case_images: PMC11235248_01
case_images: Contrast-enhanced CT scans before initiation of ICI therapy and as interim examination after 3 cycles of atezolizumab / bevacizumab treatment. Both intrahepatic (A + C) and intrapulmonary (B + D) HCC metastases are marked in colour. (A) Pretherapeutic axially reconstructed abdominal CT scan showing a large recurrence of HCC in the left liver lobe. (B) Pretherapeutic coronary reconstructed thoracic CT scan showing a pulmonary metastasis of HCC. (C) Axially reconstucted abdominal interim CT scan showing an example of a pronounced progression of intrahepatic HCC. (D) Coronary reconstucted thoracic interim CT scan showing marked progression of pulmonal HCC metastases.
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case_images: F1
case_images: At short-term re-staging, several new intrahepatic HCC foci were identified, as well as new pulmonary metastases (Figures 1A,B). HCC progression with multiple intrahepatic foci and new pulmonary metastases (Figures 1C,D). Hence, despite completing a full course of Atezo/Bev therapy without a serious irAE or acute rejection occurring, the treatment was ultimately ineffective. In total, we found 19 articles describing 20 unique biomarkers (Supplementary Figure S1).
case_images: Routine biochemical liver parameters in the course of ICI therapy. (A,B) Liver enzymes (GOT & GPT) to assess the vitality of the hepatocytes. (C-E) Cholestasis parameters (gammaGT, GLDH & AP) to assess the vitality of the cholangiocytes. (F,G) Bilirubin and CHE for assessing metabolic functionality of the transplanted liver.
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case_images: F2
case_images: We further excluded comorbidities as contraindications for immunotherapy, including synchronous tumors, autoimmune diseases, and occult infections (Supplementary Figure 2). Specifically, liver enzyme values were stable after each cycle (Figure 2) and ultrasound imaging revealed no signs of acute liver rejection.
case_images: Histopathology of biopsies of the transplant liver (A-C) as well as intrahepatic HCC foci (D,E) prior to initiation of immune checkpoint therapy (200x magnification). (A) HE-stained representative section of the transplant liver biopsy. * intrahepatic fat vacuoles,   inflammatory infiltrate. (B) Corresponding immunohistochemical staining for PD-L1. (C) Corresponding immunohistochemical staining for PD-1.   inflammatory infiltrate with scattered PD-1 positive lymphocytes. (D) HE-stained representative section of HCC-infiltrated liver biopsy. (E) Corresponding immunohistochemical staining for PD-L1. (F) Immunohistochemical staining for CD3.
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case_images: F3
case_images: Histopathological examination of a liver biopsy taken before starting Atezo/Bev therapy revealed acute steatohepatitis with distinct fatty degeneration of the hepatocytes (70%) and fibrosis (Ishak fibrosis grade 3-4) (Figure 3A). A biopsy from the tumor showed solid and trabecular infiltrates of malignant and moderately-differentiated hepatocellular carcinoma (G2) with typical shift of the nuclear-plasma relation, small-foci necrosis and marked fragmentation (Figure 3D). The intrahepatic immune cells, especially the lymphocytes, showed minimal expression of PD-L1 (< 1%) and about 5% positivity for PD-1 (Figures 3B-C). Tumor Proportion Score (TPS) of 0%, an Immune Cell Score (ICS) <1% and a Combined Positive Score (CPS) <1% (Figure 3E), registering a scattered CD3-positive intra/peritumoral T lymphocyte infiltrate (Figure 3F). Thus, we add another case of a stable LTx patient lacking histological PD-L1 expression that safely underwent ICI therapy without rejection. Acquisition from Beckman Coulter. Analyses were performed using Kaluza version 2.1 (Supplementary Figure S3).
case_images: Immunomonitoring data in the course of ICI therapy. (A-C) Clinical routine Inflammatory parameters. (D) Torque Teno Virus level (TTV) as a surrogate parameter for the patient's immunocompetence. (E) AFP tumor marker level. (F) CD28 expression level in CD4+ T cells in peripheral blood. (G) Frequency of Tregs in the peripheral blood.
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case_images: F4
case_images: We observed a persistent ~4-fold increase in IL-6 levels after starting immunotherapy (Figure 4C). OS and PFS. Our patient presented with an AFP of 731 ng/ml at baseline, and 6 weeks after the start of therapy there was a progressive increase in AFP levels by ~7.5-fold (5,435 ng/ml) (Figure 4E). Based on this parameter, our patient had a score of 1 (AFP 731 ng/ml; CRP 0.46 mg/dl), indicative of inferior OS and inferior PFS (Figures 4B,E). TTV load after each cycle of Atezo/Bev therapy, suggesting intensified T cell activity; however, TTV titers recovered quickly after each cycle (Figure 4D). TTV values should be interpreted with caution. In our patient, baseline Treg frequency was 1.6% and we observed a reduction to 0.9% Tregs after starting therapy, which did not recover during follow-up (Figure 4G). Our flow cytometry results indicated a progressive downregulation in CD28 MFI during Atezo/Bev therapy, suggesting our patient did not have an elevated risk of rejection (Figure 4F).