; POST: monocytes, CD4 naïve & Tem, pDC, cDC2), and angiogenesis (EBRT: NK; POST: monocytes, cDC2) pathways. Interestingly, enrichment of protein secretion pathway in NK cells was associated with EFS-L, but among other cells were associated with EFS-S (PRE: CD16 mono, Treg; POST: CD16 mono, CD4 & D8 Tem). Compared to phase I, addition of atezo/bev in phase II pts was associated with a significant increase in Gini coefficient (p<0.0001), suggesting expansion of certain TCR clones, along with a trend for increased Gini coefficient from Pre to Post in both phase I and II. Conclusions: Preliminary analysis of this study combining EBRT with intratumoral DC vaccination +/- PD-L1/VEGF blockade identified distinct treatment-related changes in systemic cellular immune profiles. Enhanced TCR clonal diversity in phase II suggests added immunologic benefit from PD-L1/VEGF blockade. As accrual continues, integrated analyses will identify systemic immune correlates of clinical benefit and resistance to this multimodal immunotherapy approach. Citation Format: Melody Wu, Panwen Wang, Chen Wu, Ying Li, Christopher L. Hallemeier, Thomas D. Atwell, Nguyen H. Tran, Andre de Menezes Silva Corraes, Kevin Regan, Zuoyi Shao, Rayaan Kamal, Haidong Dong, Lewis R. Roberts, Sean Park, Yi Lin, Lionel Aurelien Kankeu Fonkoua. Radiation-dendritic cell combination therapy drives systemic cellular immune shifts in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3741.

Abstract Prostate-specific membrane antigen (PSMA) is highly expressed in tumor-associated neovasculature in hepatocellular carcinoma (HCC), highlighting its promise as a theranostic target. This prospective study aimed to evaluate the utility of novel biomarkers derived from PSMA positron emission tomography computed tomography (PET/CT) to assess treatment response in advanced HCC patients (pts) receiving first line immune checkpoint inhibitors (ICI). Methods: This study (NCT05176223) enrolled unresectable, advanced HCC pts eligible for first-line ICI (atezolizumab/bevacizumab [A/B] or durvalumab/tremelimumab [D/T]) with measurable disease according to RECIST criteria. Primary endpoints: progression-free survival (PFS) per RECIST 1.1 and mRECIST; overall survival (OS); and best overall response. The survival distribution was estimated using the Kaplan-Meier method. Observed agreement is defined as the proportion of pts whose responses, as classified by PET/CT or CT, were concordant. Weighted kappa and Cohen’s kappa were used to quantify the strength of agreement between PET/CT and CT. Pts completed up to five 68Ga-PSMA PET/CT scans and blood collections. Results: Twenty-six pts were enrolled (25 evaluable) between Oct 2022 and Nov 2024. Median follow up was 22.1 months (m) (Q1, Q3: 14.5-23.7). Median age 68 yrs, 72% male, 88% White, 68% Child-Pugh [CP] A, 32% CP B, 32% Barcelona Clinic Liver Cancer [BCLC] stage B, 68% BCLC stage C, 36% with microvascular invasion; 56% received A/B and 40% received D/T treatment. PSMA was positive in 96% of pts at baseline with median SUVmax 14.3 (range 5.1-40.5) and median background liver SUVmax 3.9 (range 2.1-6.8). Median (95%CI) PFS was 5.6 m (4.6-12.5) by both RECIST and mRECIST. Median (95%CI) OS was 18.6 m (7.2-not estimable), with 56% deceased. The observed agreement between PET/CT adapted PERCIST criteria compared to RECIST and mRECIST in determining the best response was 46% and 50% and weighted kappa of 0.63 (95% CI: 0.37-0.90) and 0.66 (0.41-0.92), respectively. Observed agreement between PERCIST compared to RECIST and mRECIST for responders’ assessment was 67% and 71% with Cohen’s kappa of 0.36 (0.03-0.68) and 0.43 (0.11-0.76), respectively. Conclusion: In this cohort, PSMA PET/CT avidity was observed in all but one pt with advanced HCC, each demonstrating moderate to high SUVmax values. Median OS and PFS were consistent with outcomes reported in clinical trials. Response assessment using 68Ga-PSMA PET/CT according to PERCIST criteria showed good concordance with both RECIST and mRECIST standards. Analysis of immune biomarkers is ongoing. Citation Format: Nguyen H. Tran, Jacob Hirdler, Ajith Antony, Jacob Teske, Sudhakar K. Venkatesh, Amit Mahipal, Michael S. Torbenson, Scott M. Thompson, Thor R. Halfdanarson, Zhaohui Jin, Lionel Aurelien Kankeu Fonkoua, Leslie A. Washburn, Alexander Revzin, Haidong Dong, Robert R. Mcwilliams, Aminah Jatoi, Hani M. Babiker, Mitesh J. Borad, Tanios Bekaii-Saab, Gregory J. Gores, Lewis R. Roberts, Geoffrey B. Johnson, Ajit H. Goenka. Prospective evaluation of 68Ga-PSMA PET imaging in advanced hepatocellular carcinoma patients undergoing first line immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2611.